Bio

Bio


Esther M. John. PhD, MSPH is Professor in the Department of Medicine (Oncology) and co-leader of the Population Sciences Program of the Stanford Cancer Institute. Dr. John is a cancer epidemiologist and her research focuses on the etiology and prognosis of breast and prostate cancer, to better understand modifiable lifestyle, hormonal and genetic causes and outcomes of these common cancers. She has a special interest in understanding cancer health disparities and cancer in Hispanics and African Americans, two understudied populations.

Academic Appointments


Administrative Appointments


  • Co-leader, Population Sciences Program, Stanford Cancer Institute (2014 - Present)
  • Co-leader, Cancer Epidemiology Program, Stanford Cancer Institute (2005 - 2014)
  • Lecturer & Consulting Assistant/Associate/Full Professor, Dept. Health Research & Policy, Stanford University School of Medicine (1994 - 2017)
  • Director of Research, Cancer Prevention Institute of California (2015 - 2018)
  • Director of Epidemiology, Cancer Prevention Institute of California (2000 - 2002)

Boards, Advisory Committees, Professional Organizations


  • Member, Editorial Board, Cancer Epidemiology, Biomarkers & Prevention (2013 - Present)
  • Member, American Association of Cancer Research (AACR) (2007 - Present)
  • Member, American Public Health Association (APHA) (1991 - Present)
  • Member, Society of Epidemiologic Research (SER) (1988 - Present)

Professional Education


  • D.E.S., Université de Fribourg, Fribourg, Switzerland, Secondary Education
  • M.A., University of North Carolina at Chapel Hill, Chapel Hill, NC, Geography
  • M.S.P.H., University of North Carolina at Chapel Hill, Chapel Hill, NC, Epidemiology
  • Ph.D., University of North Carolina at Chapel Hill, Chapel Hill, NC, Epidemiology

Research & Scholarship

Current Research and Scholarly Interests


Dr. John has extensive expertise in conducting population-based epidemiologic studies and has led as Principal Investigator multiple large-scale studies, including multi-center studies with a study site in the San Francisco Bay Area with its diverse population. Many of her studies and collaborations investigated cancer health disparities. Her research has focused on the role of modifiable lifestyle factors (e.g., body size, physical activity, diet), hormonal factors, early-life exposures, genetic variants, and gene-environment interactions; differences in risk factors by race/ethnicity, breast cancer subtypes, and prostate cancer subtypes; risk factors for familial breast cancer and second primary breast cancer, as well as prognostic factors related to survival disparities.

As Principal Investigator, Dr. John has led a number of studies conducted in the San Francisco Bay Area, including:

- the Northern California site of the Breast Cancer Family Registry, an on-going prospective multi-generational cohort of over 13,000 families established in 1995 at six international sites;
- the Northern California site of the WECARE Study that investigates risk factors for second primary breast cancer;
- the California site of the Breast Cancer Health Disparities Study that investigated genetic variability and breast cancer risk and survival in Hispanic and non-Hispanic white populations in the context of genetic admixture;
- the Breast Cancer Etiology in Minorities (BEM) Study, a pooled analysis of risk factors for breast cancer subtypes in racial/ethnic minorities;
- the San Francisco Bay Area Breast Cancer Study, a population-based case-control study in nearly 5,000 Hispanic, African American and non-Hispanic white women that investigated the role of modifiable lifestyle factors and other risk factors;
- the San Francisco Bay Area Prostate Cancer Study, a population-based case-control study of lifestyle and genetic risk factors for advanced and localized disease.

These studies collected and pooled extensive data and biospecimens and continue to support numerous ancillary studies, collaborations and international consortia and have contributed to a better understanding of cancer risk and survival in racial/ethnic minority populations.

Dr. John is also a founding PI of the LEGACY Girls Study, an on-going prospective cohort established in 2011 that investigates early life exposures in relation to pubertal development outcomes, breast tissue characteristics, and behavioral and psychosocial outcomes in the context of having a family history or breast cancer.

Teaching

2019-20 Courses


Publications

All Publications


  • Alcohol consumption, cigarette smoking, and risk of breast cancer for BRCA1 and BRCA2 mutation carriers: results from The BRCA1 and BRCA2 Cohort Consortium. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Li, H., Terry, M. B., Antoniou, A. C., Phillips, K., Kast, K., Mooij, T. M., Engel, C., Nogues, C., Stoppa-Lyonnet, D., Lasset, C., Berthet, P., Mari, V., Caron, O., Barrowdale, D., Frost, D., Brewer, C., Evans, D. G., Izatt, L., Side, L., Walker, L., Tischkowitz, M., Rogers, M. T., Porteous, M. E., Meijers-Heijboer, H. E., Gille, J. J., Blok, M. J., Hoogerbrugge, N., Daly, M. B., Andrulis, I. L., Buys, S. S., John, E. M., McLachlan, S., Friedlander, M., Tan, Y. Y., Osorio, A., Caldes, T., Jakubowska, A., Simard, J., Singer, C. F., Olah, E., Navratilova, M., Foretova, L., Gerdes, A., Roos-Blom, M., Arver, B., Olsson, H., Schmutzler, R. K., Hopper, J. L., Milne, R. L., Easton, D. F., Van Leeuwen, F. E., Rookus, M. A., Andrieu, N., Goldgar, D. E. 2019

    Abstract

    BACKGROUND: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer (BC), but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high BC risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with BC risk is essential.METHODS: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers; 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers; 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models.RESULTS: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with BC risk, except smoking for more than five years before a first full-term pregnancy (FFTP) when compared to parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 (95%CI:1.02,1.39) and the HR from prospective analysis (HRP) was 1.36 (95%CI:0.99,1.87). For BRCA2 mutation carriers, smoking for more than five years before a FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR=1.25,95%CI:1.01,1.55 and HRP=1.30,95%CI:0.83,2.01). For both carrier groups, alcohol consumption was not associated with BC risk.CONCLUSIONS: The finding that smoking during the pre-reproductive years increases BC risk for mutation carriers warrants further investigation.IMPACT: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.

    View details for DOI 10.1158/1055-9965.EPI-19-0546

    View details for PubMedID 31792088

  • Recreational physical activity is associated with reduced breast cancer risk in adult women at high risk for breast cancer: a cohort study of women selected for familial and genetic risk. Cancer research Kehm, R. D., Genkinger, J. M., MacInnis, R. J., John, E. M., Phillips, K., Dite, G. S., Milne, R. L., Zeinomar, N., Liao, Y., Knight, J. A., Southey, M. C., Chung, W. K., Giles, G. G., McLachlan, S., Whitaker, K. D., Friedlander, M., Weideman, P. C., Glendon, G., Nesci, S., Investigators, k., Andrulis, I. L., Buys, S. S., Daly, M. B., Hopper, J. L., Terry, M. B. 2019

    Abstract

    While physical activity is associated with lower breast cancer risk for average-risk women, it is not known if this association applies to women at high familial/genetic risk. We examined the association of recreational physical activity (self-reported by questionnaire) with breast cancer risk using the Prospective Family Study Cohort (ProF-SC), which is enriched with women who have a breast cancer family history (N=15,550). We examined associations of adult and adolescent recreational physical activity (quintiles of age-adjusted total metabolic equivalents (METs) per week) with breast cancer risk using multivariable Cox proportional hazards regression, adjusted for demographics, lifestyle factors, and body mass index. We tested for multiplicative interactions of physical activity with predicted absolute breast cancer familial risk based on pedigree data and with BRCA1 and BRCA2 mutation status. Baseline recreational physical activity level in the highest 4 quintiles compared with the lowest quintile was associated with a 20% lower breast cancer risk (HR=0.80, 95% CI=0.68, 0.93). The association was not modified by familial risk or BRCA mutation status (p-interactions>0.05). No overall association was found for adolescent recreational physical activity. Recreational physical activity in adulthood may lower breast cancer risk for women across the spectrum of familial risk.

    View details for DOI 10.1158/0008-5472.CAN-19-1847

    View details for PubMedID 31578201

  • A polygenic risk score for breast cancer in U.S. Latinas and Latin-American women. Journal of the National Cancer Institute Shieh, Y., Fejerman, L., Lott, P. C., Marker, K., Sawyer, S. D., Hu, D., Huntsman, S., Torres, J., Echeverry, M., Bohorquez, M. E., Martinez-Chequer, J. C., Polanco-Echeverry, G., Estrada-Florez, A. P., COLUMBUS Consortium, Haiman, C. A., John, E. M., Kushi, L. H., Torres-Mejia, G., Vidaurre, T., Weitzel, J. N., Zambrano, S. C., Carvajal-Carmona, L. G., Ziv, E., Neuhausen, S. L., Benavides, J., Bohorquez, M., Bolanos, F., Carvajal-Carmona, L. G., Carmona, J., Criollo, A., Echeverry, M., Estrada, A., Mateus, G., Murillo, R., Ramirez, J., Sanchez, Y., Sanabria, C., Serrano, M. L., Suarez, J. J., Velez, A. 2019

    Abstract

    BACKGROUND: Over 180 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified; these SNPs can be combined into polygenic risk scores (PRS) to predict breast cancer risk. Since most SNPs were identified in predominantly European populations, little is known about the performance of PRS in non-Europeans. We tested the performance of a 180-SNP PRS in Latinas, a large ethnic group with variable levels of Indigenous American, European, and African ancestry.METHODS: We conducted a pooled case-control analysis of U.S. Latinas and Latin-American women (4,658 cases, 7,622 controls). We constructed a 180-SNP PRS consisting of SNPs associated with breast cancer risk (p<5 x 10-8). We evaluated the association between the PRS and breast cancer risk using multivariable logistic regression and assessed discrimination using area under the receiver operating characteristic curve (AUROC). We also assessed PRS performance across quartiles of Indigenous American genetic ancestry. All statistical tests were two-sided.RESULTS: Of 180 SNPs tested, 142 showed directionally consistent associations compared with European populations, and 39 were nominally statistically significant (p<0.05). The PRS was associated with breast cancer risk, with an odds ratio (OR) per standard deviation increment of 1.58 (95% CI 1.52 to 1.64) and AUCROC of 0.63 (95% CI 0.62 to 0.64). The discrimination of the PRS was similar between the top and bottom quartiles of Indigenous American ancestry.CONCLUSIONS: The 180-SNP PRS predicts breast cancer risk in Latinas, with similar performance as reported for Europeans. The performance of the PRS did not vary substantially according to Indigenous American ancestry.

    View details for DOI 10.1093/jnci/djz174

    View details for PubMedID 31553449

  • Benign breast disease increases breast cancer risk independent of underlying familial risk profile: Findings from a Prospective Family Study Cohort INTERNATIONAL JOURNAL OF CANCER Zeinomar, N., Phillips, K., Daly, M. B., Milne, R. L., Dite, G. S., MacInnis, R. J., Liao, Y., Kehm, R. D., Knight, J. A., Southey, M. C., Chung, W. K., Giles, G. G., McLachlan, S., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., Andrulis, I. L., Buys, S. S., John, E. M., Hopper, J. L., Terry, M., kConFab Investigators 2019; 145 (2): 370?79

    View details for DOI 10.1002/ijc.32112

    View details for Web of Science ID 000468195900008

  • A polygenic risk score predicts breast cancer risk in Latinas Shieh, Y., Fejerman, L., Sawyer, S. D., Hu, D., Huntsman, S., John, E. M., Kushi, L. H., Torres-Mejia, G., Weitzel, J. N., Haiman, C. A., Ziv, E., Neuhausen, S. L. AMER ASSOC CANCER RESEARCH. 2019
  • Runs of homozygosity and testicular cancer risk ANDROLOGY Loveday, C., Sud, A., Litchfield, K., Levy, M., Holroyd, A., Broderick, P., Kote-Jarai, Z., Dunning, A. M., Muir, K., Peto, J., Eeles, R., Easton, D. F., Dudakia, D., Orr, N., Pashayan, N., Rustin, G., Srihari, N. N., Cole, D., Askill, C., Bertelli, G., Barber, J., Gilby, E., White, J., Baybrooke, J., Leahy, M., Welch, R., Chakraborti, P., Joffe, J., Brown, R., Faust, G., Simmonds, P., Mazhar, D., Stockdale, A., Hrounda, D., Humber, C., Appel, W., Hong, A., Howard, G., Douglas, F., Bloomfield, D., Butt, M., Kelly, K., Mehra, R., Brown, R., Rogers, P., Chakraborti, P., Hatton, M., Hennig, I., McAteer, J., Savage, P., Seckl, M., Gale, J., Rustin, G., Clark, P., Woby, S., Rathmell, A., Lamont, A., Sarwar, N., Stuart, N., Chowdhury, S., Beesley, S., Winkler, M., Hamid, A., Pathak, S., Madhavan, K., Highley, M., Money-Kryle, J., Brock, C., Sreenivasan, T., Henderson, B. E., Haiman, C. A., Schumacher, F. R., Al Olama, A., Benlloch, S., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., Gapster, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Schleutker, J., Albanes, D., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Maehle, L., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B. S., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albrigh, L., Pandha, H., Thibodeau, S. N., Reid, A., Huddart, R. A., Houlston, R. S., Turnbull, C., UK Testicular Canc Collaboration, PRACTICAL Consortium, Australian Prostate Canc Res Ctr 2019; 7 (4): 555?64

    Abstract

    Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types.To examine whether RoH are associated with TGCT risk.We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform.Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology.Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.

    View details for DOI 10.1111/andr.12667

    View details for Web of Science ID 000475940600021

    View details for PubMedID 31310061

  • The genetic interplay between body mass index, breast size and breast cancer risk: a Mendelian randomization analysis. International journal of epidemiology Ooi, B. N., Loh, H., Ho, P. J., Milne, R. L., Giles, G., Gao, C., Kraft, P., John, E. M., Swerdlow, A., Brenner, H., Wu, A. H., Haiman, C., Evans, D. G., Zheng, W., Fasching, P. A., Castelao, J. E., Kwong, A., Shen, X., Czene, K., Hall, P., Dunning, A., Easton, D., Hartman, M., Li, J. 2019

    Abstract

    BACKGROUND: Evidence linking breast size to breast cancer risk has been inconsistent, and its interpretation is often hampered by confounding factors such as body mass index (BMI). Here, we used linkage disequilibrium score regression and two-sample Mendelian randomization (MR) to examine the genetic associations between BMI, breast size and breast cancer risk.METHODS: Summary-level genotype data from 23andMe, Inc (breast size, n=33790), the Breast Cancer Association Consortium (breast cancer risk, n=228951) and the Genetic Investigation of ANthropometric Traits (BMI, n=183507) were used for our analyses. In assessing causal relationships, four complementary MR techniques [inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger regression] were used to test the robustness of the results.RESULTS: The genetic correlation (rg) estimated between BMI and breast size was high (rg=0.50, P=3.89x10-43). All MR methods provided consistent evidence that higher genetically predicted BMI was associated with larger breast size [odds ratio (ORIVW): 2.06 (1.80-2.35), P=1.38x10-26] and lower overall breast cancer risk [ORIVW: 0.81 (0.74-0.89), P=9.44x10-6]. No evidence of a relationship between genetically predicted breast size and breast cancer risk was found except when using the weighted median and weighted mode methods, and only with oestrogen receptor (ER)-negative risk. There was no evidence of reverse causality in any of the analyses conducted (P>0.050).CONCLUSION: Our findings indicate a potential positive causal association between BMI and breast size and a potential negative causal association between BMI and breast cancer risk. We found no clear evidence for a direct relationship between breast size and breast cancer risk.

    View details for DOI 10.1093/ije/dyz124

    View details for PubMedID 31243447

  • A Genome-wide Association Study of Prostate Cancer in Latinos. International journal of cancer Du, Z., Hopp, H., Ingles, S. A., Huff, C., Sheng, X., Weaver, B., Stern, M., Hoffmann, T. J., John, E. M., Van Den Eeden, S. K., Strom, S., Leach, R. J., Thompson, I. M., Witte, J. S., Conti, D. V., Haiman, C. A. 2019

    Abstract

    Latinos represent less than 1% of samples analyzed to date in genome-wide association studies of cancer. The clinical value of genetic information in guiding personalized medicine in populations of non-European ancestry will require additional discovery and risk locus characterization efforts across populations. In the present study, we performed a GWAS of PrCa in 2,820 Latino PrCa cases and 5,293 controls to search for novel PrCa risk loci and to examine the generalizability of known PrCa risk loci in Latino men. We also conducted a genetic admixture mapping scan to identify PrCa risk alleles associated with local ancestry. Genome-wide significant associations were observed with 84 variants all located at the known PrCa risk regions at 8q24 (128.484-128.548) and 10q11.22 (MSMB gene). In admixture mapping, we observed genome-wide significant associations with local African ancestry at 8q24. Of the 162 established PrCa risk variants that are common in Latino men, 135 (83.3%) had effects that were directionally consistent as previously reported, among which 55 (34.0%) were statistically significant with P<0.05. A polygenic risk model of the known PrCa risk variants showed that, compared to men with average risk (25th -75th percentile of the polygenic risk score distribution), men in the top 10% had a 3.19-fold (95% CI: 2.65, 3.84) increased PrCa risk. In conclusion, we found that the known PrCa risk variants can effectively stratify PrCa risk in Latino men. Larger studies in Latino populations will be required to discover and characterize genetic risk variants for PrCa and improve risk stratification for this population. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ijc.32525

    View details for PubMedID 31226226

  • Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers. British journal of cancer Qian, F., Rookus, M. A., Leslie, G., Risch, H. A., Greene, M. H., Aalfs, C. M., Adank, M. A., Adlard, J., Agnarsson, B. A., Ahmed, M., Aittomaki, K., Andrulis, I. L., Arnold, N., Arun, B. K., Ausems, M. G., Azzollini, J., Barrowdale, D., Barwell, J., Benitez, J., Bialkowska, K., Bonadona, V., Borde, J., Borg, A., Bradbury, A. R., Brunet, J., Buys, S. S., Caldes, T., Caligo, M. A., Campbell, I., Carter, J., Chiquette, J., Chung, W. K., Claes, K. B., Collee, J. M., Collonge-Rame, M., Couch, F. J., Daly, M. B., Delnatte, C., Diez, O., Domchek, S. M., Dorfling, C. M., Eason, J., Easton, D. F., Eeles, R., Engel, C., Evans, D. G., Faivre, L., Feliubadalo, L., Foretova, L., Friedman, E., Frost, D., Ganz, P. A., Garber, J., Garcia-Barberan, V., Gehrig, A., Glendon, G., Godwin, A. K., Gomez Garcia, E. B., Hamann, U., Hauke, J., Hopper, J. L., Hulick, P. J., Imyanitov, E. N., Isaacs, C., Izatt, L., Jakubowska, A., Janavicius, R., John, E. M., Karlan, B. Y., Kets, C. M., Laitman, Y., Lazaro, C., Leroux, D., Lester, J., Lesueur, F., Loud, J. T., Lubinski, J., Lukomska, A., McGuffog, L., Mebirouk, N., Meijers-Heijboer, H. E., Meindl, A., Miller, A., Montagna, M., Mooij, T. M., Mouret-Fourme, E., Nathanson, K. L., Nehoray, B., Neuhausen, S. L., Nevanlinna, H., Nielsen, F. C., Offit, K., Olah, E., Ong, K., Oosterwijk, J. C., Ottini, L., Parsons, M. T., Peterlongo, P., Pfeiler, G., Pradhan, N., Radice, P., Ramus, S. J., Rantala, J., Rennert, G., Robson, M., Rodriguez, G. C., Salani, R., Scheuner, M. T., Schmutzler, R. K., Shah, P. D., Side, L. E., Simard, J., Singer, C. F., Steinemann, D., Stoppa-Lyonnet, D., Tan, Y. Y., Teixeira, M. R., Terry, M. B., Thomassen, M., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tung, N., van Asperen, C. J., van Engelen, K., van Rensburg, E. J., Venat-Bouvet, L., Vierstraete, J., Wagner, G., Walker, L., Weitzel, J. N., Yannoukakos, D., KConFab Investigators, HEBON Investigators, GEMO Study Collaborators, EMBRACE Collaborators, Antoniou, A. C., Goldgar, D. E., Olopade, O. I., Chenevix-Trench, G., Rebbeck, T. R., Huo, D., CIMBA 2019

    Abstract

    BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown.METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models.RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR=1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR=1.25 (95% CI: 1.06-1.48) and HR=1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction<0.05).CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

    View details for DOI 10.1038/s41416-019-0492-8

    View details for PubMedID 31213659

  • The functional ALDH2 polymorphism is associated with breast cancer risk: A pooled analysis from the Breast Cancer Association Consortium MOLECULAR GENETICS & GENOMIC MEDICINE Ugai, T., Milne, R. L., Ito, H., Aronson, K. J., Bolla, M. K., Chan, T., Chan, C. W., Choi, J., Conroy, D. M., Dennis, J., Dunning, A. M., Easton, D. F., Gaborieau, V., Gonzalez-Neira, A., Hartman, M., Healey, C. S., Iwasaki, M., John, E. M., Kang, D., Kim, S., Kwong, A., Lophatananon, A., Michailidou, K., Taib, N., Muir, K., Park, S. K., Pharoah, P. P., Sangrajrang, S., Shen, C., Shu, X., Spinelli, J. J., Teo, S. H., Tessier, D. C., Tseng, C., Tsugane, S., Vincent, D., Wang, Q., Wu, A. H., Wu, P., Zheng, W., Matsuo, K. 2019; 7 (6)

    View details for DOI 10.1002/mgg3.707

    View details for Web of Science ID 000476745400047

  • Genetic predisposition to breast cancer among African American women. Palmer, J. R., Hu, C., Hart, S., Gnanaolivu, R., Gao, C., Anton-Culver, H., Trentham-Dietz, A., Bernstein, L., Weitzel, J. N., Domchek, S. M., Goldgar, D., Nathanson, K., Pal, T., John, E. M., Gaudet, M., Haiman, C., Yao, S., Kraft, P., Polley, E., Couch, F. AMER SOC CLINICAL ONCOLOGY. 2019
  • Association analyses identify 31 new risk loci for colorectal cancer susceptibility NATURE COMMUNICATIONS Law, P. J., Timofeeva, M., Fernandez-Rozadilla, C., Timofeeva, A., Broderick, P., Studd, J., Fernandez-Tajes, J., Farrington, S., Svinti, V., Palles, C., Orlando, G., Sud, A., Holroyd, A., Penegar, S., Theodoratou, E., Vaughan-Shaw, P., Campbell, H., Zgaga, L., Hayward, C., Campbell, A., Harris, S., Deary, I. J., Starr, O., Gatcombe, L., Pinna, M., Briggs, S., Martin, L., Jaeger, E., Sharma-Oates, A., East, J., Leedham, S., Arnold, R., Johnstone, E., Wang, H., Kerr, D., Kerr, R., Maughan, T., Kaplan, R., Al-Tassan, N., Palin, K., Hanninen, U. A., Cajuso, T., Tanskanen, T., Kondelin, J., Kaasinen, E., Sarin, A., Eriksson, J. G., Rissanen, H., Knekt, P., Pukkala, E., Jousilahti, P., Salomaa, V., Ripatti, S., Palotie, A., Renkonen-Sinisalo, L., Lepisto, A., Bohm, J., Mecklin, J., Buchanan, D. D., Win, A., Hopper, J., Jenkins, M. E., Lindor, N. M., Newcomb, P. A., Gallinger, S., Duggan, D., Casey, G., Hoffmann, P., Nothen, M. M., Jockel, K., Easton, D. F., Pharoah, P. P., Peto, J., Canzian, F., Swerdlow, A., Eeles, R. A., Kote-Jarai, Z., Muir, K., Pashayan, N., Harkin, A., Allan, K., McQueen, J., Paul, J., Iveson, T., Saunders, M., Butterbach, K., Chang-Claude, J., Hoffmeister, M., Brenner, H., Kirac, I., Matosevic, P., Hofer, P., Brezina, S., Gsur, A., Cheadle, J. P., Aaltonen, L. A., Tomlinson, I., Houlston, R. S., Dunlop, M. G., Henderson, B. E., Haiman, C. A., Schumacher, F. R., Al Olama, A., Benlloch, S., Berndt, S., Conti, D., Wiklund, F., Chanock, S., Gapstur, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Schleutker, J., Albanes, D., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Grindeda, E., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B. S., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Gamulin, M., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L., Pandha, H., Thibodeau, S. N., PRACTICAL Consortium 2019; 10: 2154

    Abstract

    Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.

    View details for DOI 10.1038/s41467-019-09775-w

    View details for Web of Science ID 000467836900008

    View details for PubMedID 31089142

    View details for PubMedCentralID PMC6517433

  • Regular use of aspirin and other non-steroidal anti-inflammatory drugs and breast cancer risk for women at familial or genetic risk: a cohort study BREAST CANCER RESEARCH Kehm, R. D., Hopper, J. L., John, E. M., Phillips, K., MacInnis, R. J., Dite, G. S., Milne, R. L., Liao, Y., Zeinomar, N., Knight, J. A., Southey, M. C., Vahdat, L., Kornhauser, N., Cigler, T., Chung, W. K., Giles, G. G., McLachlan, S., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., Andrulis, I. L., Buys, S. S., Daly, M. B., Terry, M., kConFab Investigators 2019; 21
  • Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer NATURE COMMUNICATIONS Ferreira, M. A., Gamazon, E. R., Al-Ejeh, F., Aittomaki, K., Andrulis, I. L., Anton-Culver, H., Arason, A., Arndt, V., Aronson, K. J., Arun, B. K., Asseryanis, E., Azzollini, J., Balmana, J., Barnes, D. R., Barrowdale, D., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bialkowska, K., Blomqvist, C., Bogdanova, N., Bojesen, S. E., Bolla, M. K., Borg, A., Brauch, H., Brenner, H., Broeks, A., Burwinkel, B., Caldes, T., Caligo, M. A., Campa, D., Campbell, I., Canzian, F., Carter, J., Carter, B. D., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Christiansen, H., Chung, W. K., Claes, K. M., Clarke, C. L., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., de la Hoya, M., Dennis, J., Devilee, P., Diez, O., Doerk, T., Dunning, A. M., Dwek, M., Eccles, D. M., Ejlertsen, B., Ellberg, C., Engel, C., Eriksson, M., Fasching, P. A., Fletcher, O., Flyger, H., Friedman, E., Frost, D., Gabrielson, M., Gago-Dominguez, M., Ganz, P. A., Gapstur, S. M., Garber, J., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Greene, M. H., Gronwald, J., Guenel, P., Haiman, C. A., Hall, P., Hamann, U., He, W., Heyworth, J., Hogervorst, F. L., Hollestelle, A., Hoover, R. N., Hopper, J. L., Hulick, P. J., Humphreys, K., Imyanitov, E. N., Isaacs, C., Jakimovska, M., Jakubowska, A., James, P. A., Janavicius, R., Jankowitz, R. C., John, E. M., Johnson, N., Joseph, V., Karlan, B. Y., Khusnutdinova, E., Kiiski, J., Ko, Y., Jones, M. E., Konstantopoulou, I., Kristensen, V. N., Laitman, Y., Lambrechts, D., Lazaro, C., Leslie, G., Lester, J., Lesueur, F., Lindstrom, S., Long, J., Loud, J. T., Lubinski, J., Makalic, E., Mannermaa, A., Manoochehri, M., Margolin, S., Maurer, T., Mavroudis, D., McGuffog, L., Meindl, A., Menon, U., Michailidou, K., Miller, A., Montagna, M., Moreno, F., Moserle, L., Mulligan, A., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nevelsteen, I., Nielsen, F. C., Nikitina-Zake, L., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O., Olsson, H., Osorio, A., Papp, J., Park-Simon, T., Parsons, M. T., Pedersen, I., Peixoto, A., Peterlongo, P., Pharoah, P. P., Plaseska-Karanfilska, D., Poppe, B., Presneau, N., Radice, P., Rantala, J., Rennert, G., Risch, H. A., Saloustros, E., Sanden, K., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Sharma, P., Shu, X., Simard, J., Singer, C. F., Soucy, P., Southey, M. C., Spinelli, J. J., Spurdle, A. B., Stone, J., Swerdlow, A. J., Tapper, W. J., Taylor, J. A., Teixeira, M. R., Terry, M., Teule, A., Thomassen, M., Thoene, K., Thull, D. L., Tischkowitz, M., Toland, A. E., Torres, D., Truong, T., Tung, N., Vachon, C. M., van Asperen, C. J., van den Ouweland, A. W., van Rensburg, E. J., Vega, A., Viel, A., Wang, Q., Wappenschmidt, B., Weitzel, J. N., Wendt, C., Winqvist, R., Yang, X. R., Yannoukakos, D., Ziogas, A., Kraft, P., Antoniou, A. C., Zheng, W., Easton, D. F., Milne, R. L., Beesley, J., Chenevix-Trench, G., Arnold, N., Auber, B., Bogdanova-Markov, N., Borde, J., Caliebe, A., Ditsch, N., Dworniczak, B., Engert, S., Faust, U., Gehrig, A., Hahnen, E., Hauke, J., Hentschel, J., Herold, N., Honisch, E., Just, W., Kast, K., Larsen, M., Lemke, J., Huu Phuc Nguyen, Niederacher, D., Ott, C., Platzer, K., Pohl-Rescigno, E., Ramser, J., Rhiem, K., Steinemann, D., Sutter, C., Varon-Mateeva, R., Wang-Gohrke, S., Weber, B. F., Prieur, F., Pujol, P., Sagne, C., Sevenet, N., Sobol, H., Sokolowska, J., Stoppa-Lyonnet, D., Venat-Bouvet, L., Adlard, J., Ahmed, M., Barwell, J., Brady, A., Brewer, C., Cook, J., Davidson, R., Donaldson, A., Eason, J., Eeles, R., Evans, D., Gregory, H., Hanson, H., Henderson, A., Hodgson, S., Izatt, L., Kennedy, M., Lalloo, F., Miller, C., Morrison, P. J., Ong, K., Perkins, J., Porteous, M. E., Rogers, M. T., Side, L. E., Snape, K., Walker, L., Harrington, P. A., Heemskerk-Gerritsen, B. M., Rookus, M. A., Seynaeve, C. M., van der Baan, F. H., van der Hout, A. H., van der Kolk, L. E., van der Luijt, R. B., van Deurzen, C. M., van Doorn, H. C., van Engelen, K., van Hest, L., van Os, T. M., Verhoef, S., Vogel, M. J., Wijnen, J. T., Miron, A., Kapuscinski, M., Bane, A., Ross, E., Buys, S. S., Conner, T. A., Balleine, R., Baxter, R., Braye, S., Carpenter, J., Dahlstrom, J., Forbes, J., Lee, S. C., Marsh, D., Morey, A., Pathmanathan, N., Simpson, P., Spigelman, A., Wilcken, N., Yip, D., GC-HBOC Study Collaborators, GEMO Study Collaborators, EMBRACE Collaborators, HEBON Investigators, BCFR Investigators, ABCTB Investigators 2019; 10
  • Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer. Nature communications Ferreira, M. A., Gamazon, E. R., Al-Ejeh, F., Aittomaki, K., Andrulis, I. L., Anton-Culver, H., Arason, A., Arndt, V., Aronson, K. J., Arun, B. K., Asseryanis, E., Azzollini, J., Balmana, J., Barnes, D. R., Barrowdale, D., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bialkowska, K., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Borg, A., Brauch, H., Brenner, H., Broeks, A., Burwinkel, B., Caldes, T., Caligo, M. A., Campa, D., Campbell, I., Canzian, F., Carter, J., Carter, B. D., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Christiansen, H., Chung, W. K., Claes, K. B., Clarke, C. L., EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., de la Hoya, M., Dennis, J., Devilee, P., Diez, O., Dork, T., Dunning, A. M., Dwek, M., Eccles, D. M., Ejlertsen, B., Ellberg, C., Engel, C., Eriksson, M., Fasching, P. A., Fletcher, O., Flyger, H., Friedman, E., Frost, D., Gabrielson, M., Gago-Dominguez, M., Ganz, P. A., Gapstur, S. M., Garber, J., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Greene, M. H., Gronwald, J., Guenel, P., Haiman, C. A., Hall, P., Hamann, U., He, W., Heyworth, J., Hogervorst, F. B., Hollestelle, A., Hoover, R. N., Hopper, J. L., Hulick, P. J., Humphreys, K., Imyanitov, E. N., ABCTB Investigators, HEBON Investigators, BCFR Investigators, Isaacs, C., Jakimovska, M., Jakubowska, A., James, P. A., Janavicius, R., Jankowitz, R. C., John, E. M., Johnson, N., Joseph, V., Karlan, B. Y., Khusnutdinova, E., Kiiski, J. I., Ko, Y., Jones, M. E., Konstantopoulou, I., Kristensen, V. N., Laitman, Y., Lambrechts, D., Lazaro, C., Leslie, G., Lester, J., Lesueur, F., Lindstrom, S., Long, J., Loud, J. T., Lubinski, J., Makalic, E., Mannermaa, A., Manoochehri, M., Margolin, S., Maurer, T., Mavroudis, D., McGuffog, L., Meindl, A., Menon, U., Michailidou, K., Miller, A., Montagna, M., Moreno, F., Moserle, L., Mulligan, A. M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nevelsteen, I., Nielsen, F. C., Nikitina-Zake, L., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O. I., Olsson, H., Osorio, A., Papp, J., Park-Simon, T., Parsons, M. T., Pedersen, I. S., Peixoto, A., Peterlongo, P., Pharoah, P. D., Plaseska-Karanfilska, D., Poppe, B., Presneau, N., Radice, P., Rantala, J., Rennert, G., Risch, H. A., Saloustros, E., Sanden, K., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Sharma, P., Shu, X., Simard, J., Singer, C. F., Soucy, P., Southey, M. C., Spinelli, J. J., Spurdle, A. B., Stone, J., Swerdlow, A. J., Tapper, W. J., Taylor, J. A., Teixeira, M. R., Terry, M. B., Teule, A., Thomassen, M., Thone, K., Thull, D. L., Tischkowitz, M., Toland, A. E., Torres, D., Truong, T., Tung, N., Vachon, C. M., van Asperen, C. J., van den Ouweland, A. M., van Rensburg, E. J., Vega, A., Viel, A., Wang, Q., Wappenschmidt, B., Weitzel, J. N., Wendt, C., Winqvist, R., Yang, X. R., Yannoukakos, D., Ziogas, A., Kraft, P., Antoniou, A. C., Zheng, W., Easton, D. F., Milne, R. L., Beesley, J., Chenevix-Trench, G., Adlard, J., Ahmed, M., Barwell, J., Brady, A., Brewer, C., Cook, J., Davidson, R., Donaldson, A., Eason, J., Eeles, R., Evans, D. G., Gregory, H., Hanson, H., Henderson, A., Hodgson, S., Izatt, L., Kennedy, M. J., Lalloo, F., Miller, C., Morrison, P. J., Ong, K., Perkins, J., Porteous, M. E., Rogers, M. T., Side, L. E., Snape, K., Walker, L., Harrington, P. A., Arnold, N., Auber, B., Bogdanova-Markov, N., Borde, J., Caliebe, A., Ditsch, N., Dworniczak, B., Engert, S., Faust, U., Gehrig, A., Hahnen, E., Hauke, J., Hentschel, J., Herold, N., Honisch, E., Just, W., Kast, K., Larsen, M., Lemke, J., Nguyen, H. P., Niederacher, D., Ott, C., Platzer, K., Pohl-Rescigno, E., Ramser, J., Rhiem, K., Steinemann, D., Sutter, C., Varon-Mateeva, R., Wang-Gohrke, S., Weber, B. H., Prieur, F., Pujol, P., Sagne, C., Sevenet, N., Sobol, H., Sokolowska, J., Stoppa-Lyonnet, D., Venat-Bouvet, L., Balleine, R., Baxter, R., Braye, S., Carpenter, J., Dahlstrom, J., Forbes, J., Lee, S. C., Marsh, D., Morey, A., Pathmanathan, N., Simpson, P., Spigelman, A., Wilcken, N., Yip, D., Heemskerk-Gerritsen, B. A., Rookus, M. A., Seynaeve, C. M., van der Baan, F. H., van der Hout, A. H., van der Kolk, L. E., van der Luijt, R. B., van Deurzen, C. H., van Doorn, H. C., van Engelen, K., van Hest, L., van Os, T. A., Verhoef, S., Vogel, M. J., Wijnen, J. T., Miron, A., Kapuscinski, M., Bane, A., Ross, E., Buys, S. S., Conner, T. A. 2019; 10 (1): 1741

    Abstract

    Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

    View details for PubMedID 30988301

  • 10-year performance of four models of breast cancer risk:a validation study LANCET ONCOLOGY Terry, M., Liao, Y., Whittemore, A. S., Leoce, N., Buchsbaum, R., Zeinotnar, N., Dite, G. S., Chung, W. K., Knight, J. A., Southey, M. C., Milne, R. L., Goldgar, D., Giles, G. G., McLachlan, S., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., Andrulis, I. L., John, E. M., Phillips, K., Daly, M. B., Buys, S. S., Hopper, J. L., MacInnis, R. 2019; 20 (4): 504?17
  • Enrollment and biospecimen collection in a multiethnic family cohort: the Northern California site of the Breast Cancer Family Registry CANCER CAUSES & CONTROL John, E. M., Sangaramoorthy, M., Koo, J., Whittemore, A. S., West, D. W. 2019; 30 (4): 395?408
  • Genome-wide association study of germline variants and breast cancer-specific mortality BRITISH JOURNAL OF CANCER Escala-Garcia, M., Guo, Q., Doerk, T., Canisius, S., Keeman, R., Dennis, J., Beesley, J., Lecarpentier, J., Bolla, M. K., Wang, Q., Abraham, J., Andrulis, I. L., Anton-Culver, H., Arndt, V., Auer, P. L., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Boeckx, B., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brauch, H., Brenner, H., Brentnall, A., Brinton, L., Broberg, P., Brock, I. W., Brucker, S. Y., Burwinkel, B., Caldas, C., Caldes, T., Campa, D., Canzian, F., Carracedo, A., Carter, B. D., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Chenevix-Trench, G., Cheng, T., Chin, S., Clarke, C. L., Cordina-Duverger, E., Couch, F. J., Cox, D. G., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Dunn, J. A., Dunning, A. M., Durcan, L., Dwek, M., Earl, H. M., Ekici, A. B., Eliassen, A., Ellberg, C., Engel, C., Eriksson, M., Evans, D., Figueroa, J., Flesch-Janys, D., Flyger, H., Gabrielson, M., Gago-Dominguez, M., Galle, E., Gapstur, S. M., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., George, A., Georgoulias, V., Giles, G. G., Glendon, G., Goldgar, D. E., Gonzalez-Neira, A., Alnaes, G., Grip, M., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hall, P., Hamann, U., Hankinson, S., Harkness, E. F., Harrington, P. A., Hart, S. N., Hartikainen, J. M., Hein, A., Hillemanns, P., Hiller, L., Holleczek, B., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Howell, A., Huang, G., Humphreys, K., Hunter, D. J., Janni, W., John, E. M., Jones, M. E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kabisch, M., Kaczmarek, K., Kerin, M. J., Khan, S., Khusnutdinova, E., Kiiski, J., Kitahara, C. M., Knight, J. A., Ko, Y., Koppert, L. B., Kosma, V., Kraft, P., Kristensen, V. N., Kruger, U., Kuehl, T., Lambrechts, D., Le Marchand, L., Lee, E., Lejbkowicz, F., Li, L., Lindblom, A., Lindstrom, S., Linet, M., Lissowska, J., Lo, W., Loibl, S., Lubinski, J., Lux, M. P., MacInnis, R. J., Maierthaler, M., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M., Mavroudis, D., McLean, C., Meindl, A., Middha, P., Miller, N., Milne, R. L., Moreno, F., Mulligan, A., Mulot, C., Nassir, R., Neuhausen, S. L., Newman, W. T., Nielsen, S. F., Nordestgaard, B. G., Norman, A., Olsson, H., Orr, N., Pankratz, V., Park-Simon, T., Perez, J. A., Perez-Barrios, C., Peterlongo, P., Petridis, C., Pinchev, M., Prajzendanc, K., Prentice, R., Presneau, N., Prokofieva, D., Pylkas, K., Rack, B., Radice, P., Ramachandran, D., Rennert, G., Rennert, H. S., Rhenius, V., Romero, A., Roylance, R., Saloustros, E., Sawyer, E. J., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schumacher, F., Schwentner, L., Scott, R. J., Scott, C., Seynaeve, C., Shah, M., Simard, J., Smeets, A., Sohn, C., Southey, M. C., Swerdlow, A. J., Talhouk, A., Tamimi, R. M., Tapper, W. J., Teixeira, M. R., Tengstrom, M., Terry, M., Thoene, K., Tollenaar, R. M., Tomlinson, I., Torres, D., Truong, T., Turman, C., Turnbull, C., Ulmer, H., Untch, M., Vachon, C., van Asperen, C. J., van den Ouweland, A. W., van Veen, E. M., Wendt, C., Whittemore, A. S., Willett, W., Winqvist, R., Wolk, A., Yang, X. R., Zhang, Y., Easton, D. F., Fasching, P. A., Nevanlinna, H., Eccles, D. M., Pharoah, P. P., Schmidt, M. K., NBCS Collaborators 2019; 120 (6): 647?57
  • Enrollment and biospecimen collection in a multiethnic family cohort: the Northern California site of the Breast Cancer Family Registry. Cancer causes & control : CCC John, E. M., Sangaramoorthy, M., Koo, J., Whittemore, A. S., West, D. W. 2019

    Abstract

    PURPOSE: Racial/ethnic minorities are often assumed to be less willing to participate in and provide biospecimens for biomedical research. We examined racial/ethnic differences in enrollment of women with breast cancer (probands) and their first-degree relatives in the Northern California site of the Breast Cancer Family Registry from 1996 to 2011.METHODS: We evaluated participation in several study components, including biospecimen collection, for probands and relatives by race/ethnicity, cancer history, and other factors.RESULTS: Of 4,780 eligible probands, 76% enrolled in the family registry by completing the family history and risk factor questionnaires and 68% also provided a blood or mouthwash sample. Enrollment was highest (81%) for non-Hispanic whites (NHWs) and intermediate (73-76%) for Hispanics, African Americans, and all Asian American subgroups, except Filipina women (66%). Of 4,279 eligible relatives, 77% enrolled in the family registry, and 65% also provided a biospecimen sample. Enrollment was highest for NHWs (87%) and lowest for Chinese (68%) and Filipinas (67%). Among those enrolled, biospecimen collection rates were similar for NHW, Hispanic, and African American women, both for probands (92-95%) and relatives (82-87%), but lower for some Asian-American subgroups (probands: 72-88%; relatives: 71-88%), foreign-born Asian Americans, and probands those who were more recent immigrants or had low English language proficiency.CONCLUSIONS: These results show that racial/ethnic minority populations are willing to provide biospecimen samples for research, although some Asian American subgroups in particular may need more directed recruitment methods. To address long-standing and well-documented cancer health disparities, minority populations need equal opportunities to contribute to biomedical research.

    View details for PubMedID 30835011

  • Risk-Reducing Oophorectomy and Breast Cancer Risk Across the Spectrum of Familial Risk JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Terry, M., Daly, M. B., Phillips, K., Ma, X., Zeinomar, N., Leoce, N., Dite, G. S., MacInnis, R. J., Chung, W. K., Knight, J. A., Southey, M. C., Milne, R. L., Goldgar, D., Giles, G. G., Weideman, P. C., Glendon, G., Buchsbaum, R., Andrulis, I. L., John, E. M., Buys, S. S., Hopper, J. L., kConFab Investigators 2019; 111 (3): 331?34
  • 10-year performance of four models of breast cancer risk: a validation study. The Lancet. Oncology Terry, M. B., Liao, Y., Whittemore, A. S., Leoce, N., Buchsbaum, R., Zeinomar, N., Dite, G. S., Chung, W. K., Knight, J. A., Southey, M. C., Milne, R. L., Goldgar, D., Giles, G. G., McLachlan, S., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., Andrulis, I. L., John, E. M., Phillips, K., Daly, M. B., Buys, S. S., Hopper, J. L., MacInnis, R. J. 2019

    Abstract

    BACKGROUND: Independent validation is essential to justify use of models of breast cancer risk prediction and inform decisions about prevention options and screening. Few independent validations had been done using cohorts for common breast cancer risk prediction models, and those that have been done had small sample sizes and short follow-up periods, and used earlier versions of the prediction tools. We aimed to validate the relative performance of four commonly used models of breast cancer risk and assess the effect of limited data input on each one's performance.METHODS: In this validation study, we used the Breast Cancer Prospective Family Study Cohort (ProF-SC), which includes 18?856 women from Australia, Canada, and the USA who did not have breast cancer at recruitment, between March 17, 1992, and June 29, 2011. We selected women from the cohort who were 20-70 years old and had no previous history of bilateral prophylactic mastectomy or ovarian cancer, at least 2 months of follow-up data, and information available about family history of breast cancer. We used this selected cohort to calculate 10-year risk scores and compare four models of breast cancer risk prediction: the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm model (BOADICEA), BRCAPRO, the Breast Cancer Risk Assessment Tool (BCRAT), and the International Breast Cancer Intervention Study model (IBIS). We compared model calibration based on the ratio of the expected number of breast cancer cases to the observed number of breast cancer cases in the cohort, and on the basis of their discriminatory ability to separate those who will and will not have breast cancer diagnosed within 10 years as measured with the concordance statistic (C-statistic). We did subgroup analyses to compare the performance of the models at 10 years in BRCA1 or BRCA2 mutation carriers (ie, BRCA-positive women), tested non-carriers and untested participants (ie, BRCA-negative women), and participants younger than 50 years at recruitment. We also assessed the effect that limited data input (eg, restriction of the amount of family history and non-genetic information included) had on the models' performance.FINDINGS: After median follow-up of 11·1 years (IQR 6·0-14·4), 619 (4%) of 15?732 women selected from the ProF-SC cohort study were prospectively diagnosed with breast cancer after recruitment, of whom 519 (84%) had histologically confirmed disease. BOADICEA and IBIS were well calibrated in the overall validation cohort, whereas BRCAPRO and BCRAT underpredicted risk (ratio of expected cases to observed cases 1·05 [95% CI 0·97-1·14] for BOADICEA, 1·03 [0·96-1·12] for IBIS, 0·59 [0·55-0·64] for BRCAPRO, and 0·79 [0·73-0·85] for BRCAT). The estimated C-statistics for the complete validation cohort were 0·70 (95% CI 0·68-0·72) for BOADICEA, 0·71 (0·69-0·73) for IBIS, 0·68 (0·65-0·70) for BRCAPRO, and 0·60 (0·58-0·62) for BCRAT. In subgroup analyses by BRCA mutation status, the ratio of expected to observed cases for BRCA-negative women was 1·02 (95% CI 0·93-1·12) for BOADICEA, 1·00 (0·92-1·10) for IBIS, 0·53 (0·49-0·58) for BRCAPRO, and 0·97 (0·89-1·06) for BCRAT. For BRCA-positive participants, BOADICEA and IBIS were well calibrated, but BRCAPRO underpredicted risk (ratio of expected to observed cases 1·17 [95% CI 0·99-1·38] for BOADICEA, 1·14 [0·96-1·35] for IBIS, and 0·80 [0·68-0·95] for BRCAPRO). We noted similar patterns of calibration for women younger than 50 years at recruitment. Finally, BOADICEA and IBIS predictive scores were not appreciably affected by limiting input data to family history for first-degree and second-degree relatives.INTERPRETATION: Our results suggest that models that include multigenerational family history, such as BOADICEA and IBIS, have better ability to predict breast cancer risk, even for women at average or below-average risk of breast cancer. Although BOADICEA and IBIS performed similarly, further improvements in the accuracy of predictions could be possible with hybrid models that incorporate the polygenic risk component of BOADICEA and the non-family-history risk factors included in IBIS.FUNDING: US National Institutes of Health, National Cancer Institute, Breast Cancer Research Foundation, Australian National Health and Medical Research Council, Victorian Health Promotion Foundation, Victorian Breast Cancer Research Consortium, Cancer Australia, National Breast Cancer Foundation, Queensland Cancer Fund, Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and Cancer Foundation of Western Australia.

    View details for PubMedID 30799262

  • Genome-wide association study of germline variants and breast cancer-specific mortality. British journal of cancer Escala-Garcia, M., Guo, Q., Dork, T., Canisius, S., Keeman, R., Dennis, J., Beesley, J., Lecarpentier, J., Bolla, M. K., Wang, Q., Abraham, J., Andrulis, I. L., Anton-Culver, H., Arndt, V., Auer, P. L., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Boeckx, B., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brauch, H., Brenner, H., Brentnall, A., Brinton, L., Broberg, P., Brock, I. W., Brucker, S. Y., Burwinkel, B., Caldas, C., Caldes, T., Campa, D., Canzian, F., Carracedo, A., Carter, B. D., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Chenevix-Trench, G., Cheng, T. D., Chin, S., Clarke, C. L., NBCS Collaborators, Cordina-Duverger, E., Couch, F. J., Cox, D. G., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Dunn, J. A., Dunning, A. M., Durcan, L., Dwek, M., Earl, H. M., Ekici, A. B., Eliassen, A. H., Ellberg, C., Engel, C., Eriksson, M., Evans, D. G., Figueroa, J., Flesch-Janys, D., Flyger, H., Gabrielson, M., Gago-Dominguez, M., Galle, E., Gapstur, S. M., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., George, A., Georgoulias, V., Giles, G. G., Glendon, G., Goldgar, D. E., Gonzalez-Neira, A., Alnas, G. I., Grip, M., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hall, P., Hamann, U., Hankinson, S., Harkness, E. F., Harrington, P. A., Hart, S. N., Hartikainen, J. M., Hein, A., Hillemanns, P., Hiller, L., Holleczek, B., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Howell, A., Huang, G., Humphreys, K., Hunter, D. J., Janni, W., John, E. M., Jones, M. E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kabisch, M., Kaczmarek, K., Kerin, M. J., Khan, S., Khusnutdinova, E., Kiiski, J. I., Kitahara, C. M., Knight, J. A., Ko, Y., Koppert, L. B., Kosma, V., Kraft, P., Kristensen, V. N., Kruger, U., Kuhl, T., Lambrechts, D., Le Marchand, L., Lee, E., Lejbkowicz, F., Li, L., Lindblom, A., Lindstrom, S., Linet, M., Lissowska, J., Lo, W., Loibl, S., Lubinski, J., Lux, M. P., MacInnis, R. J., Maierthaler, M., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M. E., Mavroudis, D., McLean, C., Meindl, A., Middha, P., Miller, N., Milne, R. L., Moreno, F., Mulligan, A. M., Mulot, C., Nassir, R., Neuhausen, S. L., Newman, W. T., Nielsen, S. F., Nordestgaard, B. G., Norman, A., Olsson, H., Orr, N., Pankratz, V. S., Park-Simon, T., Perez, J. I., Perez-Barrios, C., Peterlongo, P., Petridis, C., Pinchev, M., Prajzendanc, K., Prentice, R., Presneau, N., Prokofieva, D., Pylkas, K., Rack, B., Radice, P., Ramachandran, D., Rennert, G., Rennert, H. S., Rhenius, V., Romero, A., Roylance, R., Saloustros, E., Sawyer, E. J., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schumacher, F., Schwentner, L., Scott, R. J., Scott, C., Seynaeve, C., Shah, M., Simard, J., Smeets, A., Sohn, C., Southey, M. C., Swerdlow, A. J., Talhouk, A., Tamimi, R. M., Tapper, W. J., Teixeira, M. R., Tengstrom, M., Terry, M. B., Thone, K., Tollenaar, R. A., Tomlinson, I., Torres, D., Truong, T., Turman, C., Turnbull, C., Ulmer, H., Untch, M., Vachon, C., van Asperen, C. J., van den Ouweland, A. M., van Veen, E. M., Wendt, C., Whittemore, A. S., Willett, W., Winqvist, R., Wolk, A., Yang, X. R., Zhang, Y., Easton, D. F., Fasching, P. A., Nevanlinna, H., Eccles, D. M., Pharoah, P. D., Schmidt, M. K. 2019

    Abstract

    BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).RESULTS: We did not find any variant associated with breast cancer-specific mortality at P<5*10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP=7%, P=1.28*10-7, hazard ratio [HR]=0.88, 95% confidence interval [CI]=0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP=11%, P=1.38*10-7, HR=1.27, 95% CI=1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP<15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

    View details for PubMedID 30787463

  • A pooled analysis of breast-feeding and breast cancer risk by hormone receptor status in parous Hispanic women. Epidemiology (Cambridge, Mass.) Sangaramoorthy, M., Hines, L. M., Torres-Mejia, G., Phipps, A. I., Baumgartner, K. B., Wu, A. H., Koo, J., Ingles, S. A., Slattery, M. L., John, E. M. 2019

    Abstract

    BACKGROUND: Data on breast-feeding and breast cancer risk are sparse and inconsistent for Hispanic women.METHODS: Pooling data for nearly 6,000 parous Hispanic women from four population-based studies conducted between 1995 and 2007 in the U.S. and Mexico, we examined the association of breast-feeding with risk of breast cancer overall and subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status, as well as the joint effects of breast-feeding, parity, and age at first birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression.RESULTS: Among parous Hispanic women, older age at first birth was associated with increased breast cancer risk, whereas parity was associated with reduced risk. These associations were found for hormone receptor positive (HR+) breast cancer only and limited to premenopausal women. Age at first birth and parity were not associated with risk of ER-PR- breast cancer. Increasing duration of breast-feeding was associated with decreasing breast cancer risk (?25 vs. 0 months: OR=0.73, 95% CI=0.60-0.89, Ptrend =0.03), with no heterogeneity by menopausal status or subtype. At each parity level, breast-feeding further reduced HR+ breast cancer risk. Additionally, breast-feeding attenuated the increase in risk of HR+ breast cancer associated with older age at first birth.CONCLUSIONS: Our findings suggest that breast-feeding is associated with reduced risk of both HR+ and ER-PR- breast cancer among Hispanic women, as reported for other populations, and may attenuate the increased risk in women with a first pregnancy at older ages.

    View details for DOI 10.1097/EDE.0000000000000981

    View details for PubMedID 30789436

  • Benign Breast Disease Increases Breast Cancer Risk Independent of Underlying Familial Risk Profile: Findings from a Prospective Family Study Cohort (ProF-SC). International journal of cancer Zeinomar, N., Phillips, K., Daly, M. B., Milne, R. L., Dite, G. S., MacInnis, R. J., Liao, Y., Kehm, R. D., Knight, J. A., Southey, M. C., Chung, W. K., Giles, G. G., McLachlan, S., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., kConFab Investigators, Andrulis, I. L., Buys, S. S., John, E. M., Hopper, J. L., Terry, M. B. 2019

    Abstract

    Benign breast disease(BBD) is an established breast cancer(BC) risk factor, but it is unclear whether the magnitude of the association applies to women at familial or genetic risk. This information is needed to improve BC risk assessment in clinical settings. Using the Prospective Family Study Cohort (ProF-SC), we used Cox proportional hazards models to estimate hazard ratios(HRs) and 95% confidence intervals(CIs) for the association of BBD with BC risk. We also examined whether the association with BBD differed by underlying familial risk profile(FRP), calculated using absolute risk estimates from the BOADICEA model. During 176,756 person-years of follow-up (median: 10.9 years, maximum: 23.7) of 17,154 women unaffected with BC at baseline, we observed 968 incident cases of BC. A total of 4,704 (27%) women reported a history of BBD diagnosis. A history of BBD was associated with a greater risk of BC: HR = 1.31(95% CI: 1.14 - 1.50), and did not differ by underlying FRP, with HRs of 1.35(95% CI: 1.11-1.65), 1.26(95% CI: 1.00-1.60), and 1.40(95% CI: 1.01-1.93), for categories of full lifetime BOADICEA score <20%, 20% - <35%, ? 35%, respectively. There was no difference in the association for women with BRCA1 mutations (HR: 1.64; 95% CI: 1.04-2.58), women with BRCA2 mutations (HR: 1.34; 95% CI: 0.78-2.3) or for women without a known BRCA1 or BRCA2 mutation (HR: 1.31; 95% CI: 1.13-1.53) (pinteraction = 0.95). Women with a history of BBD have an increased risk of BC that is independent of, and multiplies, their underlying familial and genetic risk. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30725480

  • Association of Prepubertal and Adolescent Androgen Concentrations With Timing of Breast Development and Family History of Breast Cancer. JAMA network open Houghton, L. C., Knight, J. A., Wei, Y., Romeo, R. D., Goldberg, M., Andrulis, I. L., Bradbury, A. R., Buys, S. S., Daly, M. B., John, E. M., Chung, W. K., Santella, R. M., Stanczyk, F. Z., Terry, M. B. 2019; 2 (2): e190083

    Abstract

    Importance: Early breast development is a risk factor for breast cancer, and girls with a breast cancer family history (BCFH) experience breast development earlier than girls without a BCFH.Objectives: To assess whether prepubertal androgen concentrations are associated with timing of breast development (analysis 1) and to compare serum androgen concentrations in girls with and without a BCFH (analysis 2).Design, Setting, and Participants: Prospective cohort study of 104 girls aged 6 to 13 years at baseline using data collected between August 16, 2011, and March 24, 2016, from the Lessons in Epidemiology and Genetics of Adult Cancer From Youth (LEGACY) Girls Study, New York site.Exposures: Analysis 1 included serum concentrations of dehydroepiandrosterone sulfate, androstenedione, and testosterone (free and total) measured before breast development and divided at the median into high and low categories. Analysis 2 included the degree of BCFH: first-degree was defined as having a mother with breast cancer and second-degree was defined as having a grandmother or aunt with breast cancer.Main Outcomes and Measures: Analysis 1 included age at onset of breast development measured using the Pubertal Development Scale (scores range from 1-4; scores ?2 indicate breast development), and analysis 2 included serum androgen concentrations. We also assessed breast cancer-specific distress using the 8-item Child Impact of Events Scale.Results: Our analyses included 36 girls for the prospective model, 92 girls for the cross-sectional model, and 104 girls for the longitudinal model. Of the 104 girls, the mean (SD) age at baseline was 10.3 (2.5) years, and 41 (39.4%) were non-Hispanic white, 41 (39.4%) were Hispanic, 13 (12.5%) were non-Hispanic black, and 9 (8.7%) were other race/ethnicity. Forty-two girls (40.4%) had a positive BCFH. Girls with prepubertal androstenedione concentrations above the median began breast development 1.5 years earlier than girls with concentrations below the median (Weibull survival model-estimated median age, 9.4 [95% CI, 9.0-9.8] years vs 10.9 [95% CI, 10.4-11.5] years; P=.001). Similar patterns were observed for dehydroepiandrosterone sulfate (1.1 years earlier: age, 9.6 [95% CI, 9.1-10.1] years vs 10.7 [95% CI, 10.2-11.3] years; P=.009), total testosterone (1.4 years earlier: age, 9.5 [95% CI, 9.1-9.9] years vs 10.9 [95% CI, 10.4-11.5] years; P=.001), and free testosterone (1.1 years earlier: age, 9.7 [95% CI, 9.2-10.1] years vs 10.8 [95% CI, 10.2-11.4] years; P=.01). Compared with girls without BCFH, girls with a first-degree BCFH, but not a second-degree BCFH, had 240% higher androstenedione concentrations (geometric means: no BCFH, 0.49 ng/mL vs first-degree BCFH, 1.8 ng/mL vs second-degree, 1.6 ng/mL; P=.01), 10% higher total testosterone concentrations (12.7 ng/dL vs 14.0 ng/dL vs 13.7 ng/dL; P=.01), and 92% higher free testosterone concentrations (1.3 pg/mL vs 2.5 pg/mL vs 0.3 pg/mL; P=.14). The dehydroepiandrosterone sulfate concentration did not differ between BCFH-positive and BCFH-negative girls but was elevated in girls with breast cancer-specific distress.Conclusions and Relevance: Our findings suggest that androgen concentrations may differ between girls with and without a BCFH and that elevated hormone concentrations during adolescence may be another factor to help explain the familial clustering of breast cancer.

    View details for PubMedID 30794303

  • Association of Prepubertal and Adolescent Androgen Concentrations With Timing of Breast Development and Family History of Breast Cancer JAMA NETWORK OPEN Houghton, L. C., Knight, J. A., Wei, Y., Romeo, R. D., Goldberg, M., Andrulis, I. L., Bradbury, A. R., Buys, S. S., Daly, M. B., John, E. M., Chung, W. K., Santella, R. M., Stanczyk, F. Z., Terry, M. 2019; 2 (2)
  • Shared heritability and functional enrichment across six solid cancers. Nature communications Jiang, X., Finucane, H. K., Schumacher, F. R., Schmit, S. L., Tyrer, J. P., Han, Y., Michailidou, K., Lesseur, C., Kuchenbaecker, K. B., Dennis, J., Conti, D. V., Casey, G., Gaudet, M. M., Huyghe, J. R., Albanes, D., Aldrich, M. C., Andrew, A. S., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Antonenkova, N. N., Arnold, S. M., Aronson, K. J., Arun, B. K., Bandera, E. V., Barkardottir, R. B., Barnes, D. R., Batra, J., Beckmann, M. W., Benitez, J., Benlloch, S., Berchuck, A., Berndt, S. I., Bickeboller, H., Bien, S. A., Blomqvist, C., Boccia, S., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Brauch, H., Brenner, H., Brenton, J. D., Brook, M. N., Brunet, J., Brunnstrom, H., Buchanan, D. D., Burwinkel, B., Butzow, R., Cadoni, G., Caldes, T., Caligo, M. A., Campbell, I., Campbell, P. T., Cancel-Tassin, G., Cannon-Albright, L., Campa, D., Caporaso, N., Carvalho, A. L., Chan, A. T., Chang-Claude, J., Chanock, S. J., Chen, C., Christiani, D. C., Claes, K. B., Claessens, F., Clements, J., Collee, J. M., Correa, M. C., Couch, F. J., Cox, A., Cunningham, J. M., Cybulski, C., Czene, K., Daly, M. B., deFazio, A., Devilee, P., Diez, O., Gago-Dominguez, M., Donovan, J. L., Dork, T., Duell, E. J., Dunning, A. M., Dwek, M., Eccles, D. M., Edlund, C. K., Edwards, D. R., Ellberg, C., Evans, D. G., Fasching, P. A., Ferris, R. L., Liloglou, T., Figueiredo, J. C., Fletcher, O., Fortner, R. T., Fostira, F., Franceschi, S., Friedman, E., Gallinger, S. J., Ganz, P. A., Garber, J., Garcia-Saenz, J. A., Gayther, S. A., Giles, G. G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Goode, E. L., Goodman, M. T., Goodman, G., Grankvist, K., Greene, M. H., Gronberg, H., Gronwald, J., Guenel, P., Hakansson, N., Hall, P., Hamann, U., Hamdy, F. C., Hamilton, R. J., Hampe, J., Haugen, A., Heitz, F., Herrero, R., Hillemanns, P., Hoffmeister, M., Hogdall, E., Hong, Y., Hopper, J. L., Houlston, R., Hulick, P. J., Hunter, D. J., Huntsman, D. G., Idos, G., Imyanitov, E. N., Ingles, S. A., Isaacs, C., Jakubowska, A., James, P., Jenkins, M. A., Johansson, M., Johansson, M., John, E. M., Joshi, A. D., Kaneva, R., Karlan, B. Y., Kelemen, L. E., Kuhl, T., Khaw, K., Khusnutdinova, E., Kibel, A. S., Kiemeney, L. A., Kim, J., Kjaer, S. K., Knight, J. A., Kogevinas, M., Kote-Jarai, Z., Koutros, S., Kristensen, V. N., Kupryjanczyk, J., Lacko, M., Lam, S., Lambrechts, D., Landi, M. T., Lazarus, P., Le, N. D., Lee, E., Lejbkowicz, F., Lenz, H., Leslie, G., Lessel, D., Lester, J., Levine, D. A., Li, L., Li, C. I., Lindblom, A., Lindor, N. M., Liu, G., Loupakis, F., Lubinski, J., Maehle, L., Maier, C., Mannermaa, A., Marchand, L. L., Margolin, S., May, T., McGuffog, L., Meindl, A., Middha, P., Miller, A., Milne, R. L., MacInnis, R. J., Modugno, F., Montagna, M., Moreno, V., Moysich, K. B., Mucci, L., Muir, K., Mulligan, A. M., Nathanson, K. L., Neal, D. E., Ness, A. R., Neuhausen, S. L., Nevanlinna, H., Newcomb, P. A., Newcomb, L. F., Nielsen, F. C., Nikitina-Zake, L., Nordestgaard, B. G., Nussbaum, R. L., Offit, K., Olah, E., Olama, A. A., Olopade, O. I., Olshan, A. F., Olsson, H., Osorio, A., Pandha, H., Park, J. Y., Pashayan, N., Parsons, M. T., Pejovic, T., Penney, K. L., Peters, W. H., Phelan, C. M., Phipps, A. I., Plaseska-Karanfilska, D., Pring, M., Prokofyeva, D., Radice, P., Stefansson, K., Ramus, S. J., Raskin, L., Rennert, G., Rennert, H. S., van Rensburg, E. J., Riggan, M. J., Risch, H. A., Risch, A., Roobol, M. J., Rosenstein, B. S., Rossing, M. A., De Ruyck, K., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schabath, M. B., Schleutker, J., Schmidt, M. K., Setiawan, V. W., Shen, H., Siegel, E. M., Sieh, W., Singer, C. F., Slattery, M. L., Sorensen, K. D., Southey, M. C., Spurdle, A. B., Stanford, J. L., Stevens, V. L., Stintzing, S., Stone, J., Sundfeldt, K., Sutphen, R., Swerdlow, A. J., Tajara, E. H., Tangen, C. M., Tardon, A., Taylor, J. A., Teare, M. D., Teixeira, M. R., Terry, M. B., Terry, K. L., Thibodeau, S. N., Thomassen, M., Bjorge, L., Tischkowitz, M., Toland, A. E., Torres, D., Townsend, P. A., Travis, R. C., Tung, N., Tworoger, S. S., Ulrich, C. M., Usmani, N., Vachon, C. M., Van Nieuwenhuysen, E., Vega, A., Aguado-Barrera, M. E., Wang, Q., Webb, P. M., Weinberg, C. R., Weinstein, S., Weissler, M. C., Weitzel, J. N., West, C. M., White, E., Whittemore, A. S., Wichmann, H., Wiklund, F., Winqvist, R., Wolk, A., Woll, P., Woods, M., Wu, A. H., Wu, X., Yannoukakos, D., Zheng, W., Zienolddiny, S., Ziogas, A., Zorn, K. K., Lane, J. M., Saxena, R., Thomas, D., Hung, R. J., Diergaarde, B., McKay, J., Peters, U., Hsu, L., Garcia-Closas, M., Eeles, R. A., Chenevix-Trench, G., Brennan, P. J., Haiman, C. A., Simard, J., Easton, D. F., Gruber, S. B., Pharoah, P. D., Price, A. L., Pasaniuc, B., Amos, C. I., Kraft, P., Lindstrom, S. 2019; 10 (1): 431

    Abstract

    Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg=0.57, p=4.6*10-8), breast and ovarian cancer (rg=0.24, p=7*10-5), breast and lung cancer (rg=0.18, p=1.5*10-6) and breast and colorectal cancer (rg=0.15, p=1.1*10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

    View details for PubMedID 30683880

  • Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia (vol 9, 1340, 2018) NATURE COMMUNICATIONS Vijayakrishnan, J., Studd, J., Broderick, P., Kinnersley, B., Holroyd, A., Law, P. J., Kumar, R., Allan, J. M., Harrison, C. J., Moorman, A. V., Vora, A., Roman, E., Rachakonda, S., Kinsey, S. E., Sheridan, E., Thompson, P. D., Irving, J. A., Koehler, R., Hoffmann, P., Noethen, M. M., Heilmann-Heimbach, S., Joeckel, K., Easton, D. F., Pharaoh, P. P., Dunning, A. M., Peto, J., Canzian, F., Swerdlow, A., Eeles, R. A., Kote-Jarai, Z., Muir, K., Pashayan, N., Henderson, B. E., Haiman, C. A., Benlloch, S., Schumacher, F. R., Al Olama, A., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Schleutker, J., Albanes, D., Weinstein, S., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Maehle, L., Neal, D. E., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., Greaves, M., Zimmerman, M., Bartram, C. R., Schrappe, M., Stanulla, M., Hemminki, K., Houlston, R. S., PRACTICAL Consortium 2019; 10: 419

    Abstract

    The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

    View details for DOI 10.1038/s41467-018-08106-9

    View details for Web of Science ID 000456165300001

    View details for PubMedID 30664635

    View details for PubMedCentralID PMC6341085

  • Germline variation at 8q24 and prostate cancer risk in men of European ancestry (vol 9, 4616, 2018) NATURE COMMUNICATIONS Matejcic, M., Saunders, E. J., Dadaev, T., Brook, M. N., Wang, K., Sheng, X., Al Olama, A., Schumacher, F. R., Ingles, S. A., Govindasami, K., Benlloch, S., Berndt, S. I., Albanes, D., Koutros, S., Muir, K., Stevens, V. L., Gapstur, S. M., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Pashayan, N., Schleutker, J., Wolk, A., West, C., Mucci, L., Kraft, P., Cancel-Tassin, G., Sorensen, K. D., Maehle, L., Grindedal, E. M., Strom, S. S., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Bensen, J. T., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L. A., Pandha, H., Thibodeau, S. N., Schaid, D. J., Wiklund, F., Chanock, S. J., Easton, D. F., Eeles, R. A., Kote-Jarai, Z., Conti, D. V., Haiman, C. A., Henderson, B. E., Stern, M. C., Thwaites, A., Guy, M., Whitmore, I., Morgan, A., Fisher, C., Hazel, S., Livni, N., Cook, M., Fachal, L., Weinstein, S., Freeman, L., Hoover, R. N., Machiela, M. J., Lophatananon, A., Carter, B. D., Goodman, P., Moya, L., Srinivasan, S., Kedda, M., Yeadon, T., Eckert, A., Eklund, M., Cavalli-Bjoerkman, C., Dunning, A. M., Sipeky, C., Hakansson, N., Elliott, R., Ranu, H., Giovannucci, E., Turman, C., Hunter, D. J., Cussenot, O., Orntoft, T., Lane, A., Lewis, S. J., Davis, M., Key, T. J., Brown, P., Kulkarni, G. S., Zlotta, A. R., Fleshner, N. E., Finelli, A., Mao, X., Marzec, J., MacInnis, R. J., Milne, R., Hopper, J. L., Aguado, M., Bustamante, M., Castano-Vinyals, G., Gracia-Lavedan, E., Cecchini, L., Stampfer, M., Ma, J., Sellers, T. A., Geybels, M. S., Park, H., Zachariah, B., Kolb, S., Wokolorczyk, D., Lubinski, J., Kluzniak, W., Nielsen, S. F., Weisher, M., Cuk, K., Vogel, W., Luedeke, M., Logothetis, C. J., Paulo, P., Cardoso, M., Maia, S., Silva, M. P., Steele, L., Ding, Y., De Meerleer, G., De Langhe, S., Thierens, H., Lim, J., Tan, M. H., Ong, A. T., Lin, D. W., Kachakova, D., Mitkova, A., Mitev, V., Parliament, M., Jenster, G., Bangma, C., Schroder, F. H., Truong, T., Koudou, Y., Michael, A., Kierzek, A., Karlsson, A., Broms, M., Wu, H., Aukim-Hastie, C., Tillmans, L., Riska, S., McDonnell, S. K., Dearnaley, D., Spurdle, A., Gardiner, R., Hayes, V., Butler, L., Taylor, R., Papargiris, M., Saunders, P., Kujala, P., Talala, K., Taari, K., Bentzen, S., Hicks, B., Vogt, A., Hutchinson, A., Cox, A., George, A., Toi, A., Evans, A., van der Kwast, T. H., Imai, T., Saito, S., Zhao, S., Ren, G., Zhang, Y., Yu, Y., Wu, Y., Wu, J., Zhou, B., Pedersen, J., Lobato-Busto, R., Manuel Ruiz-Dominguez, J., Mengual, L., Alcaraz, A., Pow-Sang, J., Herkommer, K., Vlahova, A., Dikov, T., Christova, S., Carracedo, A., Tretarre, B., Rebillard, X., Mulot, C., Adolfsson, J., Stattin, P., Johansson, J., Martin, R. M., Thompson, I. M., Chambers, S., Aitken, J., Horvath, L., Haynes, A., Tilley, W., Risbridger, G., Aly, M., Nordstrom, T., Pharoah, P., Tammela, T. J., Murtola, T., Auvinen, A., Burnet, N., Barnett, G., Andriole, G., Klim, A., Drake, B. F., Borre, M., Kerns, S., Ostrer, H., Zhang, H., Cao, G., Lin, J., Ling, J., Li, M., Feng, N., Li, J., He, W., Guo, X., Sun, Z., Wang, G., Guo, J., Southey, M. C., FitzGerald, L. M., Marsden, G., Gomez-Caamano, A., Carballo, A., Peleteiro, P., Calvo, P., Szulkin, R., Llorca, J., Dierssen-Sotos, T., Gomez-Acebo, I., Lin, H., Ostrander, E. A., Bisbjerg, R., Klarskov, P., Roder, M., Iversen, P., Holleczek, B., Stegmaier, C., Schnoeller, T., Bohnert, P., John, E. M., Ost, P., Teo, S., Gamulin, M., Kulis, T., Kastelan, Z., Slavov, C., Popov, E., Van den Broeck, T., Joniau, S., Larkin, S., Esteban Castelao, J., Martinez, M., van Schaik, R. N., Xu, J., Lindstrom, S., Riboli, E., Berry, C., Siddiq, A., Canzian, F., Kolonel, L. N., Le Marchand, L., Freedman, M., Cenee, S., Sanchez, M., PRACTICAL Consortium 2019; 10: 382

    Abstract

    The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

    View details for PubMedID 30655571

  • Identification of novel common breast cancer risk variants at the 6q25 locusamong Latinas. Breast cancer research : BCR Hoffman, J., Fejerman, L., Hu, D., Huntsman, S., Li, M., John, E. M., Torres-Mejia, G., Kushi, L., Ding, Y. C., Weitzel, J., Neuhausen, S. L., Lott, P., COLUMBUS Consortium, Echeverry, M., Carvajal-Carmona, L., Burchard, E., Eng, C., Long, J., Zheng, W., Olopade, O., Huo, D., Haiman, C., Ziv, E. 2019; 21 (1): 3

    Abstract

    BACKGROUND: Breast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas.METHODS: We performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPsin 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach.RESULTS: We identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p=3.3*10-8 - 6.0*10-9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2>0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70-0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78-0.99; p=0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91-0.97; p=0.0017).CONCLUSION: Our study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.

    View details for PubMedID 30642363

  • Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma (vol 9, 3707, 2018) NATURE COMMUNICATIONS Went, M., Sud, A., Foersti, A., Halvarsson, B., Weinhold, N., Kimber, S., van Duin, M., Thorleifsson, G., Holroyd, A., Johnson, D. C., Li, N., Orlando, G., Law, P. J., Ali, M., Chen, B., Mitchell, J. S., Gudbjartsson, D. F., Kuiper, R., Stephens, O. W., Bertsch, U., Broderick, P., Campo, C., Bandapalli, O. R., Einsele, H., Gregory, W. A., Gullberg, U., Hillengass, J., Hoffmann, P., Jackson, G. H., Joeckel, K., Johnsson, E., Kristinsson, S. Y., Mellqvist, U., Nahi, H., Easton, D., Pharoah, P., Dunning, A., Peto, J., Canzian, F., Swerdlow, A., Eeles, R. A., Kote-Jarai, Z., Muir, K., Pashayan, N., Henderson, B. E., Haiman, C. A., Benlloch, S., Schumacher, F. R., Al Olama, A., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Schleutker, J., Albanes, D., Weinstein, S., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Grindedal, E., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L., Pandha, H., Thibodeau, S. N., Nickel, J., Noethen, M. M., Rafnar, T., Ross, F. M., Filho, M., Thomsen, H., Turesson, I., Vangsted, A., Andersen, N., Waage, A., Walker, B. A., Wihlborg, A., Broyl, A., Davies, F. E., Thorsteinsdottir, U., Langer, C., Hansson, M., Goldschmidt, H., Kaiser, M., Sonneveld, P., Stefansson, K., Morgan, G. J., Hemminki, K., Nilsson, B., Houlston, R. S., PRACTICAL Consortium 2019; 10: 213

    Abstract

    The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

    View details for DOI 10.1038/s41467-018-08107-8

    View details for Web of Science ID 000455355200001

    View details for PubMedID 30631080

    View details for PubMedCentralID PMC6328616

  • Large-scale transcriptome-wide association study identifies new prostate cancer risk regions (vol 9, 4079, 2018) NATURE COMMUNICATIONS Mancuso, N., Gayther, S., Gusev, A., Zheng, W., Penney, K. L., Kote-Jarai, Z., Eeles, R., Freedman, M., Haiman, C., Pasaniuc, B., Henderson, B. E., Benlloch, S., Schumacher, F. R., Al Olama, A., Muir, K., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Pashayan, N., Schleutker, J., Albanes, D., Weinstein, S., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Maehle, L., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L., Pandha, H., Thibodeau, S. N., Hunter, D. J., Kraft, P., PRACTICAL Consortium 2019; 10: 171

    Abstract

    The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, In the original HTML version of this Article, the order of authors within the author list was incorrect. The consortium PRACTICAL consortium was incorrectly listed after Bogdan Pasaniuc and should have been listed after Kathryn L. Penney. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

    View details for DOI 10.1038/s41467-018-08108-7

    View details for Web of Science ID 000455104600002

    View details for PubMedID 30622272

    View details for PubMedCentralID PMC6325152

  • Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nature genetics Schumacher, F. R., Olama, A. A., Berndt, S. I., Benlloch, S., Ahmed, M., Saunders, E. J., Dadaev, T., Leongamornlert, D., Anokian, E., Cieza-Borrella, C., Goh, C., Brook, M. N., Sheng, X., Fachal, L., Dennis, J., Tyrer, J., Muir, K., Lophatananon, A., Stevens, V. L., Gapstur, S. M., Carter, B. D., Tangen, C. M., Goodman, P. J., Thompson, I. M., Batra, J., Chambers, S., Moya, L., Clements, J., Horvath, L., Tilley, W., Risbridger, G. P., Gronberg, H., Aly, M., Nordstrom, T., Pharoah, P., Pashayan, N., Schleutker, J., Tammela, T. L., Sipeky, C., Auvinen, A., Albanes, D., Weinstein, S., Wolk, A., Hakansson, N., West, C. M., Dunning, A. M., Burnet, N., Mucci, L. A., Giovannucci, E., Andriole, G. L., Cussenot, O., Cancel-Tassin, G., Koutros, S., Beane Freeman, L. E., Sorensen, K. D., Orntoft, T. F., Borre, M., Maehle, L., Grindedal, E. M., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Travis, R. C., Key, T. J., Hamilton, R. J., Fleshner, N. E., Finelli, A., Ingles, S. A., Stern, M. C., Rosenstein, B. S., Kerns, S. L., Ostrer, H., Lu, Y., Zhang, H., Feng, N., Mao, X., Guo, X., Wang, G., Sun, Z., Giles, G. G., Southey, M. C., MacInnis, R. J., FitzGerald, L. M., Kibel, A. S., Drake, B. F., Vega, A., Gomez-Caamano, A., Szulkin, R., Eklund, M., Kogevinas, M., Llorca, J., Castano-Vinyals, G., Penney, K. L., Stampfer, M., Park, J. Y., Sellers, T. A., Lin, H., Stanford, J. L., Cybulski, C., Wokolorczyk, D., Lubinski, J., Ostrander, E. A., Geybels, M. S., Nordestgaard, B. G., Nielsen, S. F., Weischer, M., Bisbjerg, R., Roder, M. A., Iversen, P., Brenner, H., Cuk, K., Holleczek, B., Maier, C., Luedeke, M., Schnoeller, T., Kim, J., Logothetis, C. J., John, E. M., Teixeira, M. R., Paulo, P., Cardoso, M., Neuhausen, S. L., Steele, L., Ding, Y. C., De Ruyck, K., De Meerleer, G., Ost, P., Razack, A., Lim, J., Teo, S., Lin, D. W., Newcomb, L. F., Lessel, D., Gamulin, M., Kulis, T., Kaneva, R., Usmani, N., Singhal, S., Slavov, C., Mitev, V., Parliament, M., Claessens, F., Joniau, S., Van den Broeck, T., Larkin, S., Townsend, P. A., Aukim-Hastie, C., Gago-Dominguez, M., Castelao, J. E., Martinez, M. E., Roobol, M. J., Jenster, G., van Schaik, R. H., Menegaux, F., Truong, T., Koudou, Y. A., Xu, J., Khaw, K., Cannon-Albright, L., Pandha, H., Michael, A., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Lindstrom, S., Turman, C., Ma, J., Hunter, D. J., Riboli, E., Siddiq, A., Canzian, F., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Cui, Z., Kraft, P., Amos, C. I., Conti, D. V., Easton, D. F., Wiklund, F., Chanock, S. J., Henderson, B. E., Kote-Jarai, Z., Haiman, C. A., Eeles, R. A., Profile Study, Australian Prostate Cancer BioResource (APCB), IMPACT Study, Canary PASS Investigators, Breast and Prostate Cancer Cohort Consortium (BPC3), PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Cancer of the Prostate in Sweden (CAPS), Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS), Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium 2019

    Abstract

    In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.

    View details for PubMedID 30622367

  • Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility (vol 8, 1892, 2017) NATURE COMMUNICATIONS Sud, A., Thomsen, H., Law, P. J., Foersti, A., Filho, M., Holroyd, A., Broderick, P., Orlando, G., Lenive, O., Wright, L., Cooke, R., Easton, D., Pharoah, P., Dunning, A., Peto, J., Canzian, F., Eeles, R., Kote-Jarai, Z., Muir, K., Pashayan, N., Hoffmann, P., Noethen, M. M., Joeckel, K., von Strandmann, E., Lightfoot, T., Kane, E., Roman, E., Lake, A., Montgomery, D., Jarrett, R. F., Swerdlow, A. J., Engert, A., Orr, N., Hemminki, K., Houlston, R. S., Henderson, B. E., Haiman, C. A., Benlloch, S., Schumacher, F. R., Al Olama, A., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Schleutker, J., Albanes, D., Weinstein, S., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Maehle, L., Neal, D. E., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., PRACTICAL Consortium 2019; 10: 157

    Abstract

    The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

    View details for DOI 10.1038/s41467-018-08105-w

    View details for Web of Science ID 000455103700001

    View details for PubMedID 30622283

    View details for PubMedCentralID PMC6325156

  • Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes AMERICAN JOURNAL OF HUMAN GENETICS Mavaddat, N., Michailidou, K., Dennis, J., Lush, M., Fachal, L., Lee, A., Tyrer, J. P., Chen, T., Wang, Q., Bolla, M. K., Yang, X., Adank, M. A., Ahearn, T., Aittomaki, K., Allen, J., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Auer, P. L., Auvinen, P., Barrdahl, M., Freeman, L., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Bogdanova, N., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brauch, H., Bremer, M., Brenner, H., Brentnall, A., Brock, I. W., Brooks-Wilson, A., Brucker, S. Y., Bruening, T., Burwinkel, B., Campa, D., Carter, B. D., Castelao, J. E., Chanock, S. J., Chlebowski, R., Christiansen, H., Clarke, C. L., Collee, J., Cordina-Duverger, E., Cornelissen, S., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Doerk, T., dos-Santos-Silva, I., Dumont, M., Durcan, L., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A., Ellberg, C., Engel, C., Eriksson, M., Evans, D., Fasching, P. A., Figueroa, J., Fletcher, O., Flyger, H., Foersti, A., Fritschi, L., Gabrielson, M., Gago-Dominguez, M., Gapstur, S. M., Garcia-Saenz, J. A., Gaudet, M. M., Georgoulias, V., Giles, G. G., Gilyazova, I. R., Glendon, G., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Alnaes, G., Grip, M., Gronwald, J., Grundy, A., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hamann, U., Hankinson, S. E., Harkness, E. F., Hart, S. N., He, W., Hein, A., Heyworth, J., Hillemanns, P., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Howell, A., Huang, G., Humphreys, K., Hunter, D. J., Jakimovska, M., Jakubowska, A., Janni, W., John, E. M., Johnson, N., Jones, M. E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kaczmarek, K., Kataja, V., Keeman, R., Kerin, M. J., Khusnutdinova, E., Kiiski, J., Knight, J. A., Ko, Y., Kosma, V., Koutros, S., Kristensen, V. N., Kruger, U., Kuehl, T., Lambrechts, D., Le Marchand, L., Lee, E., Lejbkowicz, F., Lilyquist, J., Lindblom, A., Lindstrom, S., Lissowska, J., Lo, W., Loibl, S., Long, J., Lubinski, J., Lux, M. P., MacInnis, R. J., Maishman, T., Makalic, E., Kostovska, I., Mannermaa, A., Manoukian, S., Margolin, S., Martens, J. M., Martinez, M., Mavroudis, D., McLean, C., Meindl, A., Menon, U., Middha, P., Miller, N., Moreno, F., Mulligan, A., Mulot, C., Munoz-Garzon, V. M., Neuhausen, S. L., Nevanlinna, H., Neven, P., Newman, W. G., Nielsen, S. F., Nordestgaard, B. G., Norman, A., Offit, K., Olson, J. E., Olsson, H., Orr, N., Pankratz, V., Park-Simon, T., Perez, J. A., Perez-Barrios, C., Peterlongo, P., Peto, J., Pinchev, M., Plaseska-Karanfilska, D., Polley, E. C., Prentice, R., Presneau, N., Prokofyeva, D., Purrington, K., Pylkas, K., Rack, B., Radice, P., Rau-Murthy, R., Rennert, G., Rennert, H. S., Rhenius, V., Robson, M., Romero, A., Ruddy, K. J., Ruebner, M., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schumacher, F., Schuermann, P., Schwentner, L., Scott, C., Scott, R. J., Seynaeve, C., Shah, M., Sherman, M. E., Shrubsole, M. J., Shu, X., Slager, S., Smeets, A., Sohn, C., Soucy, P., Southey, M. C., Spinelli, J. J., Stegmaier, C., Stone, J., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Terry, M., Thoene, K., Tollenaar, R. M., Tomlinson, I., Truong, T., Tzardi, M., Ulmer, H., Untch, M., Vachon, C. M., van Veen, E. M., Vijai, J., Weinberg, C. R., Wendt, C., Whittemore, A. S., Wildiers, H., Willett, W., Winqvist, R., Wolk, A., Yang, X. R., Yannoukakos, D., Zhang, Y., Zheng, W., Ziogas, A., Clarke, C., Balleine, R., Baxter, R., Braye, S., Carpenter, J., Dahlstrom, J., Forbes, J., Lee, C., Marsh, D., Morey, A., Pathmanathan, N., Scott, R., Simpson, P., Spigelman, A., Wilcken, N., Yip, D., Zeps, N., Sexton, A., Dobrovic, A., Christian, A., Trainer, A., Fellows, A., Shelling, A., De Fazio, A., Blackburn, A., Crook, A., Meiser, B., Patterson, B., Clarke, C., Saunders, C., Hunt, C., Scott, C., Amor, D., Ortega, D., Marsh, D., Edkins, E., Salisbury, E., Haan, E., Macrea, F., Farshid, G., Lindeman, G., Trench, G., Mann, G., Giles, G., Gill, G., Thorne, H., Campbell, I., Hickie, I., Caldon, L., Winship, I., Cui, J., Flanagan, J., Kollias, J., Visvader, J., Taylor, J., Burke, J., Saunus, J., Forbs, J., Hopper, J., Beesley, J., Kirk, J., French, J., Tucker, K., Wu, K., Phillips, K., Forrest, L., Lipton, L., Andrews, L., Lobb, L., Walker, L., Kentwell, M., Spurdle, M., Cummings, M., Gleeson, M., Harris, M., Jenkins, M., Young, M., Delatycki, M., Wallis, M., Burgess, M., Brown, M., Southey, M., Bogwitz, M., Field, M., Friedlander, M., Gattas, M., Saleh, M., Aghmesheh, M., Hayward, N., Pachter, N., Cohen, P., Duijf, P., James, P., Simpson, P., Fong, P., Butow, P., Williams, R., Kefford, R., Simard, J., Balleine, R., Dawson, S., Lok, S., O'connell, S., Greening, S., Nightingale, S., Edwards, S., Fox, S., McLachlan, S., Lakhani, S., Dudding, T., Antill, Y., Sahlberg, K. K., Ottestad, L., Karesen, R., Schlichting, E., Holmen, M., Sauer, T., Haakensen, V., Engebraten, O., Naume, B., Fossa, A., Kiserud, C. E., Reinertsen, K., Helland, A., Riis, M., Geisler, J., Dunning, A. M., Thompson, D. J., Chenevix-Trench, G., Chang-Claude, J., Schmidt, M. K., Hall, P., Milne, R. L., Pharoah, P. P., Antoniou, A. C., Chatterjee, N., Kraft, P., Garcia-Closas, M., Easton, D. F., ABCTB Investigators, kConFab AOCS Investigators, NBCS Collaborators 2019; 104 (1): 21?34
  • Identification of novel susceptibility loci and genes for prostate cancer risk: A transcriptome-wide association study in over 140,000 European descendants. Cancer research Wu, L., Wang, J., Cai, Q., Cavazos, T. B., Emami, N. C., Long, J., Shu, X. O., Lu, Y., Guo, X., Bauer, J. A., Pasaniuc, B., Penney, K. L., Freedman, M. L., Kote-Jarai, Z., Witte, J. S., Haiman, C. A., Eeles, R. A., Zheng, W. 2019

    Abstract

    Genome-wide association studies have identified genetic variants associated with prostate cancer risk. However, these variants explain only a small fraction of the heritable component of prostate cancer risk, and the genes responsible for many of the identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61×10-6, a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61×10-6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology.

    View details for DOI 10.1158/0008-5472.CAN-18-3536

    View details for PubMedID 31101764

  • A Pooled Analysis of Breastfeeding and Breast Cancer Risk by Hormone Receptor Status in Parous Hispanic Women. Epidemiology (Cambridge, Mass.) Sangaramoorthy, M., Hines, L. M., Torres-Mejía, G., Phipps, A. I., Baumgartner, K. B., Wu, A. H., Koo, J., Ingles, S. A., Slattery, M. L., John, E. M. 2019; 30 (3): 449?57

    Abstract

    Data on breastfeeding and breast cancer risk are sparse and inconsistent for Hispanic women.Pooling data for nearly 6,000 parous Hispanic women from four population-based studies conducted between 1995 and 2007 in the United States and Mexico, we examined the association of breastfeeding with risk of breast cancer overall and subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status, and the joint effects of breastfeeding, parity, and age at first birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression.Among parous Hispanic women, older age at first birth was associated with increased breast cancer risk, whereas parity was associated with reduced risk. These associations were found for hormone receptor positive (HR+) breast cancer only and limited to premenopausal women. Age at first birth and parity were not associated with risk of ER- and PR- breast cancer. Increasing duration of breastfeeding was associated with decreasing breast cancer risk (?25 vs. 0 months: OR = 0.73; 95% CI = 0.60, 0.89; Ptrend = 0.03), with no heterogeneity by menopausal status or subtype. At each parity level, breastfeeding further reduced HR+ breast cancer risk. Additionally, breastfeeding attenuated the increase in risk of HR+ breast cancer associated with older age at first birth.Our findings suggest that breastfeeding is associated with reduced risk of both HR+ and ER- and PR- breast cancer among Hispanic women, as reported for other populations, and may attenuate the increased risk in women with a first pregnancy at older ages.

    View details for PubMedID 30964816

    View details for PubMedCentralID PMC6472273

  • Regular use of aspirin and other non-steroidal anti-inflammatory drugs and breast cancer risk for women at familial or genetic risk: a cohort study. Breast cancer research : BCR Kehm, R. D., Hopper, J. L., John, E. M., Phillips, K. A., MacInnis, R. J., Dite, G. S., Milne, R. L., Liao, Y., Zeinomar, N., Knight, J. A., Southey, M. C., Vahdat, L., Kornhauser, N., Cigler, T., Chung, W. K., Giles, G. G., McLachlan, S. A., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., Andrulis, I. L., Buys, S. S., Daly, M. B., Terry, M. B. 2019; 21 (1): 52

    Abstract

    The use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced breast cancer risk, but it is not known if this association extends to women at familial or genetic risk. We examined the association between regular NSAID use and breast cancer risk using a large cohort of women selected for breast cancer family history, including 1054 BRCA1 or BRCA2 mutation carriers.We analyzed a prospective cohort (N =?5606) and a larger combined, retrospective and prospective, cohort (N =?8233) of women who were aged 18 to 79?years, enrolled before June 30, 2011, with follow-up questionnaire data on medication history. The prospective cohort was further restricted to women without breast cancer when medication history was asked by questionnaire. Women were recruited from seven study centers in the United States, Canada, and Australia. Associations were estimated using multivariable Cox proportional hazards regression models adjusted for demographics, lifestyle factors, family history, and other medication use. Women were classified as regular or non-regular users of aspirin, COX-2 inhibitors, ibuprofen and other NSAIDs, and acetaminophen (control) based on self-report at follow-up of ever using the medication for at least twice a week for ?1?month prior to breast cancer diagnosis. The main outcome was incident invasive breast cancer, based on self- or relative-report (81% confirmed pathologically).From fully adjusted analyses, regular aspirin use was associated with a 39% and 37% reduced risk of breast cancer in the prospective (HR?=?0.61; 95% CI?=?0.33-1.14) and combined cohorts (HR?=?0.63; 95% CI?=?0.57-0.71), respectively. Regular use of COX-2 inhibitors was associated with a 61% and 71% reduced risk of breast cancer (prospective HR?=?0.39; 95% CI?=?0.15-0.97; combined HR?=?0.29; 95% CI?=?0.23-0.38). Other NSAIDs and acetaminophen were not associated with breast cancer risk in either cohort. Associations were not modified by familial risk, and consistent patterns were found by BRCA1 and BRCA2 carrier status, estrogen receptor status, and attained age.Regular use of aspirin and COX-2 inhibitors might reduce breast cancer risk for women at familial or genetic risk.

    View details for PubMedID 30999962

  • The functional ALDH2 polymorphism is associated with breast cancer risk: A pooled analysis from the Breast Cancer Association Consortium. Molecular genetics & genomic medicine Ugai, T., Milne, R. L., Ito, H., Aronson, K. J., Bolla, M. K., Chan, T., Chan, C. W., Choi, J. Y., Conroy, D. M., Dennis, J., Dunning, A. M., Easton, D. F., Gaborieau, V., Gonzalez-Neira, A., Hartman, M., Healey, C. S., Iwasaki, M., John, E. M., Kang, D., Kim, S. W., Kwong, A., Lophatananon, A., Michailidou, K., Taib, N. A., Muir, K., Park, S. K., Pharoah, P. D., Sangrajrang, S., Shen, C. Y., Shu, X. O., Spinelli, J. J., Teo, S. H., Tessier, D. C., Tseng, C. C., Tsugane, S., Vincent, D., Wang, Q., Wu, A. H., Wu, P. E., Zheng, W., Matsuo, K. 2019: e707

    Abstract

    Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium.We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models.The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537).This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.

    View details for PubMedID 31066241

  • Two truncating variants in FANCC and breast cancer risk. Scientific reports Dörk, T., Peterlongo, P., Mannermaa, A., Bolla, M. K., Wang, Q., Dennis, J., Ahearn, T., Andrulis, I. L., Anton-Culver, H., Arndt, V., Aronson, K. J., Augustinsson, A., Freeman, L. E., Beckmann, M. W., Beeghly-Fadiel, A., Behrens, S., Bermisheva, M., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Brauch, H., Brenner, H., Burwinkel, B., Canzian, F., Chan, T. L., Chang-Claude, J., Chanock, S. J., Choi, J. Y., Christiansen, H., Clarke, C. L., Couch, F. J., Czene, K., Daly, M. B., Dos-Santos-Silva, I., Dwek, M., Eccles, D. M., Ekici, A. B., Eriksson, M., Evans, D. G., Fasching, P. A., Figueroa, J., Flyger, H., Fritschi, L., Gabrielson, M., Gago-Dominguez, M., Gao, C., Gapstur, S. M., García-Closas, M., García-Sáenz, J. A., Gaudet, M. M., Giles, G. G., Goldberg, M. S., Goldgar, D. E., Guénel, P., Haeberle, L., Haiman, C. A., Hĺkansson, N., Hall, P., Hamann, U., Hartman, M., Hauke, J., Hein, A., Hillemanns, P., Hogervorst, F. B., Hooning, M. J., Hopper, J. L., Howell, T., Huo, D., Ito, H., Iwasaki, M., Jakubowska, A., Janni, W., John, E. M., Jung, A., Kaaks, R., Kang, D., Kapoor, P. M., Khusnutdinova, E., Kim, S. W., Kitahara, C. M., Koutros, S., Kraft, P., Kristensen, V. N., Kwong, A., Lambrechts, D., Marchand, L. L., Li, J., Lindström, S., Linet, M., Lo, W. Y., Long, J., Lophatananon, A., Lubi?ski, J., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, E., Matsuo, K., Mavroudis, D., Meindl, A., Menon, U., Milne, R. L., Mohd Taib, N. A., Muir, K., Mulligan, A. M., Neuhausen, S. L., Nevanlinna, H., Neven, P., Newman, W. G., Offit, K., Olopade, O. I., Olshan, A. F., Olson, J. E., Olsson, H., Park, S. K., Park-Simon, T. W., Peto, J., Plaseska-Karanfilska, D., Pohl-Rescigno, E., Presneau, N., Rack, B., Radice, P., Rashid, M. U., Rennert, G., Rennert, H. S., Romero, A., Ruebner, M., Saloustros, E., Schmidt, M. K., Schmutzler, R. K., Schneider, M. O., Schoemaker, M. J., Scott, C., Shen, C. Y., Shu, X. O., Simard, J., Slager, S., Smichkoska, S., Southey, M. C., Spinelli, J. J., Stone, J., Surowy, H., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Teo, S. H., Terry, M. B., Toland, A. E., Tollenaar, R. A., Torres, D., Torres-Mejía, G., Troester, M. A., Truong, T., Tsugane, S., Untch, M., Vachon, C. M., Ouweland, A. M., Veen, E. M., Vijai, J., Wendt, C., Wolk, A., Yu, J. C., Zheng, W., Ziogas, A., Ziv, E., Dunning, A. M., Pharoah, P. D., Schindler, D., Devilee, P., Easton, D. F. 2019; 9 (1): 12524

    Abstract

    Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p?=?0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

    View details for DOI 10.1038/s41598-019-48804-y

    View details for PubMedID 31467304

  • Association of a Pathway-Specific Genetic Risk Score With Risk of Radiation-Associated Contralateral Breast Cancer. JAMA network open Watt, G. P., Reiner, A. S., Smith, S. A., Stram, D. O., Capanu, M., Malone, K. E., Lynch, C. F., John, E. M., Knight, J. A., Mellemkjćr, L., Bernstein, L., Brooks, J. D., Woods, M., Liang, X., Haile, R. W., Riaz, N., Conti, D. V., Robson, M., Duggan, D., Boice, J. D., Shore, R. E., Tischkowitz, M., Orlow, I., Thomas, D. C., Concannon, P., Bernstein, J. L. 2019; 2 (9): e1912259

    Abstract

    Radiation therapy for breast cancer is associated with increased risk of a second primary contralateral breast cancer, but the genetic factors modifying this association are not well understood.To determine whether a genetic risk score comprising single nucleotide polymorphisms in the nonhomologous end-joining DNA repair pathway is associated with radiation-associated contralateral breast cancer.This case-control study included a case group of women with contralateral breast cancer that was diagnosed at least 1 year after a first primary breast cancer who were individually matched to a control group of women with unilateral breast cancer. Inclusion criteria were receiving a first invasive breast cancer diagnosis prior to age 55 years between 1985 and 2008. Women were recruited through 8 population-based cancer registries in the United States, Canada, and Denmark as part of the Women's Environment, Cancer, and Radiation Epidemiology Studies I (November 2000 to August 2004) and II (March 2010 to December 2012). Data analysis was conducted from July 2017 to August 2019.Stray radiation dose to the contralateral breast during radiation therapy for the first breast cancer. A novel genetic risk score comprised of genetic variants in the nonhomologous end-joining DNA repair pathway was considered the potential effect modifier, dichotomized as high risk if the score was above the median of 74 and low risk if the score was at or below the median.The main outcome was risk of contralateral breast cancer associated with stray radiation dose stratified by genetic risk score, age, and latency.A total of 5953 women were approached for study participation, and 3732 women (62.7%) agreed to participate. The median (range) age at first diagnosis was 46 (23-54) years. After 5 years of latency or more, among women who received the first diagnosis when they were younger than 40 years, exposure to 1.0 Gy (to convert to rad, multiply by 100) or more of stray radiation was associated with a 2-fold increased risk of contralateral breast cancer compared with women who were not exposed (rate ratio, 2.0 [95% CI, 1.1-3.6]). The risk was higher among women with a genetic risk score above the median (rate ratio, 3.0 [95% CI, 1.1-8.1]), and there was no association among women with a genetic risk score below the median (rate ratio, 1.3 [95% CI, 0.5-3.7]). Among younger women with a high genetic risk score, the attributable increased risk for contralateral breast cancer associated with stray radiation dose was 28%.This study found an increased risk of contralateral breast cancer that was attributable to stray radiation exposure among women with a high genetic risk score and who received a first breast cancer diagnosis when they were younger than 40 years after 5 years or more of latency. This genetic risk score may help guide treatment and surveillance for women with breast cancer.

    View details for DOI 10.1001/jamanetworkopen.2019.12259

    View details for PubMedID 31560388

  • Publisher Correction: Shared heritability and functional enrichment across six solid cancers. Nature communications Jiang, X., Finucane, H. K., Schumacher, F. R., Schmit, S. L., Tyrer, J. P., Han, Y., Michailidou, K., Lesseur, C., Kuchenbaecker, K. B., Dennis, J., Conti, D. V., Casey, G., Gaudet, M. M., Huyghe, J. R., Albanes, D., Aldrich, M. C., Andrew, A. S., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Antonenkova, N. N., Arnold, S. M., Aronson, K. J., Arun, B. K., Bandera, E. V., Barkardottir, R. B., Barnes, D. R., Batra, J., Beckmann, M. W., Benitez, J., Benlloch, S., Berchuck, A., Berndt, S. I., Bickeböller, H., Bien, S. A., Blomqvist, C., Boccia, S., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Brauch, H., Brenner, H., Brenton, J. D., Brook, M. N., Brunet, J., Brunnström, H., Buchanan, D. D., Burwinkel, B., Butzow, R., Cadoni, G., Caldés, T., Caligo, M. A., Campbell, I., Campbell, P. T., Cancel-Tassin, G., Cannon-Albright, L., Campa, D., Caporaso, N., Carvalho, A. L., Chan, A. T., Chang-Claude, J., Chanock, S. J., Chen, C., Christiani, D. C., Claes, K. B., Claessens, F., Clements, J., Collée, J. M., Correa, M. C., Couch, F. J., Cox, A., Cunningham, J. M., Cybulski, C., Czene, K., Daly, M. B., deFazio, A., Devilee, P., Diez, O., Gago-Dominguez, M., Donovan, J. L., Dörk, T., Duell, E. J., Dunning, A. M., Dwek, M., Eccles, D. M., Edlund, C. K., Edwards, D. R., Ellberg, C., Evans, D. G., Fasching, P. A., Ferris, R. L., Liloglou, T., Figueiredo, J. C., Fletcher, O., Fortner, R. T., Fostira, F., Franceschi, S., Friedman, E., Gallinger, S. J., Ganz, P. A., Garber, J., García-Sáenz, J. A., Gayther, S. A., Giles, G. G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Goode, E. L., Goodman, M. T., Goodman, G., Grankvist, K., Greene, M. H., Gronberg, H., Gronwald, J., Guénel, P., Hĺkansson, N., Hall, P., Hamann, U., Hamdy, F. C., Hamilton, R. J., Hampe, J., Haugen, A., Heitz, F., Herrero, R., Hillemanns, P., Hoffmeister, M., Hřgdall, E., Hong, Y. C., Hopper, J. L., Houlston, R., Hulick, P. J., Hunter, D. J., Huntsman, D. G., Idos, G., Imyanitov, E. N., Ingles, S. A., Isaacs, C., Jakubowska, A., James, P., Jenkins, M. A., Johansson, M., Johansson, M., John, E. M., Joshi, A. D., Kaneva, R., Karlan, B. Y., Kelemen, L. E., Kühl, T., Khaw, K. T., Khusnutdinova, E., Kibel, A. S., Kiemeney, L. A., Kim, J., Kjaer, S. K., Knight, J. A., Kogevinas, M., Kote-Jarai, Z., Koutros, S., Kristensen, V. N., Kupryjanczyk, J., Lacko, M., Lam, S., Lambrechts, D., Landi, M. T., Lazarus, P., Le, N. D., Lee, E., Lejbkowicz, F., Lenz, H. J., Leslie, G., Lessel, D., Lester, J., Levine, D. A., Li, L., Li, C. I., Lindblom, A., Lindor, N. M., Liu, G., Loupakis, F., Lubi?ski, J., Maehle, L., Maier, C., Mannermaa, A., Marchand, L. L., Margolin, S., May, T., McGuffog, L., Meindl, A., Middha, P., Miller, A., Milne, R. L., MacInnis, R. J., Modugno, F., Montagna, M., Moreno, V., Moysich, K. B., Mucci, L., Muir, K., Mulligan, A. M., Nathanson, K. L., Neal, D. E., Ness, A. R., Neuhausen, S. L., Nevanlinna, H., Newcomb, P. A., Newcomb, L. F., Nielsen, F. C., Nikitina-Zake, L., Nordestgaard, B. G., Nussbaum, R. L., Offit, K., Olah, E., Olama, A. A., Olopade, O. I., Olshan, A. F., Olsson, H., Osorio, A., Pandha, H., Park, J. Y., Pashayan, N., Parsons, M. T., Pejovic, T., Penney, K. L., Peters, W. H., Phelan, C. M., Phipps, A. I., Plaseska-Karanfilska, D., Pring, M., Prokofyeva, D., Radice, P., Stefansson, K., Ramus, S. J., Raskin, L., Rennert, G., Rennert, H. S., van Rensburg, E. J., Riggan, M. J., Risch, H. A., Risch, A., Roobol, M. J., Rosenstein, B. S., Rossing, M. A., De Ruyck, K., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schabath, M. B., Schleutker, J., Schmidt, M. K., Setiawan, V. W., Shen, H., Siegel, E. M., Sieh, W., Singer, C. F., Slattery, M. L., Sorensen, K. D., Southey, M. C., Spurdle, A. B., Stanford, J. L., Stevens, V. L., Stintzing, S., Stone, J., Sundfeldt, K., Sutphen, R., Swerdlow, A. J., Tajara, E. H., Tangen, C. M., Tardon, A., Taylor, J. A., Teare, M. D., Teixeira, M. R., Terry, M. B., Terry, K. L., Thibodeau, S. N., Thomassen, M., Bjřrge, L., Tischkowitz, M., Toland, A. E., Torres, D., Townsend, P. A., Travis, R. C., Tung, N., Tworoger, S. S., Ulrich, C. M., Usmani, N., Vachon, C. M., Van Nieuwenhuysen, E., Vega, A., Aguado-Barrera, M. E., Wang, Q., Webb, P. M., Weinberg, C. R., Weinstein, S., Weissler, M. C., Weitzel, J. N., West, C. M., White, E., Whittemore, A. S., Wichmann, H. E., Wiklund, F., Winqvist, R., Wolk, A., Woll, P., Woods, M., Wu, A. H., Wu, X., Yannoukakos, D., Zheng, W., Zienolddiny, S., Ziogas, A., Zorn, K. K., Lane, J. M., Saxena, R., Thomas, D., Hung, R. J., Diergaarde, B., McKay, J., Peters, U., Hsu, L., García-Closas, M., Eeles, R. A., Chenevix-Trench, G., Brennan, P. J., Haiman, C. A., Simard, J., Easton, D. F., Gruber, S. B., Pharoah, P. D., Price, A. L., Pasaniuc, B., Amos, C. I., Kraft, P., Lindström, S. 2019; 10 (1): 4386

    Abstract

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    View details for DOI 10.1038/s41467-019-12095-8

    View details for PubMedID 31548585

  • Estrogenic activity, race/ethnicity, and Indigenous American ancestry among San Francisco Bay Area women. PloS one Sanchez, S. S., Tachachartvanich, P., Stanczyk, F. Z., Gomez, S. L., John, E. M., Smith, M. T., Fejerman, L. 2019; 14 (3): e0213809

    Abstract

    Estrogens play a significant role in breast cancer development and are not only produced endogenously, but are also mimicked by estrogen-like compounds from environmental exposures. We evaluated associations between estrogenic (E) activity, demographic factors and breast cancer risk factors in Non-Latina Black (NLB), Non-Latina White (NLW), and Latina women. We examined the association between E activity and Indigenous American (IA) ancestry in Latina women. Total E activity was measured with a bioassay in plasma samples of 503 women who served as controls in the San Francisco Bay Area Breast Cancer Study. In the univariate model that included all women with race/ethnicity as the independent predictor, Latinas had 13% lower E activity (p = 0.239) and NLBs had 35% higher activity (p = 0.04) compared to NLWs. In the multivariable model that adjusted for demographic factors, Latinas continued to show lower E activity levels (26%, p = 0.026), but the difference between NLBs and NLWs was no longer statistically significant (p = 0.431). An inverse association was observed between E activity and IA ancestry among Latina women (50% lower in 0% vs. 100% European ancestry, p = 0.027) consistent with our previously reported association between IA ancestry and breast cancer risk. These findings suggest that endogenous estrogens and exogenous estrogen-like compounds that act on the estrogen receptor and modulate E activity may partially explain racial/ethnic differences in breast cancer risk.

    View details for DOI 10.1371/journal.pone.0213809

    View details for PubMedID 30908519

  • Considerations when using breast cancer risk models for women with negative BRCA1/BRCA2 mutation results. Journal of the National Cancer Institute MacInnis, R. J., Liao, Y., Knight, J. A., Milne, R. L., Whittemore, A. S., Chung, W. K., Leoce, N., Buchsbaum, R., Zeinomar, N., Dite, G. S., Southey, M. C., Goldgar, D., Giles, G. G., McLachlan, S. A., Weideman, P. C., Nesci, S., Friedlander, M. L., Glendon, G., Andrulis, I. L., John, E. M., Daly, M. B., Buys, S. S., Phillips, K. A., Hopper, J. L., Terry, M. B. 2019

    Abstract

    The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14,657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (BOADICEA, BRCAPRO and IBIS). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models under-predicted risk by 26.3-56.7% for women who tested negative but whose relatives had not been tested (N?=?1,363; 63 breast cancers). While replication studies with larger sample sizes are needed, until these models are re-calibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models.

    View details for DOI 10.1093/jnci/djz194

    View details for PubMedID 31584660

  • Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Adams, C. D., Richmond, R., Ferreira, D., Spiller, W., Tan, V., Zheng, J., Wurtz, P., Donovan, J., Hamdy, F., Neal, D., Lane, J., Smith, G., Relton, C., Eeles, R. A., Haiman, C. A., Kote-Jarai, Z. S., Schumacher, F. R., Al Olama, A., Benlloch, S., Muir, K., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S. J., Gapstur, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J. A., Gronberg, H., Pashayan, N., Schleutker, J., Albanes, D., Wolk, A., West, C. L., Mucci, L. A., Cancel-Tassin, G., Koutros, S., Sorensen, K., Maehle, L., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B. S., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R. P., Usmani, N., Claessens, F., Townsend, P. A., Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L. A., Pandha, H., Thibodeau, S. N., Martin, R. M., PRACTICAL Consortium 2019; 28 (1): 208?16
  • Assessing patient readiness for personalized genomic medicine. Journal of community genetics Frost, C. J., Andrulis, I. L., Buys, S. S., Hopper, J. L., John, E. M., Terry, M. B., Bradbury, A., Chung, W. K., Colbath, K., Quintana, N., Gamarra, E., Egleston, B., Galpern, N., Bealin, L., Glendon, G., Miller, L. P., Daly, M. B. 2019; 10 (1): 109?20

    Abstract

    The Human Genome Project and the continuing advances in DNA sequencing technology have ushered in a new era in genomic medicine. Successful translation of genomic medicine into clinical care will require that providers of this information are aware of the level of understanding, attitudes, perceived risks, benefits, and concerns of their patients. We used a mixed methods approach to conduct in-depth interviews with participants in the NCI-funded Breast Cancer Family Registry (BCFR). Our goal was to gain a better understanding of attitudes towards different types and amounts of genomic information, current interest in pursuing genomic testing, and perceived risks and benefits. We interviewed 32 women from the six BCFR sites in the USA, Canada, and Australia. In this sample of women with a personal or family history of breast cancer, we found high acknowledgement of the potential of genetics/genomics to improve their own health and that of their family members through lifestyle changes or alterations in their medical management. Respondents were more familiar with cancer genetics than the genetics of other diseases. Concerns about the testing itself included a potential sense of loss of control over health, feelings of guilt on passing on a mutation to a child, loss of privacy and confidentiality, questions about the test accuracy, and the potential uncertainty of the significance of test results. These data provide important insights into attitudes about the introduction of increasingly complex genetic testing, to inform interventions to prepare individuals for the introduction of this new technology into their clinical care.

    View details for PubMedID 29804257

    View details for PubMedCentralID PMC6325047

  • Race/ethnicity and accuracy of self-reported female first-degree family history of breast and other cancers in the Northern California Breast Cancer Family Registry. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology John, E. M., Canchola, A. J., Sanagaramoorthy, M., Koo, J., Whittemore, A. S., West, D. W. 2019

    Abstract

    Few studies have evaluated accuracy of self-reported family history of breast and other cancers in racial/ethnic minorities.We assessed the accuracy of cancer family history reports by women with breast cancer (probands) from the Northern California Breast Cancer Family Registry compared to two reference standards: personal cancer history reports by female first-degree relatives and California Cancer Registry records.Probands reported breast cancer in first-degree relatives with high accuracy, but accuracy was lower for other cancers. Sensitivity (% correctly identifying relatives with cancer) was 93% (95% CI, 89.5-95.4) when compared to the relatives' self-report of breast cancer as the reference standard and varied little by proband race/ethnicity and other demographic factors, except for marginally lower sensitivity for Hispanic white probands (87.3%, 95% CI, 78.0-93.1, P=0.07) than non-Hispanic white probands (95.1%, 95% CI=88.9-98.0). Accuracy was also high when compared to cancer registry records as the reference standard, with a sensitivity of 95.5% (95% CI, 93.4-96.9) for breast cancer, but lower sensitivity for Hispanic white probands (91.2%, 95% CI, 84.4-95.2, P=0.05) and probands with low English language proficiency (80%, 95% CI, 52.8-93.5, P <0.01).Non-Hispanic white, African American, and Asian American probands reported first-degree breast cancer family history with high accuracy, although sensitivity was lower for Hispanic white probands and those with low English language proficiency.Self-reported family history of breast cancer in first-degree relatives is highly accurate and can be used as a reliable standard when other validation methods are not available.

    View details for DOI 10.1158/1055-9965.EPI-19-0444

    View details for PubMedID 31488412

  • Surveillance of cancer among sexual and gender minority populations: Where are we and where do we need to go? Cancer Gomez, S. L., Duffy, C., Griggs, J. J., John, E. M. 2019

    View details for DOI 10.1002/cncr.32384

    View details for PubMedID 31593334

  • The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer. NPJ breast cancer Figlioli, G., Bogliolo, M., Catucci, I., Caleca, L., Lasheras, S. V., Pujol, R., Kiiski, J. I., Muranen, T. A., Barnes, D. R., Dennis, J., Michailidou, K., Bolla, M. K., Leslie, G., Aalfs, C. M., ABCTB Investigators, Adank, M. A., Adlard, J., Agata, S., Cadoo, K., Agnarsson, B. A., Ahearn, T., Aittomaki, K., Ambrosone, C. B., Andrews, L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Arnold, N., Aronson, K. J., Arun, B. K., Asseryanis, E., Auber, B., Auvinen, P., Azzollini, J., Balmana, J., Barkardottir, R. B., Barrowdale, D., Barwell, J., Beane Freeman, L. E., Beauparlant, C. J., Beckmann, M. W., Behrens, S., Benitez, J., Berger, R., Bermisheva, M., Blanco, A. M., Blomqvist, C., Bogdanova, N. V., Bojesen, A., Bojesen, S. E., Bonanni, B., Borg, A., Brady, A. F., Brauch, H., Brenner, H., Bruning, T., Burwinkel, B., Buys, S. S., Caldes, T., Caliebe, A., Caligo, M. A., Campa, D., Campbell, I. G., Canzian, F., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Claes, K. B., Clarke, C. L., Collavoli, A., Conner, T. A., Cox, D. G., Cybulski, C., Czene, K., Daly, M. B., de la Hoya, M., Devilee, P., Diez, O., Ding, Y. C., Dite, G. S., Ditsch, N., Domchek, S. M., Dorfling, C. M., Dos-Santos-Silva, I., Durda, K., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A. H., Ellberg, C., Eriksson, M., Evans, D. G., Fasching, P. A., Figueroa, J., Flyger, H., Foulkes, W. D., Friebel, T. M., Friedman, E., Gabrielson, M., Gaddam, P., Gago-Dominguez, M., Gao, C., Gapstur, S. M., Garber, J., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., Gayther, S. A., GEMO Study Collaborators, Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Guenel, P., Gutierrez-Barrera, A. M., Haeberle, L., Haiman, C. A., Hakansson, N., Hall, P., Hamann, U., Harrington, P. A., Hein, A., Heyworth, J., Hillemanns, P., Hollestelle, A., Hopper, J. L., Hosgood, H. D., Howell, A., Hu, C., Hulick, P. J., Hunter, D. J., Imyanitov, E. N., KConFab, Isaacs, C., Jakimovska, M., Jakubowska, A., James, P., Janavicius, R., Janni, W., John, E. M., Jones, M. E., Jung, A., Kaaks, R., Karlan, B. Y., Khusnutdinova, E., Kitahara, C. M., Konstantopoulou, I., Koutros, S., Kraft, P., Lambrechts, D., Lazaro, C., Le Marchand, L., Lester, J., Lesueur, F., Lilyquist, J., Loud, J. T., Lu, K. H., Luben, R. N., Lubinski, J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martens, J. W., Maurer, T., Mavroudis, D., Mebirouk, N., Meindl, A., Menon, U., Miller, A., Montagna, M., Nathanson, K. L., Neuhausen, S. L., Newman, W. G., Nguyen-Dumont, T., Nielsen, F. C., Nielsen, S., Nikitina-Zake, L., Offit, K., Olah, E., Olopade, O. I., Olshan, A. F., Olson, J. E., Olsson, H., Osorio, A., Ottini, L., Peissel, B., Peixoto, A., Peto, J., Plaseska-Karanfilska, D., Pocza, T., Presneau, N., Pujana, M. A., Punie, K., Rack, B., Rantala, J., Rashid, M. U., Rau-Murthy, R., Rennert, G., Lejbkowicz, F., Rhenius, V., Romero, A., Rookus, M. A., Ross, E. A., Rossing, M., Rudaitis, V., Ruebner, M., Saloustros, E., Sanden, K., Santamarina, M., Scheuner, M. T., Schmutzler, R. K., Schneider, M., Scott, C., Senter, L., Shah, M., Sharma, P., Shu, X., Simard, J., Singer, C. F., Sohn, C., Soucy, P., Southey, M. C., Spinelli, J. J., Steele, L., Stoppa-Lyonnet, D., Tapper, W. J., Teixeira, M. R., Terry, M. B., Thomassen, M., Thompson, J., Thull, D. L., Tischkowitz, M., Tollenaar, R. A., Torres, D., Troester, M. A., Truong, T., Tung, N., Untch, M., Vachon, C. M., van Rensburg, E. J., van Veen, E. M., Vega, A., Viel, A., Wappenschmidt, B., Weitzel, J. N., Wendt, C., Wieme, G., Wolk, A., Yang, X. R., Zheng, W., Ziogas, A., Zorn, K. K., Dunning, A. M., Lush, M., Wang, Q., McGuffog, L., Parsons, M. T., Pharoah, P. D., Fostira, F., Toland, A. E., Andrulis, I. L., Ramus, S. J., Swerdlow, A. J., Greene, M. H., Chung, W. K., Milne, R. L., Chenevix-Trench, G., Dork, T., Schmidt, M. K., Easton, D. F., Radice, P., Hahnen, E., Antoniou, A. C., Couch, F. J., Nevanlinna, H., Surralles, J., Peterlongo, P., Balleine, R., Baxter, R., Braye, S., Carpenter, J., Dahlstrom, J., Forbes, J., Lee, C. S., Marsh, D., Morey, A., Pathmanathan, N., Scott, R., Simpson, P., Spigelman, A., Wilcken, N., Yip, D., Zeps, N., Belotti, M., Bertrand, O., Birot, A., Buecher, B., Caputo, S., Dupre, A., Fourme, E., Gauthier-Villars, M., Golmard, L., Le Mentec, M., Moncoutier, V., de Pauw, A., Saule, C., Boutry-Kryza, N., Calender, A., Giraud, S., Leone, M., Bressac-de-Paillerets, B., Caron, O., Guillaud-Bataille, M., Bignon, Y., Uhrhammer, N., Bonadona, V., Lasset, C., Berthet, P., Castera, L., Vaur, D., Bourdon, V., Nogues, C., Noguchi, T., Popovici, C., Remenieras, A., Sobol, H., Coupier, I., Pujol, P., Adenis, C., Dumont, A., Revillion, F., Muller, D., Barouk-Simonet, E., Bonnet, F., Bubien, V., Longy, M., Sevenet, N., Gladieff, L., Guimbaud, R., Feillel, V., Toulas, C., Dreyfus, H., Leroux, C. D., Peysselon, M., Rebischung, C., Legrand, C., Baurand, A., Bertolone, G., Coron, F., Faivre, L., Jacquot, C., Lizard, S., Kientz, C., Lebrun, M., Prieur, F., Fert-Ferrer, S., Mari, V., Venat-Bouvet, L., Bezieau, S., Delnatte, C., Mortemousque, I., Colas, C., Coulet, F., Soubrier, F., Warcoin, M., Bronner, M., Sokolowska, J., Collonge-Rame, M., Damette, A., Gesta, P., Lallaoui, H., Chiesa, J., Molina-Gomes, D., Ingster, O., Manouvrier-Hanu, S., Lejeune, S., Aghmesheh, M., Greening, S., Amor, D., Gattas, M., Botes, L., Buckley, M., Friedlander, M., Koehler, J., Meiser, B., Saleh, M., Salisbury, E., Trainer, A., Tucker, K., Antill, Y., Dobrovic, A., Fellows, A., Fox, S., Harris, M., Nightingale, S., Phillips, K., Sambrook, J., Thorne, H., Armitage, S., Arnold, L., Balleine, R., Kefford, R., Kirk, J., Rickard, E., Bastick, P., Beesley, J., Hayward, N., Spurdle, A., Walker, L., Beilby, J., Saunders, C., Bennett, I., Blackburn, A., Bogwitz, M., Gaff, C., Lindeman, G., Pachter, N., Scott, C., Sexton, A., Visvader, J., Taylor, J., Winship, I., Brennan, M., Brown, M., French, J., Edwards, S., Burgess, M., Burke, J., Patterson, B., Butow, P., Culling, B., Caldon, L., Callen, D., Chauhan, D., Eisenbruch, M., Heiniger, L., Chauhan, M., Christian, A., Dixon, J., Kidd, A., Cohen, P., Colley, A., Fenton, G., Crook, A., Dickson, R., Field, M., Marsh, D., Cui, J., Cummings, M., Dawson, S., DeFazio, A., Delatycki, M., Dudding, T., Edkins, T., Farshid, G., Flanagan, J., Fong, P., Forrest, L., Gallego-Ortega, D., George, P., Gill, G., Kollias, J., Haan, E., Hart, S., Jenkins, M., Hunt, C., Lakhani, S., Lipton, L., Lobb, L., Mann, G., McLachlan, S. A., O'Connell, S., O'Sullivan, S., Pieper, E., Robinson, B., Saunus, J., Scott, E., Scott, R., Shelling, A., Simpson, P., Williams, R., Young, M. A. 2019; 5: 38

    Abstract

    Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR=2.44, P=0.034 and OR=3.79; P=0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR=1.96; P=0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

    View details for DOI 10.1038/s41523-019-0127-5

    View details for PubMedID 31700994

  • Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness. Cancer research Patel, V. L., Busch, E. L., Friebel, T. M., Cronin, A., Leslie, G., McGuffog, L., Adlard, J., Agata, S., Agnarsson, B. A., Ahmed, M., Aittomäki, K., Alducci, E., Andrulis, I. L., Arason, A., Arnold, N., Artioli, G., Arver, B., Auber, B., Azzollini, J., Balmańa, J., Barkardottir, R. B., Barnes, D. R., Barroso, A., Barrowdale, D., Belotti, M., Benitez, J., Bertelsen, B., Blok, M. J., Bodrogi, I., Bonadona, V., Bonanni, B., Bondavalli, D., Boonen, S. E., Borde, J., Borg, A., Bradbury, A. R., Brady, A., Brewer, C., Brunet, J., Buecher, B., Buys, S. S., Cabezas-Camarero, S., Caldés, T., Caliebe, A., Caligo, M. A., Calvello, M., Campbell, I. G., Carnevali, I., Carrasco, E., Chan, T. L., Chu, A. T., Chung, W. K., Claes, K. B., Collaborators, G. S., Collaborators, E., Cook, J., Cortesi, L., Couch, F. J., Daly, M. B., Damante, G., Darder, E., Davidson, R., de la Hoya, M., Della Puppa, L., Dennis, J., Díez, O., Ding, Y. C., Ditsch, N., Domchek, S. M., Donaldson, A., Dworniczak, B., Easton, D. F., Eccles, D. M., Eeles, R. A., Ehrencrona, H., Ejlertsen, B., Engel, C., Evans, D. G., Faivre, L., Faust, U., Feliubadaló, L., Foretova, L., Fostira, F., Fountzilas, G., Frost, D., García-Barberán, V., Garre, P., Gauthier-Villars, M., Géczi, L., Gehrig, A., Gerdes, A. M., Gesta, P., Giannini, G., Glendon, G., Godwin, A. K., Goldgar, D. E., Greene, M. H., Gutierrez-Barrera, A. M., Hahnen, E., Hamann, U., Hauke, J., Herold, N., Hogervorst, F. B., Honisch, E., Hopper, J. L., Hulick, P. J., Investigators, k., Investigators, H., Izatt, L., Jager, A., James, P., Janavicius, R., Jensen, U. B., Jensen, T. D., Johannsson, O. T., John, E. M., Joseph, V., Kang, E., Kast, K., Kiiski, J. I., Kim, S. W., Kim, Z., Ko, K. P., Konstantopoulou, I., Kramer, G., Krogh, L., Kruse, T. A., Kwong, A., Larsen, M., Lasset, C., Lautrup, C., Lázaro, C., Lee, J., Lee, J. W., Lee, M. H., Lemke, J., Lesueur, F., Liljegren, A., Lindblom, A., Llovet, P., Lopez-Fernández, A., Lopez-Perolio, I., Lorca, V., Loud, J. T., Ma, E. S., Mai, P. L., Manoukian, S., Mari, V., Martin, L., Matricardi, L., Mebirouk, N., Medici, V., Meijers-Heijboer, H. E., Meindl, A., Mensenkamp, A. R., Miller, C., Molina Gomes, D., Montagna, M., Mooij, T. M., Moserle, L., Mouret-Fourme, E., Mulligan, A. M., Nathanson, K. L., Navratilova, M., Nevanlinna, H., Niederacher, D., Cilius Nielsen, F. C., Nikitina-Zake, L., Offit, K., Olah, E., Olopade, O. I., Ong, K. R., Osorio, A., Ott, C. E., Palli, D., Park, S. K., Parsons, M. T., Pedersen, I. S., Peissel, B., Peixoto, A., Pérez-Segura, P., Peterlongo, P., Hřgh Petersen, A., Porteous, M. E., Pujana, M. A., Radice, P., Ramser, J., Rantala, J., Rashid, M. U., Rhiem, K., Rizzolo, P., Robson, M. E., Rookus, M. A., Rossing, C. M., Ruddy, K. J., Santos, C., Saule, C., Scarpitta, R., Schmutzler, R. K., Schuster, H., Senter, L., Seynaeve, C. M., Shah, P. D., Sharma, P., Shin, V. Y., Silvestri, V., Simard, J., Singer, C. F., Skytte, A. B., Snape, K., Solano, A. R., Soucy, P., Southey, M. C., Spurdle, A. B., Steele, L., Steinemann, D., Stoppa-Lyonnet, D., Stradella, A., Sunde, L., Sutter, C., Tan, Y. Y., Teixeira, M. R., Teo, S. H., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tommasi, S., Torres, D., Toss, A., Trainer, A. H., Tung, N., van Asperen, C. J., van der Baan, F. H., van der Kolk, L. E., van der Luijt, R. B., van Hest, L. P., Varesco, L., Varon-Mateeva, R., Viel, A., Vierstraete, J., Villa, R., von Wachenfeldt, A., Wagner, P., Wang-Gohrke, S., Wappenschmidt, B., Weitzel, J. N., Wieme, G., Yadav, S., Yannoukakos, D., Yoon, S. Y., Zanzottera, C., Zorn, K. K., D'Amico, A. V., Freedman, M. L., Pomerantz, M. M., Chenevix-Trench, G., Antoniou, A. C., Neuhausen, S. L., Ottini, L., Nielsen, H. R., Rebbeck, T. R. 2019

    Abstract

    Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer (PCa). We evaluated whether PSVs in BRCA1/2 were associated with risk of overall PCa or high grade (Gleason 8+) PCa using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with PCa, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without PCa. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of PCa compared with reference bin c.1001-c.7913 (HR=1.78, 95%CI: 1.25-2.52, p=0.001), as well as elevated risk of Gleason 8+ PCa (HR=3.11, 95%CI: 1.63-5.95, p=0.001). c.756-c.1000 was also associated with elevated PCa risk (HR=2.83, 95%CI: 1.71-4.68, p=0.00004) and elevated risk of Gleason 8+ PCa (HR=4.95, 95%CI: 2.12-11.54, p=0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive PCa.

    View details for DOI 10.1158/0008-5472.CAN-19-1840

    View details for PubMedID 31723001

  • Alcohol consumption, cigarette smoking, and familial breast cancer risk: findings from the Prospective Family Study Cohort (ProF-SC). Breast cancer research : BCR Zeinomar, N., Knight, J. A., Genkinger, J. M., Phillips, K. A., Daly, M. B., Milne, R. L., Dite, G. S., Kehm, R. D., Liao, Y., Southey, M. C., Chung, W. K., Giles, G. G., McLachlan, S. A., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., Andrulis, I. L., Buys, S. S., John, E. M., MacInnis, R. J., Hopper, J. L., Terry, M. B. 2019; 21 (1): 128

    Abstract

    Alcohol consumption and cigarette smoking are associated with an increased risk of breast cancer (BC), but it is unclear whether these associations vary by a woman's familial BC risk.Using the Prospective Family Study Cohort, we evaluated associations between alcohol consumption, cigarette smoking, and BC risk. We used multivariable Cox proportional hazard models to estimate hazard ratios (HR) and 95% confidence intervals (CI). We examined whether associations were modified by familial risk profile (FRP), defined as the 1-year incidence of BC predicted by Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), a pedigree-based algorithm.We observed 1009 incident BC cases in 17,435 women during a median follow-up of 10.4?years. We found no overall association of smoking or alcohol consumption with BC risk (current smokers compared with never smokers HR 1.02, 95% CI 0.85-1.23; consuming ??7 drinks/week compared with non-regular drinkers HR 1.10, 95% CI 0.92-1.32), but we did observe differences in associations based on FRP and by estrogen receptor (ER) status. Women with lower FRP had an increased risk of ER-positive BC associated with consuming ??7 drinks/week (compared to non-regular drinkers), whereas there was no association for women with higher FRP. For example, women at the 10th percentile of FRP (5-year BOADICEA?=?0.15%) had an estimated HR of 1.46 (95% CI 1.07-1.99), whereas there was no association for women at the 90th percentile (5-year BOADICEA?=?4.2%) (HR 1.07, 95% CI 0.80-1.44). While the associations with smoking were not modified by FRP, we observed a positive multiplicative interaction by FRP (pinteraction?=?0.01) for smoking status in women who also consumed alcohol, but not in women who were non-regular drinkers.Moderate alcohol intake was associated with increased BC risk, particularly for women with ER-positive BC, but only for those at lower predicted familial BC risk (5-year BOADICEA

    View details for DOI 10.1186/s13058-019-1213-1

    View details for PubMedID 31779655

  • Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestry. EBioMedicine Yang, Y., Shu, X., Shu, X. O., Bolla, M. K., Kweon, S. S., Cai, Q., Michailidou, K., Wang, Q., Dennis, J., Park, B., Matsuo, K., Kwong, A., Park, S. K., Wu, A. H., Teo, S. H., Iwasaki, M., Choi, J. Y., Li, J., Hartman, M., Shen, C. Y., Muir, K., Lophatananon, A., Li, B., Wen, W., Gao, Y. T., Xiang, Y. B., Aronson, K. J., Spinell, J. J., Gago-Dominguez, M., John, E. M., Kurian, A. W., Chang-Claude, J., Chen, S. T., Dörk, T., Evans, D. G., Schmidt, M. K., Shin, M. H., Giles, G. G., Milne, R. L., Simard, J., Kubo, M., Kraft, P., Kang, D., Easton, D. F., Zheng, W., Long, J. 2019

    Abstract

    We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets.Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets.Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P?

    View details for DOI 10.1016/j.ebiom.2019.09.006

    View details for PubMedID 31629678

  • CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study. Breast cancer research : BCR Brooks, J. D., Comen, E. A., Reiner, A. S., Orlow, I., Leong, S. F., Liang, X., Mellemkjar, L., Knight, J. A., Lynch, C. F., John, E. M., Bernstein, L., Woods, M., Doody, D. R., WECARE Study collaborative group, Malone, K. E., Bernstein, J. L., Bernstein, J. L., Capanu, M., Liang, X., Orlow, I., Reiner, A. S., Robson, M., Woods, M., Bernstein, L., Boice, J. D., Brooks, J. D., Concannon, P., Conti, D. V., Duggan, D., Elena, J. W., Haile, R. W., John, E. M., Knight, J. A., Lynch, C. F., Malone, K. E., Mellemkjar, L., Olsen, J. H., Seminara, D., Shore, R. E., Stovall, M., Stram, D. O., Tischkowitz, M., Thomas, D. C., Blackmore, K., Diep, A. T., Goldstein, J., Harris, I., Langballe, R., O'Brien, C., Smith, S., Weathers, R., West, M. 2018; 20 (1): 149

    Abstract

    BACKGROUND: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown.METHODS: Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS=2), EM/IM (AS=1.5), EM/PM (AS=1), IM/IM (AS=0.75), IM/PM (AS=0.5), and PM/PM (AS=0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ? 1; IM, AS=0.5-0.75; PM, AS=0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS.RESULTS: Among women with AS ? 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS=2, RR=-0.81, 95% CI 0.62-1.06; AS=1.5, RR=0.45, 95% CI 0.30-0.68; and AS=1, RR=0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS=0.5, RR=1.08, 95% CI 0.59-1.96; and AS=0, RR=1.17, 95% CI 0.58-2.35) (p for homogeneity=-0.02).CONCLUSION: This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.

    View details for PubMedID 30526633

  • Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes. American journal of human genetics Mavaddat, N., Michailidou, K., Dennis, J., Lush, M., Fachal, L., Lee, A., Tyrer, J. P., Chen, T., Wang, Q., Bolla, M. K., Yang, X., Adank, M. A., Ahearn, T., Aittomaki, K., Allen, J., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Auer, P. L., Auvinen, P., Barrdahl, M., Beane Freeman, L. E., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brauch, H., Bremer, M., Brenner, H., Brentnall, A., Brock, I. W., Brooks-Wilson, A., Brucker, S. Y., Bruning, T., Burwinkel, B., Campa, D., Carter, B. D., Castelao, J. E., Chanock, S. J., Chlebowski, R., Christiansen, H., Clarke, C. L., Collee, J. M., Cordina-Duverger, E., Cornelissen, S., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Dork, T., Dos-Santos-Silva, I., Dumont, M., Durcan, L., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A. H., Ellberg, C., Engel, C., Eriksson, M., Evans, D. G., Fasching, P. A., Figueroa, J., Fletcher, O., Flyger, H., Forsti, A., Fritschi, L., Gabrielson, M., Gago-Dominguez, M., Gapstur, S. M., Garcia-Saenz, J. A., Gaudet, M. M., Georgoulias, V., Giles, G. G., Gilyazova, I. R., Glendon, G., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Grenaker Alnas, G. I., Grip, M., Gronwald, J., Grundy, A., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hamann, U., Hankinson, S. E., Harkness, E. F., Hart, S. N., He, W., Hein, A., Heyworth, J., Hillemanns, P., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Howell, A., Huang, G., Humphreys, K., Hunter, D. J., Jakimovska, M., Jakubowska, A., Janni, W., John, E. M., Johnson, N., Jones, M. E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kaczmarek, K., Kataja, V., Keeman, R., Kerin, M. J., Khusnutdinova, E., Kiiski, J. I., Knight, J. A., Ko, Y., Kosma, V., Koutros, S., Kristensen, V. N., Kruger, U., Kuhl, T., Lambrechts, D., Le Marchand, L., Lee, E., Lejbkowicz, F., Lilyquist, J., Lindblom, A., Lindstrom, S., Lissowska, J., Lo, W., Loibl, S., Long, J., Lubinski, J., Lux, M. P., MacInnis, R. J., Maishman, T., Makalic, E., Maleva Kostovska, I., Mannermaa, A., Manoukian, S., Margolin, S., Martens, J. W., Martinez, M. E., Mavroudis, D., McLean, C., Meindl, A., Menon, U., Middha, P., Miller, N., Moreno, F., Mulligan, A. M., Mulot, C., Munoz-Garzon, V. M., Neuhausen, S. L., Nevanlinna, H., Neven, P., Newman, W. G., Nielsen, S. F., Nordestgaard, B. G., Norman, A., Offit, K., Olson, J. E., Olsson, H., Orr, N., Pankratz, V. S., Park-Simon, T., Perez, J. I., Perez-Barrios, C., Peterlongo, P., Peto, J., Pinchev, M., Plaseska-Karanfilska, D., Polley, E. C., Prentice, R., Presneau, N., Prokofyeva, D., Purrington, K., Pylkas, K., Rack, B., Radice, P., Rau-Murthy, R., Rennert, G., Rennert, H. S., Rhenius, V., Robson, M., Romero, A., Ruddy, K. J., Ruebner, M., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schumacher, F., Schurmann, P., Schwentner, L., Scott, C., Scott, R. J., Seynaeve, C., Shah, M., Sherman, M. E., Shrubsole, M. J., Shu, X., Slager, S., Smeets, A., Sohn, C., Soucy, P., Southey, M. C., Spinelli, J. J., Stegmaier, C., Stone, J., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Terry, M. B., Thone, K., Tollenaar, R. A., Tomlinson, I., Truong, T., Tzardi, M., Ulmer, H., Untch, M., Vachon, C. M., van Veen, E. M., Vijai, J., Weinberg, C. R., Wendt, C., Whittemore, A. S., Wildiers, H., Willett, W., Winqvist, R., Wolk, A., Yang, X. R., Yannoukakos, D., Zhang, Y., Zheng, W., Ziogas, A., ABCTB Investigators, kConFab/AOCS Investigators, NBCS Collaborators, Dunning, A. M., Thompson, D. J., Chenevix-Trench, G., Chang-Claude, J., Schmidt, M. K., Hall, P., Milne, R. L., Pharoah, P. D., Antoniou, A. C., Chatterjee, N., Kraft, P., Garcia-Closas, M., Simard, J., Easton, D. F. 2018

    Abstract

    Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

    View details for PubMedID 30554720

  • Risk-Reducing Oophorectomy and Breast Cancer Risk Across the Spectrum of Familial Risk. Journal of the National Cancer Institute Terry, M. B., Daly, M. B., Phillips, K. A., Ma, X., Zeinomar, N., Leoce, N., Dite, G. S., MacInnis, R. J., Chung, W. K., Knight, J. A., Southey, M. C., Milne, R. L., Goldgar, D., Giles, G. G., Weideman, P. C., Glendon, G., kConFab Investigators, Buchsbaum, R., Andrulis, I. L., John, E. M., Buys, S. S., Hopper, J. L. 2018

    Abstract

    There remains debate about whether risk-reducing salpingo-oophorectomy (RRSO), which reduces ovarian cancer risk, also reduces breast cancer risk. We examined the association between RRSO and breast cancer risk using a prospective cohort of 17917 women unaffected with breast cancer at baseline (7.2% known carriers of BRCA1 or BRCA2 mutations). During a median follow-up of 10.7years, 1046 women were diagnosed with incident breast cancer. Modeling RRSO as a time-varying exposure, there was no association with breast cancer risk overall (hazard ratio [HR] = 1.04, 95% confidence interval [CI]=0.87 to 1.24) or by tertiles of predicted absolute risk based on family history (HR=0.68, 95% CI=0.32 to 1.47, HR=0.94, 95% CI=0.70 to 1.26, and HR=1.10, 95% CI=0.88 to 1.39, for lowest, middle, and highest tertile of risk, respectively) or for BRCA1 and BRCA2 mutation carriers when examined separately. There was also no association after accounting for hormone therapy use after RRSO. These findings suggest that RRSO should not be considered efficacious for reducing breast cancer risk.

    View details for PubMedID 30496449

  • Germline variation at 8q24 and prostate cancer risk in men of European ancestry. Nature communications Matejcic, M., Saunders, E. J., Dadaev, T., Brook, M. N., Wang, K., Sheng, X., Olama, A. A., Schumacher, F. R., Ingles, S. A., Govindasami, K., Benlloch, S., Berndt, S. I., Albanes, D., Koutros, S., Muir, K., Stevens, V. L., Gapstur, S. M., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Pashayan, N., Schleutker, J., Wolk, A., West, C., Mucci, L., Kraft, P., Cancel-Tassin, G., Sorensen, K. D., Maehle, L., Grindedal, E. M., Strom, S. S., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Bensen, J. T., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Dominguez, M. G., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L. A., Pandha, H., Thibodeau, S. N., Schaid, D. J., PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Wiklund, F., Chanock, S. J., Easton, D. F., Eeles, R. A., Kote-Jarai, Z., Conti, D. V., Haiman, C. A., Henderson, B. E., Stern, M. C., Thwaites, A., Guy, M., Whitmore, I., Morgan, A., Fisher, C., Hazel, S., Livni, N., Cook, M., Fachal, L., Weinstein, S., Beane Freeman, L. E., Hoover, R. N., Machiela, M. J., Lophatananon, A., Carter, B. D., Goodman, P., Moya, L., Srinivasan, S., Kedda, M., Yeadon, T., Eckert, A., Eklund, M., Cavalli-Bjoerkman, C., Dunning, A. M., Sipeky, C., Hakansson, N., Elliott, R., Ranu, H., Giovannucci, E., Turman, C., Hunter, D. J., Cussenot, O., Orntoft, T. F., Lane, A., Lewis, S. J., Davis, M., Key, T. J., Brown, P., Kulkarni, G. S., Zlotta, A. R., Fleshner, N. E., Finelli, A., Mao, X., Marzec, J., MacInnis, R. J., Milne, R., Hopper, J. L., Aguado, M., Bustamante, M., Castano-Vinyals, G., Gracia-Lavedan, E., Cecchini, L., Stampfer, M., Ma, J., Sellers, T. A., Geybels, M. S., Park, H., Zachariah, B., Kolb, S., Wokolorczyk, D., Jan Lubinski, Kluzniak, W., Nielsen, S. F., Weisher, M., Cuk, K., Vogel, W., Luedeke, M., Logothetis, C. J., Paulo, P., Cardoso, M., Maia, S., Silva, M. P., Steele, L., Ding, Y. C., De Meerleer, G., De Langhe, S., Thierens, H., Lim, J., Tan, M. H., Ong, A. T., Lin, D. W., Kachakova, D., Mitkova, A., Mitev, V., Parliament, M., Jenster, G., Bangma, C., Schroder, F. H., Truong, T., Koudou, Y. A., Michael, A., Kierzek, A., Karlsson, A., Broms, M., Wu, H., Aukim-Hastie, C., Tillmans, L., Riska, S., McDonnell, S. K., Dearnaley, D., Spurdle, A., Gardiner, R., Hayes, V., Butler, L., Taylor, R., Papargiris, M., Saunders, P., Kujala, P., Talala, K., Taari, K., Bentzen, S., Hicks, B., Vogt, A., Hutchinson, A., Cox, A., George, A., Toi, A., Evans, A., van der Kwast, T. H., Imai, T., Saito, S., Zhao, S., Ren, G., Zhang, Y., Yu, Y., Wu, Y., Wu, J., Zhou, B., Pedersen, J., Lobato-Busto, R., Ruiz-Dominguez, J. M., Mengual, L., Alcaraz, A., Pow-Sang, J., Herkommer, K., Vlahova, A., Dikov, T., Christova, S., Carracedo, A., Tretarre, B., Rebillard, X., Mulot, C., Jan Adolfsson, Stattin, P., Johansson, J., Martin, R. M., Thompson, I. M., Chambers, S., Aitken, J., Horvath, L., Haynes, A., Tilley, W., Risbridger, G., Aly, M., Nordstrom, T., Pharoah, P., Tammela, T. L., Murtola, T., Auvinen, A., Burnet, N., Barnett, G., Andriole, G., Klim, A., Drake, B. F., Borre, M., Kerns, S., Ostrer, H., Zhang, H., Cao, G., Lin, J., Ling, J., Li, M., Feng, N., Li, J., He, W., Guo, X., Sun, Z., Wang, G., Guo, J., Southey, M. C., FitzGerald, L. M., Marsden, G., Gomez-Caamano, A., Carballo, A., Peleteiro, P., Calvo, P., Szulkin, R., Llorca, J., Dierssen-Sotos, T., Gomez-Acebo, I., Lin, H., Ostrander, E. A., Bisbjerg, R., Klarskov, P., Roder, M. A., Iversen, P., Holleczek, B., Stegmaier, C., Schnoeller, T., Bohnert, P., John, E. M., Ost, P., Teo, S., Gamulin, M., Kulis, T., Kastelan, Z., Slavov, C., Popov, E., Van den Broeck, T., Joniau, S., Larkin, S., Castelao, J. E., Martinez, M. E., van Schaik, R. H., Xu, J., Lindstrom, S., Riboli, E., Berry, C., Siddiq, A., Canzian, F., Kolonel, L. N., Le Marchand, L., Freedman, M., Cenee, S., Sanchez, M. 2018; 9 (1): 4616

    Abstract

    Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p<4.28*10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI=3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

    View details for PubMedID 30397198

  • Age-specific breast cancer risk by body mass index and familial risk: prospective family study cohort (ProF-SC). Breast cancer research : BCR Hopper, J. L., Dite, G. S., MacInnis, R. J., Liao, Y., Zeinomar, N., Knight, J. A., Southey, M. C., Milne, R. L., Chung, W. K., Giles, G. G., Genkinger, J. M., McLachlan, S., Friedlander, M. L., Antoniou, A. C., Weideman, P. C., Glendon, G., Nesci, S., kConFab Investigators, Andrulis, I. L., Buys, S. S., Daly, M. B., John, E. M., Phillips, K. A., Terry, M. B. 2018; 20 (1): 132

    Abstract

    BACKGROUND: The association between body mass index (BMI) and risk of breast cancer depends on time of life, but it is unknown whether this association depends on a woman's familial risk.METHODS: We conducted a prospective study of a cohort enriched for familial risk consisting of 16,035 women from 6701 families in the Breast Cancer Family Registry and the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer followed for up to 20years (mean 10.5years). There were 896 incident breast cancers (mean age at diagnosis 55.7years). We used Cox regression to model BMI risk associations as a function of menopausal status, age, and underlying familial risk based on pedigree data using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), all measured at baseline.RESULTS: The strength and direction of the BMI risk association depended on baseline menopausal status (P<0.001); after adjusting for menopausal status, the association did not depend on age at baseline (P=0.6). In terms of absolute risk, the negative association with BMI for premenopausal women has a much smaller influence than the positive association with BMI for postmenopausal women. Women at higher familial risk have a much larger difference in absolute risk depending on their BMI than women at lower familial risk.CONCLUSIONS: The greater a woman's familial risk, the greater the influence of BMI on her absolute postmenopausal breast cancer risk. Given that age-adjusted BMI is correlated across adulthood, maintaining a healthy weight throughout adult life is particularly important for women with a family history of breast cancer.

    View details for PubMedID 30390716

  • Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Adams, C., Richmond, R. C., Santos Ferreira, D. L., Spiller, W., Tan, V. Y., Zheng, J., Wurtz, P., Donovan, J. L., Hamdy, F. C., Neal, D. E., Lane, J. A., Davey Smith, G., Relton, C. L., Eeles, R. A., Henderson, B. E., Haiman, C. A., Kote-Jarai, Z., Schumacher, F. R., Amin Al Olama, A., Benlloch, S., Muir, K., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S. J., Gapstur, S. M., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J. A., Gronberg, H., Pashayan, N., Schleutker, J., Albanes, D., Wolk, A., West, C. M., Mucci, L. A., Cancel-Tassin, G., Koutros, S., Sorensen, K. D., Maehle, L., Travis, R. C., Hamilton, R., Ingles, S. A., Rosenstein, B. S., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., DeRuyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R. P., Usmani, N., Claessens, F., Townsend, P., Gago Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L. A., Pandha, H., Thibodeau, S. N., Martin, R. M. 2018

    Abstract

    BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

    View details for PubMedID 30352818

  • Impact of individual and neighborhood factors on socioeconomic disparities in localized and advanced prostate cancer risk CANCER CAUSES & CONTROL DeRouen, M. C., Schupp, C. W., Yang, J., Koo, J., Hertz, A., Shariff-Marco, S., Cockburn, M., Nelson, D. O., Ingles, S. A., Cheng, I., John, E. M., Gomez, S. L. 2018; 29 (10): 951?66

    Abstract

    The reasons behind socio-economic disparities in prostate cancer incidence remain unclear. We tested the hypothesis that individual-level factors act jointly with neighborhood-level social and built environment factors to influence prostate cancer risk and that specific social and built environment factors contribute to socio-econmic differences in risk.We used multi-level data, combining individual-level data (including education and known prostate cancer risk factors) for prostate cancer cases (n?=?775) and controls (n?=?542) from the San Francisco Bay Area Prostate Cancer Study, a population-based case-control study, with contextual-level data on neighborhood socio-economic status (nSES) and specific social and built environment factors from the California Neighborhoods Data System. Multivariable logistic regression models were used to compute adjusted odds ratios separately for localized and advanced stage prostate cancer while controlling for neighborhood clustering.We found a more than twofold increased risk of both localized and advanced prostate cancer with increasing levels of nSES, and decreased risk of advanced prostate cancer with increasing levels of education. For localized disease, the nSES association was largely explained by known prostate cancer risk factors and specific neighborhood environment factors; population density, crowding, and residential mobility. For advanced disease, associations with education and nSES were not fully explained by any available individual- or neighborhood-level factors.These results demonstrate the importance of specific neighborhood social and built environment factors in understanding risk of localized prostate cancer. Further research is needed to understand the factors underpinning the associations between individual- and neighborhood-level SES and risk of advanced prostate cancer.

    View details for PubMedID 30136012

  • Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma NATURE COMMUNICATIONS Went, M., Sud, A., Forsti, A., Halvarsson, B., Weinhold, N., Kimber, S., van Duin, M., Thorleifsson, G., Holroydl, A., Johnson, D. C., Li, N., Orlando, G., Law, P. J., Ali, M., Chen, B., Mitchell, J. S., Gudbjartsson, D. F., Kuiper, R., Stephens, O. W., Bertsch, U., Broderick, P., Campo, C., Bandapalli, O. R., Einsele, H., Gregory, W. A., Gullberg, U., Hillengass, J., Hoffmann, P., Jackson, G. H., Joeckel, K., Johnsson, E., Kristinsson, S. Y., Mellqvist, U., Nahi, H., Easton, D., Pharoah, P., Dunning, A., Peto, J., Canzian, F., Swerdlow, A., Eeles, R. A., Kote-Jarai, Z. S., Muir, K., Pashayan, N., Nickel, J., Noethen, M. M., Rafnar, T., Ross, F. M., Filho, M., Thomsen, H., Turesson, I., Vangsted, A., Andersen, N., Waage, A., Walker, B. A., Wihlborg, A., Broyl, A., Davies, F. E., Thorsteinsdottir, U., Langer, C., Hansson, M., Goldschmidt, H., Kaiser, M., Sonneveld, P., Stefansson, K., Morgans, G. J., Hemminki, K., Nilsson, B., Houlston, R. S., PRACTICAL Consortium 2018; 9: 3707

    Abstract

    Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.

    View details for DOI 10.1038/s41467-018-04989-w

    View details for Web of Science ID 000444493600001

    View details for PubMedID 30213928

    View details for PubMedCentralID PMC6137048

  • Germline Variation and Breast Cancer Incidence: A Gene-Based Association Study and Whole-Genome Prediction of Early-Onset Breast Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Bryan, M., Argos, M., Andrulis, I. L., Hopper, J. L., Chang-Claude, J., Malone, K. E., John, E. M., Gammon, M. D., Daly, M. B., Terry, M., Buys, S. S., Huo, D., Olopade, O. I., Genkinger, J. M., Whittemore, A. S., Jasmine, F., Kibriya, M. G., Chen, L. S., Ahsan, H. 2018; 27 (9): 1057?64

    Abstract

    Background: Although germline genetics influences breast cancer incidence, published research only explains approximately half of the expected association. Moreover, the accuracy of prediction models remains low. For women who develop breast cancer early, the genetic architecture is less established.Methods: To identify loci associated with early-onset breast cancer, gene-based tests were carried out using exome array data from 3,479 women with breast cancer diagnosed before age 50 and 973 age-matched controls. Replication was undertaken in a population that developed breast cancer at all ages of onset.Results: Three gene regions were associated with breast cancer incidence: FGFR2 (P = 1.23 × 10-5; replication P < 1.00 × 10-6), NEK10 (P = 3.57 × 10-4; replication P < 1.00 × 10-6), and SIVA1 (P = 5.49 × 10-4; replication P < 1.00 × 10-6). Of the 151 gene regions reported in previous literature, 19 (12.5%) showed evidence of association (P < 0.05) with the risk of early-onset breast cancer in the early-onset population. To predict incidence, whole-genome prediction was implemented on a subset of 3,076 participants who were additionally genotyped on a genome wide array. The whole-genome prediction outperformed a polygenic risk score [AUC, 0.636; 95% confidence interval (CI), 0.614-0.659 compared with 0.601; 95% CI, 0.578-0.623], and when combined with known epidemiologic risk factors, the AUC rose to 0.662 (95% CI, 0.640-0.684).Conclusions: This research supports a role for variation within FGFR2 and NEK10 in breast cancer incidence, and suggests SIVA1 as a novel risk locus.Impact: This analysis supports a shared genetic etiology between women with early- and late-onset breast cancer, and suggests whole-genome data can improve risk assessment. Cancer Epidemiol Biomarkers Prev; 27(9); 1057-64. ©2018 AACR.

    View details for PubMedID 29898891

  • A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer NATURE GENETICS Wu, L., Shi, W., Long, J., Guo, X., Michailidou, K., Beesley, J., Bolla, M. K., Shu, X., Lu, Y., Cai, Q., Al-Ejeh, F., Rozali, E., Wang, Q., Dennis, J., Li, B., Zeng, C., Feng, H., Gusev, A., Barfield, R. T., Andrulis, I. L., Anton-Culver, H., Arndt, V., Aronson, K. J., Auer, P. L., Barrdahl, M., Baynes, C., Beckmann, M. W., Benitez, J., Bermisheva, M., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Brauch, H., Brenner, H., Brinton, L., Broberg, P., Brucker, S. Y., Burwinkel, B., Caldes, T., Canzian, F., Carter, B. D., Castelao, J., Chang-Claude, J., Chen, X., Cheng, T., Christiansen, H., Clarke, C. L., Collee, M., Cornelissen, S., Couch, F. J., Cox, D., Cox, A., Cross, S. S., Cunningham, J. M., Czene, K., Daly, M. B., Devilee, P., Doheny, K. F., Dork, T., dos-Santos-Silva, I., Dumont, M., Dwek, M., Eccles, D. M., Eilber, U., Eliassen, A., Engel, C., Eriksson, M., Fachal, L., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fritschi, L., Gabrielson, M., Gago-Dominguez, M., Gapstur, S. M., Garcia-Closas, M., Gaudet, M. M., Ghoussaini, M., Giles, G. G., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Guenel, P., Hahnen, E., Haiman, C. A., Hakansson, N., Hall, P., Hallberg, E., Hamann, U., Harrington, P., Hein, A., Hicks, B., Hillemanns, P., Hollestelle, A., Hoover, R. N., Hopper, J. L., Huang, G., Humphreys, K., Hunter, D. J., Jakubowska, A., Janni, W., John, E. M., Johnson, N., Jones, K., Jones, M. E., Jung, A., Kaaks, R., Kerin, M. J., Khusnutdinova, E., Kosma, V., Kristensen, V. N., Lambrechts, D., Le Marchand, L., Li, J., Lindstrom, S., Lissowska, J., Lo, W., Loibl, S., Lubinski, J., Luccarini, C., Lux, M. P., MacInnis, R. J., Maishman, T., Kostovska, I., Mannermaa, A., Manson, J. E., Margolin, S., Mavroudis, D., Meijers-Heijboer, H., Meindl, A., Menon, U., Meyer, J., Mulligan, A., Neuhausen, S. L., Nevanlinna, H., Neven, P., Nielsen, S. F., Nordestgaard, B. G., Olopade, O. I., Olson, J. E., Olsson, H., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Prentice, R., Presneau, N., Pylkas, K., Rack, B., Radice, P., Rahman, N., Rennert, G., Rennert, H. S., Rhenius, V., Romero, A., Romm, J., Rudolph, A., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Schneeweiss, A., Scott, R. J., Scott, C. G., Seal, S., Shah, M., Shrubsole, M. J., Smeets, A., Southey, M. C., Spinelli, J. J., Stone, J., Surowy, H., Swerdlow, A. J., Tamimi, R. M., Tapper, W., Taylor, J. A., Terry, M., Tessier, D. C., Thomas, A., Thone, K., Tollenaar, R. M., Torres, D., Truong, T., Untch, M., Vachon, C., Van den Berg, D., Vincent, D., Waisfisz, Q., Weinberg, C. R., Wendt, C., Whittemore, A. S., Wildiers, H., Willett, W. C., Winqvist, R., Wolk, A., Xia, L., Yang, X. R., Ziogas, A., Ziv, E., Dunning, A. M., Pharoah, P. P., Simard, J., Milne, R. L., Edwards, S. L., Kraft, P., Easton, D. F., Chenevix-Trench, G., Zheng, W., NBCS Collaborators, kConFab AOCS Investigators 2018; 50 (7): 968-+

    Abstract

    The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P?

    View details for PubMedID 29915430

  • Racial/ethnic disparities in breast cancer risk associated with body size. John, E. M. AMER ASSOC CANCER RESEARCH. 2018: 41?42
  • Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci NATURE GENETICS Schumacher, F. R., Al Olama, A., Berndt, S. I., Benlloch, S., Ahmed, M., Saunders, E. J., Dadaev, T., Leongamornlert, D., Anokian, E., Cieza-Borrella, C., Goh, C., Brook, M. N., Sheng, X., Fachal, L., Dennis, J., Tyrer, J., Muir, K., Lophatananon, A., Stevens, V. L., Gapstur, S. M., Carter, B. D., Tangen, C. M., Goodman, P. J., Thompson, I. M., Batra, J., Chambers, S., Moya, L., Clements, J., Horvath, L., Tilley, W., Risbridger, G. P., Gronberg, H., Aly, M., Nordstrom, T., Pharoah, P., Pashayan, N., Schleutker, J., Tammela, T. J., Sipeky, C., Auvinen, A., Albanes, D., Weinstein, S., Wolk, A., Hakansson, N., West, C. L., Dunning, A. M., Burnet, N., Mucci, L. A., Giovannucci, E., Andriole, G. L., Cussenot, O., Cancel-Tassin, G., Koutros, S., Freeman, L., Sorensen, K., Orntoft, T., Borre, M., Maehle, L., Grindedal, E., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Travis, R. C., Key, T. J., Hamilton, R. J., Fleshner, N. E., Finelli, A., Ingles, S., Stern, M. C., Rosenstein, B. S., Kerns, S. L., Ostrer, H., Lu, Y., Zhang, H., Feng, N., Mao, X., Guo, X., Wang, G., Sun, Z., Giles, G. G., Southey, M. C., MacInnis, R. J., FitzGerald, L. M., Kibel, A. S., Drake, B. F., Vega, A., Gomez-Caamano, A., Szulkin, R., Eklund, M., Kogevinas, M., Llorca, J., Castano-Vinyals, G., Penney, K. L., Stampfer, M., Park, J. Y., Sellers, T. A., Lin, H., Stanford, J. L., Cybulski, C., Wokolorczyk, D., Lubinski, J., Ostrander, E. A., Geybels, M. S., Nordestgaard, B. G., Nielsen, S. F., Weischer, M., Bisbjerg, R., Roder, M., Iversen, P., Brenner, H., Cuk, K., Holleczek, B., Maier, C., Luedeke, M., Schnoeller, T., Kim, J., Logothetis, C. J., John, E. M., Teixeira, M. R., Paulo, P., Cardoso, M., Neuhausen, S. L., Steele, L., Ding, Y., De Ruyck, K., De Meerleer, G., Ost, P., Razack, A., Lim, J., Teo, S., Lin, D. W., Newcomb, L. F., Lessel, D., Gamulin, M., Kulis, T., Kaneva, R., Usmani, N., Singhal, S., Slavov, C., Mitev, V., Parliament, M., Claessens, F., Joniau, S., Van den Broeck, T., Larkin, S., Townsend, P. A., Aukim-Hastie, C., Dominguez, M., Castelao, J., Martinez, M., Roobol, M. J., Jenster, G., van Schaik, R. N., Menegaux, F., Truong, T., Koudou, Y., Xu, J., Khaw, K., Cannon-Albright, L., Pandha, H., Michael, A., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Lindstrom, S., Turman, C., Ma, J., Hunter, D. J., Riboli, E., Siddiq, A., Canzian, F., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Cui, Z., Kraft, P., Conti, D. V., Easton, D. F., Wiklund, F., Chanock, S. J., Henderson, B. E., Kote-Jarai, Z., Haiman, C. A., Eeles, R. A., Profile Study, APCB, IMPACT Study, Canary PASS Investigators, Breast Prostate Canc Cohort Consor, PRACTICAL Prostate Canc As, Canc Prostate Sweden CAPS, Prostate Canc Genome-wide As, Genetic Assoc Mech Oncology GAME- 2018; 50 (7): 928-+

    Abstract

    Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P?C, p.Pro1054Arg) in ATM and rs2066827 (OR?=?1.06; P?=?2.3?×?10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk?=?2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk?=?5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .

    View details for PubMedID 29892016

  • Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants NATURE COMMUNICATIONS Dadaev, T., Saunders, E. J., Newcombe, P. J., Anokian, E., Leongamornlert, D. A., Brook, M. N., Cieza-Borrella, C., Mijuskovic, M., Wakerell, S., Al Olama, A., Schumacher, F. R., Berndt, S. I., Benlloch, S., Ahmed, M., Goh, C., Sheng, X., Zhang, Z., Muir, K., Govindasami, K., Lophatananon, A., Stevens, V. L., Gapstur, S. M., Carter, B. D., Tangen, C. M., Goodman, P., Thompson, I. M., Batra, J., Chambers, S., Moya, L., Clements, J., Horvath, L., Tilley, W., Risbridger, G., Gronberg, H., Aly, M., Nordstrom, T., Pharoah, P., Pashayan, N., Schleutker, J., Tammela, T. J., Sipeky, C., Auvinen, A., Albanes, D., Weinstein, S., Wolk, A., Hakansson, N., West, C., Dunning, A. M., Burnet, N., Mucci, L., Giovannucci, E., Andriole, G., Cussenot, O., Cancel-Tassin, G., Koutros, S., Freeman, L., Sorensen, K., Orntoft, T., Borre, M., Maehle, L., Grindedal, E., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Travis, R. C., Key, T. J., Hamilton, R. J., Fleshner, N. E., Finelli, A., Ingles, S., Stern, M. C., Rosenstein, B., Kerns, S., Ostrer, H., Lu, Y., Zhang, H., Feng, N., Mao, X., Guo, X., Wang, G., Sun, Z., Giles, G. G., Southey, M. C., MacInnis, R. J., FitzGerald, L. M., Kibel, A. S., Drake, B. F., Vega, A., Gomez-Caamano, A., Fachal, L., Szulkin, R., Eklund, M., Kogevinas, M., Llorca, J., Castano-Vinyals, G., Penney, K. L., Stampfer, M., Park, J. Y., Sellers, T. A., Lin, H., Stanford, J. L., Cybulski, C., Wokolorczyk, D., Lubinski, J., Ostrander, E. A., Geybels, M. S., Nordestgaard, B. G., Nielsen, S. F., Weisher, M., Bisbjerg, R., Roder, M., Iversen, P., Brenner, H., Cuk, K., Holleczek, B., Maier, C., Luedeke, M., Schnoeller, T., Kim, J., Logothetis, C. J., John, E. M., Teixeira, M. R., Paulo, P., Cardoso, M., Neuhausen, S. L., Steele, L., Ding, Y., De Ruyck, K., De Meerleer, G., Ost, P., Razack, A., Lim, J., Teo, S., Lin, D. W., Newcomb, L. F., Lessel, D., Gamulin, M., Kulis, T., Kaneva, R., Usmani, N., Slavov, C., Mitev, V., Parliament, M., Singhal, S., Claessens, F., Joniau, S., Van den Broeck, T., Larkin, S., Townsend, P. A., Aukim-Hastie, C., Gago-Dominguez, M., Castelao, J., Martinez, M., Roobol, M. J., Jenster, G., van Schaik, R. N., Menegaux, F., Truong, T., Koudou, Y., Xu, J., Khaw, K., Cannon-Albright, L., Pandha, H., Michael, A., Kierzek, A., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Lindstrom, S., Turman, C., Ma, J., Hunter, D. J., Riboli, E., Siddiq, A., Canzian, F., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Kraft, P., Freedman, M., Wiklund, F., Chanock, S., Henderson, B. E., Easton, D. F., Haiman, C. A., Eeles, R. A., Conti, D. V., Kote-Jarai, Z., PRACTICAL Prostate Canc Assoc Grp 2018; 9: 2256

    Abstract

    Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

    View details for PubMedID 29892050

  • Reproductive history, breast-feeding and risk of triple negative breast cancer: The Breast Cancer Etiology in Minorities (BEM) study INTERNATIONAL JOURNAL OF CANCER John, E. M., Hines, L. M., Phipps, A. I., Koo, J., Longacre, T. A., Ingles, S. A., Baumgartner, K. B., Slattery, M. L., Wu, A. H. 2018; 142 (11): 2273?85

    Abstract

    Few risk factors have been identified for triple negative breast cancer (TNBC) which lacks expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). This more aggressive subtype disproportionately affects some racial/ethnic minorities and is associated with lower survival. We pooled data from three population-based studies (558 TNBC and 5,111 controls) and examined associations of TNBC risk with reproductive history and breast-feeding. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression. For younger women, aged <50 years, TNBC risk was increased two-fold for parous women who never breast-fed compared to nulliparous women (OR?=?2.02, 95% CI?=?1.12-3.63). For younger parous women, longer duration of lifetime breast-feeding was associated with a borderline reduced risk (?24 vs. 0 months: OR?=?0.52, 95% CI?=?0.26-1.04, Ptrend ?=?0.06). Considering the joint effect of parity and breast-feeding, risk was increased two-fold for women with ?3 full-term pregnancies (FTPs) and no or short-term (<12 months) breast-feeding compared to women with 1-2 FTPs and breast-feeding ?12 months (OR?=?2.56, 95% CI?=?1.22-5.35). None of these associations were observed among older women (?50 years). Differences in reproductive patterns possibly contribute to the ethnic differences in TNBC incidence. Among controls aged <50 years, the prevalence of no or short-term breast-feeding and ?3 FTPs was highest for Hispanics (22%), followed by African Americans (18%), Asian Americans (15%) and non-Hispanic whites (6%). Breast-feeding is a modifiable behavioral factor that may lower TNBC risk and mitigate the effect of FTPs in women under age 50 years.

    View details for PubMedID 29330856

    View details for PubMedCentralID PMC5893409

  • Obesity, Body Composition, and Breast Cancer An Evolving Science JAMA ONCOLOGY Bandera, E. V., John, E. M. 2018; 4 (6): 804?5

    View details for PubMedID 29621383

  • Metabolomic profiles in breast cancer: a pilot case-control study in the breast cancer family registry BMC CANCER Dougan, M. M., Li, Y., Chu, L. W., Haile, R. W., Whittemore, A. S., Han, S. S., Moore, S. C., Sampson, J. N., Andrulis, I. L., John, E. M., Hsing, A. W. 2018; 18: 532

    Abstract

    Metabolomics is emerging as an important tool for detecting differences between diseased and non-diseased individuals. However, prospective studies are limited.We examined the detectability, reliability, and distribution of metabolites measured in pre-diagnostic plasma samples in a pilot study of women enrolled in the Northern California site of the Breast Cancer Family Registry. The study included 45 cases diagnosed with breast cancer at least one year after the blood draw, and 45 controls. Controls were matched on age (within 5 years), family status, BRCA status, and menopausal status. Duplicate samples were included for reliability assessment. We used a liquid chromatography/gas chromatography mass spectrometer platform to measure metabolites. We calculated intraclass correlations (ICCs) among duplicate samples, and coefficients of variation (CVs) across metabolites.Of the 661 named metabolites detected, 338 (51%) were found in all samples, and 490 (74%) in more than 80% of samples. The median ICC between duplicates was 0.96 (25th - 75th percentile: 0.82-0.99). We observed a greater than 20% case-control difference in 24 metabolites (p?

    View details for PubMedID 29728083

  • Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations HUMAN MUTATION Rebbeck, T. R., Friebel, T. M., Friedman, E., Hamann, U., Huo, D., Kwong, A., Olah, E., Olopade, O. I., Solano, A. R., Teo, S., Thomassen, M., Weitzel, J. N., Chan, T. L., Couch, F. J., Goldgar, D. E., Kruse, T. A., Palmero, E., Park, S., Torres, D., van Rensburg, E. J., McGuffog, L., Parsons, M. T., Leslie, G., Aalfs, C. M., Abugattas, J., Adlard, J., Agata, S., Aittomaki, K., Andrews, L., Andrulis, I. L., Arason, A., Arnold, N., Arun, B. K., Asseryanis, E., Auerbach, L., Azzollini, J., Balmana, J., Barile, M., Barkardottir, R. B., Barrowdale, D., Benitez, J., Berger, A., Berger, R., Blanco, A. M., Blazer, K. R., Blok, M. J., Bonadona, V., Bonanni, B., Bradbury, A. R., Brewer, C., Buecher, B., Buys, S. S., Caldes, T., Caliebe, A., Caligo, M. A., Campbell, I., Caputo, S. M., Chiquette, J., Chung, W. K., Claes, K. M., Collee, J., Cook, J., Davidson, R., de la Hoya, M., De Leeneer, K., de Pauw, A., Delnatte, C., Diez, O., Ding, Y., Ditsch, N., Domchek, S., Dorfling, C. M., Velazquez, C., Dworniczak, B., Eason, J., Easton, D. F., Eeles, R., Ehrencrona, H., Ejlertsen, B., Engel, C., Engert, S., Evans, D., Faivre, L., Feliubadalo, L., Ferrer, S., Foretova, L., Fowler, J., Frost, D., Galvao, H. R., Ganz, P. A., Garber, J., Gauthier-Villars, M., Gehrig, A., Gerdes, A., Gesta, P., Giannini, G., Giraud, S., Glendon, G., Godwin, A. K., Greene, M. H., Gronwald, J., Gutierrez-Barrera, A., Hahnen, E., Hauke, J., Henderson, A., Hentschel, J., Hogervorst, F. L., Honisch, E., Imyanitov, E. N., Isaacs, C., Izatt, L., Izquierdo, A., Jakubowska, A., James, P., Janavicius, R., Jensen, U., John, E. M., Vijai, J., Kaczmarek, K., Karlan, B. Y., Kast, K., Kim, S., Konstantopoulou, I., Korach, J., Laitman, Y., Lasa, A., Lasset, C., Lazaro, C., Lee, A., Lee, M., Lester, J., Lesueur, F., Liljegren, A., Lindor, N. M., Longy, M., Loud, J. T., Lu, K. H., Lubinski, J., Machackova, E., Manoukian, S., Mari, V., Martinez-Bouzas, C., Matrai, Z., Mebirouk, N., Meijers-Heijboer, H. J., Meindl, A., Mensenkamp, A. R., Mickys, U., Miller, A., Montagna, M., Moysich, K. B., Mulligan, A., Musinsky, J., Neuhausen, S. L., Nevanlinna, H., Ngeow, J., Nguyen, H., Niederacher, D., Nielsen, H., Nielsen, F., Nussbaum, R. L., Offit, K., Ofverholm, A., Ong, K., Osorio, A., Papi, L., Papp, J., Pasini, B., Pedersen, I., Peixoto, A., Peruga, N., Peterlongo, P., Pohl, E., Pradhan, N., Prajzendanc, K., Prieur, F., Pujol, P., Radice, P., Ramus, S. J., Rantala, J., Rashid, M., Rhiem, K., Robson, M., Rodriguez, G. C., Rogers, M. T., Rudaitis, V., Schmidt, A. Y., Schmutzler, R., Senter, L., Shah, P. D., Sharma, P., Side, L. E., Simard, J., Singer, C. F., Skytte, A., Slavin, T. P., Snape, K., Sobol, H., Southey, M., Steele, L., Steinemann, D., Sukiennicki, G., Sutter, C., Szabo, C. I., Tan, Y. Y., Teixeira, M. R., Terry, M., Teule, A., Thomas, A., Thull, D. L., Tischkowitz, M., Tognazzo, S., Toland, A., Topka, S., Trainer, A. H., Tung, N., van Asperen, C. J., van der Hout, A. H., van der Kolk, L. E., van der Luijt, R. B., Van Heetvelde, M., Varesco, L., Varon-Mateeva, R., Vega, A., Villarreal-Garza, C., von Wachenfeldt, A., Walker, L., Wang-Gohrke, S., Wappenschmidt, B., Weber, B. F., Yannoukakos, D., Yoon, S., Zanzottera, C., Zidan, J., Zorn, K. K., Selkirk, C., Hulick, P. J., Chenevix-Trench, G., Spurdle, A. B., Antoniou, A. C., Nathanson, K. L., EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators 2018; 39 (5): 593?620

    Abstract

    The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

    View details for PubMedID 29446198

    View details for PubMedCentralID PMC5903938

  • Intake of bean fiber, beans, and grains and reduced risk of hormone receptor-negative breast cancer: the San Francisco Bay Area Breast Cancer Study CANCER MEDICINE Sangaramoorthy, M., Koo, J., John, E. M. 2018; 7 (5): 2131?44

    Abstract

    High dietary fiber intake has been associated with reduced breast cancer risk, but few studies considered tumor subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status or included racial/ethnic minority populations who vary in their fiber intake. We analyzed food frequency data from a population-based case-control study, including 2135 breast cancer cases (1070 Hispanics, 493 African Americans, and 572 non-Hispanic Whites (NHWs)) and 2571 controls (1391 Hispanics, 557 African Americans, and 623 NHWs). Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer associated with fiber intake were calculated using unconditional logistic regression. Breast cancer risk associated with high intake (high vs. low quartile) of bean fiber (p-trend = 0.01), total beans (p-trend = 0.03), or total grains (p-trend = 0.05) was reduced by 20%. Inverse associations were strongest for ER-PR- breast cancer, with risk reductions associated with high intake ranging from 28 to 36%. For bean fiber, risk was reduced among foreign-born Hispanics only, who had the highest fiber intake, whereas for grain intake, inverse associations were found among NHWs only. There was no evidence of association with fiber intake from vegetables and fruits or total intake of vegetables and fruits. A high dietary intake of bean fiber and fiber-rich foods such as beans and grains may lower the risk of ER-PR- breast cancer, an aggressive breast cancer subtype for which few risk factors have been identified.

    View details for PubMedID 29573201

  • Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies PLOS ONE Pande, M., Joon, A., Brewster, A. M., Chen, W. V., Hoppers, J. L., Eng, C., Shete, S., Casey, G., Schumacher, F., Lin, Y., Harrison, T. A., White, E., Ahsan, H., Andrulis, I. L., Whittemore, A. S., John, E. M., Win, A., Makalic, E., Schmidt, D. F., Kapuscinski, M. K., Ochs-Balcom, H. M., Gallinger, S., Jenkins, M. A., Newcomb, P. A., Lindor, N. M., Peters, U., Amos, C. I., Lynch, P. M. 2018; 13 (4): e0196245

    Abstract

    Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype.To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at P<5.0E-04 (n = 549, at 60 loci) were analyzed for replication (n = 293 cases and 2,103 controls).Multiple correlated SNPs in intron 1 of the ROBO1 gene were suggestively associated with the breast-colorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06).The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation.

    View details for PubMedID 29698419

  • Comparison of methods to assess onset of breast development in the LEGACY Girls Study: methodological considerations for studies of breast cancer BREAST CANCER RESEARCH Houghton, L. C., Knight, J. A., De Souza, M., Goldberg, M., White, M. L., O'Toole, K., Chung, W. K., Bradbury, A. R., Daly, M. B., Andrulis, I. L., John, E. M., Buys, S. S., Terry, M. 2018; 20: 33

    Abstract

    Younger age at onset of breast development, which has been declining in recent decades, is associated with increased breast cancer risk independent of age at menarche. Given the need to study the drivers of these trends, it is essential to validate methods to assess breast onset that can be used in large-scale studies when direct clinical assessment of breast onset is not feasible.Breast development is usually measured by Tanner stages (TSs), assessed either by physical examination or by mother's report using a picture-based Sexual Maturation Scale (SMS). As an alternative, a mother-reported Pubertal Development Scale (PDS) without pictures has been used in some studies. We compared agreement of SMS and PDS with each other (n = 1022) and the accuracy of PDS with clinical TS as a gold standard for the subset of girls with this measure (n = 282) using the LEGACY cohort. We further compared prediction of breast onset using ROC curves and tested whether adding urinary estrone 1-glucuronide (E1G) improved the AUC.The agreement of PDS with SMS was high (kappa = 0.80). The sensitivity of PDS vs clinical TS was 86.6%. The AUCs for PDS alone and SMS alone were 0.88 and 0.79, respectively. Including E1G concentrations improved the AUC for both methods (0.91 and 0.86 for PDS and SMS, respectively).The PDS without pictures is a highly accurate, sensitive, and specific method for assessing breast onset, especially in settings where clinical TS is not feasible. In addition, it is comparable to SMS methods with pictures and thus easier to implement in large-scale studies, particularly phone-based interviews where pictures may not be available. Urinary E1G can improve accuracy over than PDS or SMS alone.

    View details for PubMedID 29669587

    View details for PubMedCentralID PMC5907380

  • Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia NATURE COMMUNICATIONS Vijayakrishnan, J., Studd, J., Broderick, P., Kinnersley, B., Holroyd, A., Law, P. J., Kumar, R., Allan, J. M., Harrison, C. J., Moorman, A. V., Vora, A., Roman, E., Rachakonda, S., Kinsey, S. E., Sheridan, E., Thompson, P. D., Irving, J. A., Koehler, R., Hoffmann, P., Noethen, M. M., Heilmann-Heimbach, S., Joeckel, K., Easton, D. F., Pharaoh, P. P., Dunning, A. M., Peto, J., Canzian, F., Swerdlow, A., Eeles, R. A., Kote-Jarai, Z. S., Muir, K., Pashayan, N., Greaves, M., Zimmerman, M., Bartram, C. R., Schrappe, M., Stanulla, M., Hemminki, K., Houlston, R. S., PRACTICAL Consortium 2018; 9: 1340

    Abstract

    Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P?=?3.86?×?10-9, odds ratio (OR)?=?1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P?=?3.20?×?10-8, OR?=?2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.

    View details for DOI 10.1038/s41467-018-03178-z

    View details for Web of Science ID 000429498100002

    View details for PubMedID 29632299

    View details for PubMedCentralID PMC5890276

  • Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women's Environmental Cancer and Radiation Epidemiology Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Reiner, A. S., Sisti, J., John, E. M., Lynch, C. F., Brooks, J. D., Mellemkjar, L., Boice, J. D., Knight, J. A., Concannon, P., Capanu, M., Tischkowitz, M., Robson, M., Liang, X., Woods, M., Conti, D. V., Duggan, D., Shore, R., Stram, D. O., Thomas, D. C., Malone, K. E., Bernstein, L., WECARE Study Collaborative Group, Bernstein, J. L. 2018: JCO2017773424

    Abstract

    Purpose The Women's Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.

    View details for PubMedID 29620998

  • Discovery of mutations in homologous recombination genes in African-American women with breast cancer FAMILIAL CANCER Ding, Y., Adamson, A. W., Steele, L., Bailis, A. M., John, E. M., Tomlinson, G., Neuhausen, S. L. 2018; 17 (2): 187?95

    Abstract

    African-American women are more likely to develop aggressive breast cancer at younger ages and experience poorer cancer prognoses than non-Hispanic Caucasians. Deficiency in repair of DNA by homologous recombination (HR) is associated with cancer development, suggesting that mutations in genes that affect this process may cause breast cancer. Inherited pathogenic mutations have been identified in genes involved in repairing DNA damage, but few studies have focused on African-Americans. We screened for germline mutations in seven HR repair pathway genes in DNA of 181 African-American women with breast cancer, evaluated the potential effects of identified missense variants using in silico prediction software, and functionally characterized a set of missense variants by yeast two-hybrid assays. We identified five likely-damaging variants, including two PALB2 truncating variants (Q151X and W1038X) and three novel missense variants (RAD51C C135R, and XRCC3 L297P and V337E) that abolish protein-protein interactions in yeast two-hybrid assays. Our results add to evidence that HR gene mutations account for a proportion of the genetic risk for developing breast cancer in African-Americans. Identifying additional mutations that diminish HR may provide a tool for better assessing breast cancer risk and improving approaches for targeted treatment.

    View details for PubMedID 28864920

    View details for PubMedCentralID PMC5834346

  • Impact of individual and neighborhood factors on disparities in prostate cancer survival CANCER EPIDEMIOLOGY DeRouen, M. C., Schupp, C. W., Koo, J., Yang, J., Hertz, A., Shariff-Marco, S., Cockburn, M., Nelson, D. O., Ingles, S. A., John, E. M., Gomez, S. L. 2018; 53: 1?11

    Abstract

    We addressed the hypothesis that individual-level factors act jointly with social and built environment factors to influence overall survival for men with prostate cancer and contribute to racial/ethnic and socioeconomic (SES) survival disparities.We analyzed multi-level data, combining (1) individual-level data from the California Collaborative Prostate Cancer Study, a population-based study of non-Hispanic White (NHW), Hispanic, and African American prostate cancer cases (N?=?1800) diagnosed from 1997 to 2003, with (2) data on neighborhood SES (nSES) and social and built environment factors from the California Neighborhoods Data System, and (3) data on tumor characteristics, treatment and follow-up through 2009 from the California Cancer Registry. Multivariable, stage-stratified Cox proportional hazards regression models with cluster adjustments were used to assess education and nSES main and joint effects on overall survival, before and after adjustment for social and built environment factors.African American men had worse survival than NHW men, which was attenuated by nSES. Increased risk of death was associated with residence in lower SES neighborhoods (quintile 1 (lowest nSES) vs. 5: HR?=?1.56, 95% CI: 1.11-2.19) and lower education (

    View details for PubMedID 29328959

  • Associations between ALDH1A1 polymorphisms, alcohol consumption, and mortality among Hispanic and non-Hispanic white women diagnosed with breast cancer: the Breast Cancer Health Disparities Study BREAST CANCER RESEARCH AND TREATMENT Xia, Z., Baumgartner, K. B., Baumgartner, R. N., Boone, S. D., Hines, L. M., John, E. M., Wolff, R., Slattery, M. L., Connor, A. E. 2018; 168 (2): 443?55

    Abstract

    ALDH1A1, one of the main isotopes of aldehyde dehydrogenase-1 is involved in the differentiation and protection of normal hematopoietic stem cells and functions in alcohol sensitivity and dependence. We evaluated the associations between ALDH1A1 polymorphisms, alcohol consumption, and mortality among Hispanic and non-Hispanic white (NHW) breast cancer (BC) cases from the Breast Cancer Health Disparities Study.Nine SNPs in ALDH1A1 were evaluated in 920 Hispanic and 1372 NHW women diagnosed with incident invasive BC. Adjusted Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Models were stratified by Native American (NA) ancestry and alcohol consumption.A total of 443 deaths occurred over a median follow-up time of 11 years. After adjusting all results for multiple comparisons, rs7027604 was significantly associated with all-cause mortality (HRAA = 1.40; 95% CI 1.13-1.73, P adj = 0.018). The rs1424482 CC genotype (HRCC = 1.69; 95% CI 1.20-2.37, P adj = 0.027) and the rs7027604 AA genotype (HRAA = 1.65; 95% CI 1.21-2.26, P adj = 0.018) were positively associated with non-BC mortality. Among long-term light drinkers, rs1888202 was associated with decreased all-cause mortality (HRCG/GG = 0.36; 95% CI 0.20-0.64), while associations were not significant among non-drinkers or moderate/heavy drinkers (P interation = 0.218). The increased risk of all-cause mortality associated with rs63319 was limited to women with low NA ancestry (HRAA = 1.53; 95% CI 1.19-1.97).Multiple SNPs in ALDH1A1 were associated with increased risk of mortality after BC. Future BC studies examining the relationship between ALDH1A1 and mortality should consider the modifying effects of alcohol consumption and NA ancestry.

    View details for PubMedID 29190005

  • The association of mammographic density with risk of contralateral breast cancer and change in density with treatment in the WECARE study BREAST CANCER RESEARCH Knight, J. A., Blackmore, K. M., Fan, J., Malone, K. E., John, E. M., Lynch, C. F., Vachon, C. M., Bernstein, L., Brooks, J. D., Reiner, A. S., Liang, X., Woods, M., Bernstein, J. L., WECARE Study Collaborative Grp 2018; 20
  • Benign breast disease and breast cancer risk across the spectrum of familial risk using a prospective family study cohort (ProF-SC) Zeinomar, N., Phillips, K. A., Liao, Y., MacInnis, R. J., Dite, G. S., Daly, M. B., John, E. M., Andrulis, I. L., Buys, S. S., Hopper, J. L., Terry, M. B. AMER ASSOC CANCER RESEARCH. 2018
  • Risk-reducing oophorectomy and breast cancer risk across the spectrum of familial risk using a prospective family study cohort (ProF-SC) Terry, M. B., Phillips, K. A., Daly, M. B., Andrulis, I. L., Liao, Y., Ma, X., Zeinomar, N., MacInnis, R. J., Dite, G. S., John, E. M., Buys, S. S., Hopper, J. L. AMER ASSOC CANCER RESEARCH. 2018
  • Agreement between self-reported and register-based cardiovascular events among Danish breast cancer survivors JOURNAL OF CANCER SURVIVORSHIP Langballe, R., John, E. M., Malone, K. E., Bernstein, L., Knight, J. A., Lynch, C. F., Howell, R. M., Shore, R., Woods, M., Concannon, P., Bernstein, J. L., Mellemkjaer, L., WECARE Study Collaborative Grp 2018; 12 (1): 95?100

    Abstract

    We examined the degree of over- and under-reporting of cardiovascular diseases (CVDs) among female breast cancer survivors comparing self-reports to diagnostic codes from the Danish National Patient Register (NPR).The study comprised 357 Danish breast cancer patients from the WECARE study who completed a telephone interview concerning CVDs. Disease diagnoses for these women were obtained from the NPR. Agreement was calculated as the number of diagnoses that were both self-reported and in the NPR divided by (1) number of self-reported diagnoses (over-reporting) or (2) number of diagnoses in the NPR (under-reporting).In total, 68 women reported 96 specific cardiovascular outcomes of which 56 (58%) were found in the NPR. Ninety cardiovascular diagnoses were found in the NPR of which 56 (62%) were specifically reported at the interview. There was 80% agreement as to the occurrence of a cardiovascular diagnosis overall. Of 289 women reporting no CVD, 273 (94%) had no diagnoses in the NPR.Breast cancer survivors seem to report absence of CVD accurately, but they both over-report and under-report specific cardiovascular diagnoses. Using a broader definition of CVDs improves the agreement between self-reported and NPR data.Determining how cancer treatments affect the risk of cardiovascular morbidities is essential, and the development of high-quality methods for collecting such data is critical. While self-reported data are adequate for assessing the presence of any CVD condition, medical record review will yield higher quality data on specific CVD conditions.

    View details for PubMedID 28963606

    View details for PubMedCentralID PMC5790612

  • Breast cancer family history and allele-specific DNA methylation in the legacy girls study EPIGENETICS Wu, H., Do, C., Andrulis, I. L., John, E. M., Daly, M. B., Buys, S. S., Chung, W. K., Knight, J. A., Bradbury, A. R., Keegan, T. M., Schwartz, L., Krupska, I., Miller, R. L., Santella, R. M., Tycko, B., Terry, M. 2018; 13 (3): 240?50

    Abstract

    Family history, a well-established risk factor for breast cancer, can have both genetic and environmental contributions. Shared environment in families as well as epigenetic changes that also may be influenced by shared genetics and environment may also explain familial clustering of cancers. Epigenetic regulation, such as DNA methylation, can change the activity of a DNA segment without a change in the sequence; environmental exposures experienced across the life course can induce such changes. However, genetic-epigenetic interactions, detected as methylation quantitative trait loci (mQTLs; a.k.a. meQTLs) and haplotype-dependent allele-specific methylation (hap-ASM), can also contribute to inter-individual differences in DNA methylation patterns. To identify differentially methylated regions (DMRs) associated with breast cancer susceptibility, we examined differences in white blood cell DNA methylation in 29 candidate genes in 426 girls (ages 6-13 years) from the LEGACY Girls Study, 239 with and 187 without a breast cancer family history (BCFH). We measured methylation by targeted massively parallel bisulfite sequencing (bis-seq) and observed BCFH DMRs in two genes: ESR1 (?4.9%, P = 0.003) and SEC16B (?3.6%, P = 0.026), each of which has been previously implicated in breast cancer susceptibility and pubertal development. These DMRs showed high inter-individual variability in methylation, suggesting the presence of mQTLs/hap-ASM. Using single nucleotide polymorphisms data in the bis-seq amplicon, we found strong hap-ASM in SEC16B (with allele specific-differences ranging from 42% to 74%). These findings suggest that differential methylation in genes relevant to breast cancer susceptibility may be present early in life, and that inherited genetic factors underlie some of these epigenetic differences.

    View details for PubMedID 29436922

    View details for PubMedCentralID PMC5997170

  • Large-scale transcriptome-wide association study identifies new prostate cancer risk regions. Nature communications Mancuso, N., Gayther, S., Gusev, A., Zheng, W., Penney, K. L., Kote-Jarai, Z., Eeles, R., Freedman, M., Haiman, C., Pasaniuc, B. 2018; 9 (1): 4079

    Abstract

    Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here we integrate the largest PrCa GWAS (N?=?142,392) with gene expression measured in 45 tissues (N?=?4458), including normal and tumor prostate, to perform a multi-tissue transcriptome-wide association study (TWAS) for PrCa. We identify 217 genes at 84 independent 1?Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2?Mb. 23 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at a pre-defined level; this reduced the list of 217 associations to 109 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci.

    View details for DOI 10.1038/s41467-018-06302-1

    View details for PubMedID 30287866

    View details for PubMedCentralID PMC6172280

  • The association of mammographic density with risk of contralateral breast cancer and change in density with treatment in the WECARE study. Breast cancer research : BCR Knight, J. A., Blackmore, K. M., Fan, J., Malone, K. E., John, E. M., Lynch, C. F., Vachon, C. M., Bernstein, L., Brooks, J. D., Reiner, A. S., Liang, X., Woods, M., Bernstein, J. L. 2018; 20 (1): 23

    Abstract

    Mammographic density (MD) is an established predictor of risk of a first breast cancer, but the relationship of MD to contralateral breast cancer (CBC) risk is not clear, including the roles of age, mammogram timing, and change with treatment. Multivariable prediction models for CBC risk are needed and MD could contribute to these.We conducted a case-control study of MD and CBC risk in phase II of the WECARE study where cases had a CBC diagnosed ??2 years after first diagnosis at age <55 years and controls had unilateral breast cancer (UBC) with similar follow-up time. We retrieved film mammograms of the unaffected breast from two time points, prior to/at the time of the first diagnosis (253 CBC cases, 269 UBC controls) and ??6 months up to 48 months following the first diagnosis (333 CBC cases, 377 UBC controls). Mammograms were digitized and percent MD (%MD) was measured using the thresholding program Cumulus. Odds ratios (OR) and 95% confidence intervals (CI) for association between %MD and CBC, adjusted for age, treatment, and other factors related to CBC, were estimated using logistic regression. Linear regression was used to estimate the association between treatment modality and change in %MD in 467 women with mammograms at both time points.For %MD assessed following diagnosis, there was a statistically significant trend of increasing CBC with increasing %MD (p = 0.03). Lower density (<25%) was associated with reduced risk of CBC compared to 25 to

    View details for PubMedID 29566728

  • Oral Contraceptive Use and Breast Cancer Risk: Retrospective and Prospective Analyses From a BRCA1 and BRCA2 Mutation Carrier Cohort Study. JNCI cancer spectrum Schrijver, L. H., Olsson, H., Phillips, K. A., Terry, M. B., Goldgar, D. E., Kast, K., Engel, C., Mooij, T. M., Adlard, J., Barrowdale, D., Davidson, R., Eeles, R., Ellis, S., Evans, D. G., Frost, D., Izatt, L., Porteous, M. E., Side, L. E., Walker, L., Berthet, P., Bonadona, V., Leroux, D., Mouret-Fourme, E., Venat-Bouvet, L., Buys, S. S., Southey, M. C., John, E. M., Chung, W. K., Daly, M. B., Bane, A., van Asperen, C. J., Gómez Garcia, E. B., Mourits, M. J., van Os, T. A., Roos-Blom, M. J., Friedlander, M. L., McLachlan, S. A., Singer, C. F., Tan, Y. Y., Foretova, L., Navratilova, M., Gerdes, A. M., Caldes, T., Simard, J., Olah, E., Jakubowska, A., Arver, B., Osorio, A., Nogučs, C., Andrieu, N., Easton, D. F., van Leeuwen, F. E., Hopper, J. L., Milne, R. L., Antoniou, A. C., Rookus, M. A. 2018; 2 (2): pky023

    Abstract

    For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear.Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed.For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, P < .001 and P = .001, respectively; BRCA2: full retrospective analysis, P = .002).Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and nonhormonal contraceptive methods should be discussed.

    View details for DOI 10.1093/jncics/pky023

    View details for PubMedID 31360853

    View details for PubMedCentralID PMC6649757

  • Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis. International journal of epidemiology Shu, X., Wu, L., Khankari, N. K., Shu, X. O., Wang, T. J., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Milne, R. L., Schmidt, M. K., Pharoah, P. D., Andrulis, I. L., Hunter, D. J., Simard, J., Easton, D. F., Zheng, W. 2018

    Abstract

    In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI)?=?1.26-2.31, p ?=? 5.09 ?× ?10-4], 2-h glucose (OR?=?1.80 per SD increase, 95% CI?=?1.3 0-2.49, p? =? 4.02 ?×? 10-4), BMI (OR?=?0.70 per 5-unit increase, 95% CI?=?0.65-0.76, p ?=? 5.05 ?×? 10-19) and WHRadj BMI (OR?=?0.85, 95% CI?=?0.79-0.91, p? = ?9.22 ?×? 10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

    View details for DOI 10.1093/ije/dyy201

    View details for PubMedID 30277539

  • Measuring serum melatonin in postmenopausal women: Implications for epidemiologic studies and breast cancer studies. PloS one Chu, L. W., John, E. M., Yang, B., Kurian, A. W., Zia, Y., Yu, K., Ingles, S. A., Stanczyk, F. Z., Hsing, A. W. 2018; 13 (4): e0195666

    Abstract

    Circulating melatonin is a good candidate biomarker for studies of circadian rhythms and circadian disruption. However, epidemiologic studies on circulating melatonin are limited because melatonin is secreted at night, yet most epidemiologic studies collect blood during the day when melatonin levels are very low, and assays are lacking that are ultrasensitive to detect low levels of melatonin reliably.To assess the performance of a refined radioimmunoassay in measuring morning melatonin among women.We used morning serum samples from 47 postmenopausal women ages 48-80 years without a history of breast cancer who participated in the San Francisco Bay Area Breast Cancer Study, including 19 women who had duplicate measurements. The coefficient of variation (CV) and intraclass coefficient (ICC) were estimated using the random effect model.Reproducibility for the assay was satisfactory, with a CV of 11.2% and an ICC of 98.9%; correlation between the replicate samples was also high (R = 0.96). In the 47 women, serum melatonin levels ranged from 0.6 to 62.6 pg/ml, with a median of 7.0 pg/ml.Our results suggest that it is possible to reliably measure melatonin in postmenopausal women in morning serum samples in large epidemiologic studies to evaluate the role of melatonin in cancer etiology or prognosis.

    View details for PubMedID 29641614

  • Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility NATURE COMMUNICATIONS Sud, A., Thomsen, H., Law, P. J., Foersti, A., da Silva Filho, M., Holroyd, A., Broderick, P., Orlando, G., Lenive, O., Wright, L., Cooke, R., Easton, D., Pharoah, P., Dunning, A., Peto, J., Canzian, F., Eeles, R., Kote-Jarai, Z. S., Muir, K., Pashayan, N., Hoffmann, P., Noethen, M. M., Joeckel, K., von Strandmann, E., Lightfoot, T., Kane, E., Roman, E., Lake, A., Montgomery, D., Jarrett, R. F., Swerdlow, A. J., Engert, A., Orr, N., Hemminki, K., Houlston, R. S., PRACTICAL Consortium 2017; 8: 1892

    Abstract

    Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P?=?1.52?×?10-8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P?=?9.43?×?10-17), 6q23.3 (rs6928977, P?=?4.62?×?10-11), 10p14 (rs3781093, P?=?9.49?×?10-13), 13q34 (rs112998813, P?=?4.58?×?10-8) and 16p13.13 (rs34972832, P?=?2.12?×?10-8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.

    View details for DOI 10.1038/s41467-017-00320-1

    View details for Web of Science ID 000416933400014

    View details for PubMedID 29196614

    View details for PubMedCentralID PMC5711884

  • Panel sequencing of 264 candidate susceptibility genes and segregation analysis in a cohort of non-BRCA1, non-BRCA2 breast cancer families BREAST CANCER RESEARCH AND TREATMENT Li, J., Li, H., Makunin, I., Thompson, B. A., Tao, K., Young, E. L., Lopez, J., Camp, N. J., Tavtigian, S. V., John, E. M., Andrulis, I. L., Khanna, K., Goldgar, D., Chenevix-Trench, G., KConFab Investigators 2017; 166 (3): 937?49

    Abstract

    The main aim of this study was to screen epigenetic modifier genes and known breast cancer driver genes for germline mutations in non-BRCA1/2 (BRCAx) breast cancer families in order to identify novel susceptibility genes of moderate-high penetrance.We screened 264 candidate susceptibility genes in 656 index cases from non-BRCA1/2 families. Potentially pathogenic candidate mutations were then genotyped in all available family members for the assessment of co-segregation of the variant with disease in the family in order to estimate the breast cancer risks associated with these mutations. For 11 of the candidate susceptibility genes, we screened an additional 800 non-BRCA1/2 breast cancer cases and 787 controls.Only two genes, CHD8 and USH2A showed any evidence of an increased risk of breast cancer (RR = 2.40 (95% CI 1.0-7.32) and 2.48 (95% CI 1.11-6.67), respectively).We found no convincing evidence that epigenetic modifier and known breast cancer driver genes carry germline mutations that increase breast cancer risk. USH2A is no longer regarded as a breast cancer driver gene and seems an implausible candidate given its association with Usher syndrome. However, somatic mutations in CHD8 have been recently reported, making it an even more promising candidate, but further analysis of CHD8 in very large cohorts of families or case-control studies would be required to determine if it is a moderate-risk breast cancer susceptibility gene.

    View details for PubMedID 28840378

  • Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer NATURE GENETICS Milne, R. L., Kuchenbaecker, K. B., Michailidou, K., Beesley, J., Kar, S., Lindstrom, S., Hui, S., Lemacon, A., Soucy, P., Dennis, J., Jiang, X., Rostamianfar, A., Finucane, H., Bolla, M. K., McGuffog, L., Wang, Q., Aalfs, C. M., Adams, M., Adlard, J., Agata, S., Ahmed, S., Ahsan, H., Aittomaki, K., Al-Ejeh, F., Allen, J., Ambrosone, C. B., Amos, C. I., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Arnold, N., Aronson, K. J., Auber, B., Auer, P. L., Ausems, M. M., Azzollini, J., Bacot, F., Balmana, J., Barile, M., Barjhoux, L., Barkardottir, R. B., Barrdahl, M., Barnes, D., Barrowdale, D., Baynes, C., Beckmann, M. W., Benitez, J., Bermisheva, M., Bernstein, L., Bignon, Y., Blazer, K. R., Blok, M. J., Blomqvist, C., Blot, W., Bobolis, K., Boeckx, B., Bogdanova, N. V., Bojesen, A., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Bozsik, A., Bradbury, A. R., Brand, J. S., Brauch, H., Brenner, H., Bressac-de Paillerets, B., Brewer, C., Brinton, L., Broberg, P., Brooks-Wilson, A., Brunet, J., Bruening, T., Burwinkel, B., Buys, S. S., Byun, J., Cai, Q., Caldes, T., Caligo, M. A., Campbell, I., Canzian, F., Caron, O., Carracedo, A., Carter, B. D., Esteban Castelao, J., Castera, L., Caux-Moncoutier, V., Chan, S. B., Chang-Claude, J., Chanock, S. J., Chen, X., Cheng, T., Chiquette, J., Christiansen, H., Claes, K. M., Clarke, C. L., Conner, T., Conroy, D. M., Cook, J., Cordina-Duverger, E., Cornelissen, S., Coupier, I., Cox, A., Cox, D. G., Cross, S. S., Cuk, K., Cunningham, J. M., Czene, K., Daly, M. B., Damiola, F., Darabi, H., Davidson, R., De Leeneer, K., Devilee, P., Dicks, E., Diez, O., Ding, Y., Ditsch, N., Doheny, K. F., Domchek, S. M., Dorfling, C. M., Doerk, T., dos-Santos-Silva, I., Dubois, S., Dugue, P., Dumont, M., Dunning, A. M., Durcan, L., Dwek, M., Dworniczak, B., Eccles, D., Eeles, R., Ehrencrona, H., Eilber, U., Ejlertsen, B., Ekici, A. B., Eliassen, A., Engel, C., Eriksson, M., Fachal, L., Faivre, L., Fasching, P. A., Faust, U., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Foulkes, W. D., Friedman, E., Fritschi, L., Frost, D., Gabrielson, M., Gaddam, P., Gammon, M. D., Ganz, P. A., Gapstur, S. M., Garber, J., Garcia-Barberan, V., Garcia-Saenz, J. A., Gaudet, M. M., Gauthier-Villars, M., Gehrig, A., Georgoulias, V., Gerdes, A., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Goodfellow, P., Greene, M. H., Alnaes, G., Grip, M., Gronwald, J., Grundy, A., Gschwantler-Kaulich, D., Guenel, P., Guo, Q., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hallberg, E., Hamann, U., Hamel, N., Hankinson, S., Hansen, T. O., Harrington, P., Hart, S. N., Hartikainen, J. M., Healey, C. S., Hein, A., Helbig, S., Henderson, A., Heyworth, J., Hicks, B., Hillemanns, P., Hodgson, S., Hogervorst, F. B., Hollestelle, A., Hooning, M. J., Hoover, B., Hopper, J. L., Hu, C., Huang, G., Hulick, P. J., Humphreys, K., Hunter, D. J., Imyanitov, E. N., Isaacs, C., Iwasaki, M., Izatt, L., Jakubowska, A., James, P., Janavicius, R., Janni, W., Jensen, U., John, E. M., Johnson, N., Jones, K., Jones, M., Jukkola-Vuorinen, A., Kaaks, R., Kabisch, M., Kaczmarek, K., Kang, D., Kast, K., Keeman, R., Kerin, M. J., Kets, C. M., Keupers, M., Khan, S., Khusnutdinova, E., Kiiski, J. I., Kim, S., Knight, J. A., Konstantopoulou, I., Kosma, V., Kristensen, V. N., Kruse, T. A., Kwong, A., Laenkholm, A., Laitman, Y., Lalloo, F., Lambrechts, D., Landsman, K., Lasset, C., Lazaro, C., Le Marchand, L., Lecarpentier, J., Lee, A., Lee, E., Lee, J., Lee, M., Lejbkowicz, F., Lesueur, F., Li, J., Lilyquist, J., Lincoln, A., Lindblom, A., Lissowska, J., Lo, W., Loibl, S., Long, J., Loud, J. T., Lubinski, J., Luccarini, C., Lush, M., MacInnis, R. J., Maishman, T., Makalic, E., Kostovska, I., Malone, K. E., Manoukian, S., Manson, J. E., Margolin, S., Martens, J. M., Martinez, M., Matsuo, K., Mavroudis, D., Mazoyer, S., McLean, C., Meijers-Heijboer, H., Menendez, P., Meyer, J., Miao, H., Miller, A., Miller, N., Mitchell, G., Montagna, M., Muir, K., Mulligan, A., Mulot, C., Nadesan, S., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nevelsteen, I., Niederacher, D., Nielsen, S. F., Nordestgaard, B. G., Norman, A., Nussbaum, R. L., Olah, E., Olopade, O. I., Olson, J. E., Olswold, C., Ong, K., Oosterwijk, J. C., Orr, N., Osorio, A., Pankratz, V., Papi, L., Park-Simon, T., Paulsson-Karlsson, Y., Lloyd, R., Pedersen, I., Peissel, B., Peixoto, A., Perez, J. A., Peterlongo, P., Peto, J., Pfeiler, G., Phelan, C. M., Pinchev, M., Plaseska-Karanfilska, D., Poppe, B., Porteous, M. E., Prentice, R., Presneau, N., Prokofieva, D., Pugh, E., Angel Pujana, M., Pylkas, K., Rack, B., Radice, P., Rahman, N., Rantala, J., Rappaport-Fuerhauser, C., Rennert, G., Rennert, H. S., Rhenius, V., Rhiem, K., Richardson, A., Rodriguez, G. C., Romero, A., Romm, J., Rookus, M. A., Rudolph, A., Ruediger, T., Saloustros, E., Sanders, J., Sandler, D. P., Sangrajrang, S., Sawyer, E. J., Schmidt, D. F., Schoemaker, M. J., Schumacher, F., Schuermann, P., Schwentner, L., Scott, C., Scott, R. J., Seal, S., Senter, L., Seynaeve, C., Shah, M., Sharma, P., Shen, C., Sheng, X., Shimelis, H., Shrubsole, M. J., Shu, X., Side, L. E., Singer, C. F., Sohn, C., Southey, M. C., Spinelli, J. J., Spurdle, A. B., Stegmaier, C., Stoppa-Lyonnet, D., Sukiennicki, G., Surowy, H., Sutter, C., Swerdlow, A., Szabo, C. I., Tamimi, R. M., Tan, Y. Y., Taylor, J. A., Tejada, M., Tengstrom, M., Teo, S. H., Terry, M. B., Tessier, D. C., Teule, A., Thoene, K., Thull, D. L., Tibiletti, M., Tihomirova, L., Tischkowitz, M., Toland, A. E., Tollenaar, R. M., Tomlinson, I., Tong, L., Torres, D., Tranchant, M., Truong, T., Tucker, K., Tung, N., Tyrer, J., Ulmer, H., Vachon, C., van Asperen, C. J., Van Den Berg, D., van den Ouweland, A. W., van Rensburg, E. J., Varesco, L., Varon-Mateeva, R., Vega, A., Viel, A., Vijai, J., Vincent, D., Vollenweider, J., Walker, L., Wang, Z., Wang-Gohrke, S., Wappenschmidt, B., Weinberg, C. R., Weitzel, J. N., Wendt, C., Wesseling, J., Whittemore, A. S., Wijnen, J. T., Willett, W., Winqvist, R., Wolk, A., Wu, A. H., Xia, L., Yang, X. R., Yannoukakos, D., Zaffaroni, D., Zheng, W., Zhu, B., Ziogas, A., Ziv, E., Zorn, K. K., Gago-Dominguez, M., Mannermaa, A., Olsson, H., Teixeira, M. R., Stone, J., Offit, K., Ottini, L., Park, S. K., Thomassen, M., Hall, P., Meindl, A., Schmutzler, R. K., Droit, A., Bader, G. D., Pharoah, P. P., Couch, F. J., Easton, D. F., Kraft, P., Chenevix-Trench, G., Garcia-Closas, M., Schmidt, M. K., Antoniou, A. C., Simard, J., ABCTB Investigators, EMBRACE, GEMO Study Collaborators, HEBON, kConFab AOCS Investigators, NBSC Collaborators 2017; 49 (12): 1767?78

    Abstract

    Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

    View details for PubMedID 29058716

    View details for PubMedCentralID PMC5808456

  • Association analysis identifies 65 new breast cancer risk loci NATURE Michailidou, K., Lindstrom, S., Dennis, J., Beesley, J., Hui, S., Kar, S., Lemacon, A., Soucy, P., Glubb, D., Rostamianfar, A., Bolla, M. K., Wang, Q., Tyrer, J., Dicks, E., Lee, A., Wang, Z., Allen, J., Keeman, R., Eilber, U., French, J. D., Chen, X., Fachal, L., McCue, K., McCart, A. E., Reed, A., Ghoussaini, M., Carroll, J. S., Jiang, X., Finucane, H., Adams, M., Adank, M. A., Ahsan, H., Aittomaki, K., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Arun, B., Auer, P. L., Bacot, F., Barrdahl, M., Baynes, C., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brand, J. S., Brauch, H., Brennan, P., Brenner, H., Brinton, L., Broberg, P., Brock, I. W., Broeks, A., Brooks-Wilson, A., Brucker, S. Y., Bruening, T., Burwinkel, B., Butterbach, K., Cai, Q., Cai, H., Caldes, T., Canzian, F., Carracedo, A., Carter, B. D., Castelao, J. E., Chan, T. L., Cheng, T., Chia, K., Choi, J., Christiansen, H., Clarke, C. L., Collee, M., Conroy, D. M., Cordina-Duverger, E., Cornelissen, S., Cox, D. G., Cox, A., Cross, S. S., Cunningham, J. M., Czene, K., Daly, M. B., Devilee, P., Doheny, K. F., Doerk, T., dos-Santos-Silva, I., Dumont, M., Durcan, L., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A., Ellberg, C., Elvira, M., Engel, C., Eriksson, M., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fritschi, L., Gaborieau, V., Gabrielson, M., Gago-Dominguez, M., Gao, Y., Gapstur, S. M., Garcia-Saenz, J. A., Gaudet, M. M., Georgoulias, V., Giles, G. G., Glendon, G., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Alnaes, G., Grip, M., Gronwald, J., Grundy, A., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hamann, U., Hamel, N., Hankinson, S., Harrington, P., Hart, S. N., Hartikainen, J. M., Hartman, M., Hein, A., Heyworth, J., Hicks, B., Hillemanns, P., Ho, D. N., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Hou, M., Hsiung, C., Huang, G., Humphreys, K., Ishiguro, J., Ito, H., Iwasaki, M., Iwata, H., Jakubowska, A., Janni, W., John, E. M., Johnson, N., Jones, K., Jones, M., Jukkola-Vuorinen, A., Kaaks, R., Kabisch, M., Kaczmarek, K., Kang, D., Kasuga, Y., Kerin, M. J., Khan, S., Khusnutdinova, E., Kiiski, J. I., Kim, S., Knight, J. A., Kosma, V., Kristensen, V. N., Kruger, U., Kwong, A., Lambrechts, D., Le Marchand, L., Lee, E., Lee, M., Lee, J., Lee, C., Lejbkowicz, F., Li, J., Lilyquist, J., Lindblom, A., Lissowska, J., Lo, W., Loibl, S., Long, J., Lophatananon, A., Lubinski, J., Luccarini, C., Lux, M. P., Ma, E. K., MacInnis, R. J., Maishman, T., Makalic, E., Malone, K. E., Kostovska, I., Mannermaa, A., Manoukian, S., Manson, J. E., Margolin, S., Mariapun, S., Martinez, M., Matsuo, K., Mavroudis, D., McKay, J., McLean, C., Meijers-Heijboer, H., Meindl, A., Menendez, P., Menon, U., Meyer, J., Miao, H., Miller, N., Taib, N., Muir, K., Mulligan, A., Mulot, C., Neuhausen, S. L., Nevanlinna, H., Neven, P., Nielsen, S. F., Noh, D., Nordestgaard, B. G., Norman, A., Olopade, O. I., Olson, J. E., Olsson, H., Olswold, C., Orr, N., Pankratz, V., Park, S. K., Park-Simon, T., Lloyd, R., Perez, J. A., Peterlongo, P., Peto, J., Phillips, K., Pinchev, M., Plaseska-Karanfilska, D., Prentice, R., Presneau, N., Prokofyeva, D., Pugh, E., Pylkas, K., Rack, B., Radice, P., Rahman, N., Rennert, G., Rennert, H. S., Rhenius, V., Romero, A., Romm, J., Ruddy, K. J., Ruediger, T., Rudolph, A., Ruebner, M., Rutgers, E. T., Saloustros, E., Sandler, D. P., Sangrajrang, S., Sawyer, E. J., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schumacher, F., Schuermann, P., Scott, R. J., Scott, C., Seal, S., Seynaeve, C., Shah, M., Sharma, P., Shen, C., Sheng, G., Sherman, M. E., Shrubsole, M. J., Shu, X., Smeets, A., Sohn, C., Southey, M. C., Spinelli, J. J., Stegmaier, C., Stewart-Brown, S., Stone, J., Stram, D. O., Surowy, H., Swerdlow, A., Tamimi, R., Taylor, J. A., Tengstrom, M., Teo, S. H., Terry, M., Tessier, D. C., Thanasitthichai, S., Thoene, K., Tollenaar, R. M., Tomlinson, I., Tong, L., Torres, D., Truong, T., Tseng, C., Tsugane, S., Ulmer, H., Ursin, G., Untch, M., Vachon, C., van Asperen, C. J., Van Den Berg, D., van den Ouweland, A. W., van der Kolk, L., van der Luijt, R. B., Vincent, D., Vollenweider, J., Waisfisz, Q., Wang-Gohrke, S., Weinberg, C. R., Wendt, C., Whittemore, A. S., Wildiers, H., Willett, W., Winqvist, R., Wolk, A., Wu, A. H., Xia, L., Yamaji, T., Yang, X. R., Yip, C., Yoo, K., Yu, J., Zheng, W., Zheng, Y., Zhu, B., Ziogas, A., Ziv, E., Lakhani, S. R., Antoniou, A. C., Droit, A., Andrulis, I. L., Amos, C. I., Couch, F. J., Pharoah, P. P., Chang-Claude, J., Hall, P., Hunter, D. J., Milne, R. L., Garcia-Closas, M., Schmidt, M. K., Chanock, S. J., Dunning, A. M., Edwards, S. L., Bader, G. D., Chenevix-Trench, G., Simard, J., Kraft, P., Easton, D. F., NBCS Collaborators, ABCTB Investigators, KConFab AOCS Investigators 2017; 551 (7678): 92-+

    Abstract

    Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P?

    View details for PubMedID 29059683

    View details for PubMedCentralID PMC5798588

  • A pilot study on the utility of reduced urine collection frequency protocols for the assessment of reproductive hormones in adolescent girls JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM Allaway, H. M., John, E. M., Keegan, T. H., De Souza, M. 2017; 30 (10): 1083?93

    Abstract

    The objectives of this study were to assess the feasibility of and compliance to collecting urine samples in pre- and postmenarcheal girls and to determine if a less than daily collection frequency was sufficient for assessing ovarian function.Twenty-five postmenarcheal girls (11-17 years) collected samples using either a two or a three samples/week protocol during one menstrual cycle. Exposure and mean estrone-1-glucuronide (E1G) and pregnanediol glucuronide concentrations were calculated, and evidence of luteal activity (ELA) was evaluated. Sixteen premenarcheal girls (8-11 years) collected one sample/month for six consecutive months. Samples were analyzed for E1G concentration. Participant compliance was calculated using dates on the urine samples and paper calendars.Participants collecting three samples/week were more compliant to the protocol than those collecting two samples/week (83.6%±2.6% vs. 66.8%±6.6%; p=0.034). There were no differences (p>0.10) regarding paper calendar return (81.8%±12.2% vs. 92.9%±7.1%), recording menses (55.6%±17.6% vs. 92.3%±7.7%) or sample collection (88.9%±11.1% vs. 84.6%±10.4%) between the two protocols. The average cycle length was 30.5±1.3 days and 32% of cycles had ELA. The premenarcheal girls were 100% compliant to the protocol. Only 68.8% of participants returned the paper calendar and 81.8% of those participants recorded sample collection. The average E1G concentration was 15.9±3.8 ng/mL.Use of a less than daily collection frequency during one menstrual cycle in postmenarcheal, adolescent girls is feasible and provides informative data about ovarian function. Collection of one sample/month in premenarcheal girls is feasible and detects the expected low E1G concentrations. Alternate strategies to the use of a paper calendar should be considered.

    View details for DOI 10.1515/jpem-2017-0050

    View details for Web of Science ID 000412132400010

    View details for PubMedID 28949930

  • Association of Common Genetic Variants With Contralateral Breast Cancer Risk in the WECARE Study. Journal of the National Cancer Institute Robson, M. E., Reiner, A. S., Brooks, J. D., Concannon, P. J., John, E. M., Mellemkjaer, L., Bernstein, L., Malone, K. E., Knight, J. A., Lynch, C. F., Woods, M., Liang, X., Haile, R. W., Duggan, D. J., Shore, R. E., Smith, S. A., Thomas, D. C., Stram, D. O., Bernstein, J. L. 2017; 109 (10)

    Abstract

    Women with unilateral breast cancer (UBC) are at risk of developing a subsequent contralateral breast cancer (CBC). Common variants are associated with breast cancer risk. Whether these influence CBC risk is unknown.Participants were breast cancer cases from the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study. Sixty-seven established breast cancer risk loci were genotyped directly or by imputation in 1459 case subjects with CBC and 2126 UBC control subjects. An unweighted polygenic risk score (PRS) was created by summing the number of risk alleles for each directly genotyped single nucleotide polymorphism (SNP), or for imputed loci, the imputed dosage. A weighted PRS was calculated similarly, but where each SNP's contribution was weighted by the published per-allele log odds ratio. Unweighted and weighted polygenic risk scores and CBC risk were modeled using conditional logistic regression. Cumulative CBC risk was estimated and benchmarked using Surveillance, Epidemiology, and End Results population incidence rates.Both unweighted and weighted PRS were statistically significantly associated with CBC risk. The adjusted risk ratio of CBC in women in the upper quartile of unweighted PRS compared with the lowest quartile was 1.63 (95% confidence interval [CI] = 1.33 to 2.00). The estimated 10-year cumulative risk for women in the upper quartile of the unweighted PRS was 7.4% (95% CI?=?6.0% to 9.1%). For women in the upper quartile of the weighted PRS, the risk ratio for CBC was 1.75 (95% CI?=?1.41 to 2.18) compared with women in the lowest quartile. There was no statistically significant heterogeneity by age, treatment (radiation therapy dose, tamoxifen, chemotherapy), estrogen receptor status of the first primary, histology of the first primary, length of at-risk period for CBC, or breast cancer family history.Common genomic variants associated with the development of first primary breast cancer are also associated with the development of CBC; the risk is strongest among those who carry more risk alleles.

    View details for DOI 10.1093/jnci/djx051

    View details for PubMedID 28521362

  • Reply to Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The Breast Cancer Family Registry-methodological issues CANCER Zhang, F., John, E. M. 2017; 123 (18): 3639

    View details for PubMedID 28621796

  • Alcohol consumption and cigarette smoking in combination: A predictor of contralateral breast cancer risk in the WECARE study INTERNATIONAL JOURNAL OF CANCER Knight, J. A., Fan, J., Malone, K. E., John, E. M., Lynch, C. F., Langballe, R., Bernstein, L., Shore, R. E., Brooks, J. D., Reiner, A. S., Woods, M., Liang, X., Bernstein, J. L., WECARE Study Collaborative Grp 2017; 141 (5): 916?24

    Abstract

    Alcohol drinking and, to a lesser extent, cigarette smoking are risk factors for a first primary breast cancer. Information on these behaviours at diagnosis may contribute to risk prediction of contralateral breast cancer (CBC) and they are potentially modifiable. The WECARE Study is a large population-based case-control study of women with breast cancer where cases (N?=?1,521) had asynchronous CBC and controls (N?=?2,212), matched on survival time and other factors, had unilateral breast cancer (UBC). Using multivariable conditional logistic regression to estimate rate ratios (RR) and 95% confidence intervals (CI), we examined the risk of CBC in relation to drinking and smoking history at and following first diagnosis. We adjusted for treatment, disease characteristics and other factors. There was some evidence for an association between CBC risk and current drinking or current smoking at the time of first breast cancer diagnosis, but the increased risk occurred primarily among women exposed to both (RR?=?1.62, 95% CI 1.24-2.11). CBC risk was also elevated in women who both smoked and drank alcohol after diagnosis (RR?=?1.54, 95% CI 1.18-1.99). In the subset of women with detailed information on amount consumed, smoking an average of ?10 cigarettes per day following diagnosis was also associated with increased CBC risk (RR?=?1.50, 95% CI 1.08-2.08; p-trend?=?0.03). Among women with a diagnosis of breast cancer, information on current drinking and smoking could contribute to the prediction of CBC risk. Women who both drink and smoke may represent a group who merit targeted lifestyle intervention to modify their risk of CBC.

    View details for PubMedID 28524234

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  • Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Conti, D. V., Wang, K., Sheng, X., Bensen, J. T., Hazelett, D. J., Cook, M. B., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Stanford, J. L., Zheng, W., Sanderson, M., John, E. M., Park, J. Y., Xu, J., Stevens, V. L., Berndt, S. I., Haiman, C. A., PRACTICAL ELLIPSE Consortium 2017; 109 (8)

    Abstract

    Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10?202 case subjects and 10?810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10?×?10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR?=?1.62, 95% CI?=?1.39 to 1.89, P = 7.50?×?10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.

    View details for PubMedID 29117387

    View details for PubMedCentralID PMC5448553

  • Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population BREAST CANCER RESEARCH Reiner, A. S., Lynch, C. F., Sisti, J. S., John, E. M., Brooks, J. D., Bernstein, L., Knight, J. A., Hsu, L., Concannon, P., Mellemkjaer, L., Tischkowitz, M., Haile, R. W., Shen, R., Malone, K. E., Woods, M., Liang, X., Morrow, M., Bernstein, J. L., WECARE Study Collaborative Grp 2017; 19
  • Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores JOURNAL OF CLINICAL ONCOLOGY Lecarpentier, J., Silvestri, V., Kuchenbaecker, K. B., Barrowdale, D., Dennis, J., McGuffog, L., Soucy, P., Leslie, G., Rizzolo, P., Navazio, A., Valentini, V., Zelli, V., Lee, A., Al Olama, A., Tyrer, J. P., Southey, M., John, E. M., Conner, T. A., Goldgar, D. E., Buys, S. S., Janavicius, R., Steele, L., Ding, Y., Neuhausen, S. L., Hansen, T. O., Osorio, A., Weitzel, J. N., Toss, A., Medici, V., Cortesi, L., Zanna, I., Palli, D., Radice, P., Manoukian, S., Peissel, B., Azzollini, J., Viel, A., Cini, G., Damante, G., Tommasi, S., Peterlongo, P., Fostira, F., Hamann, U., Evans, D., Henderson, A., Brewer, C., Eccles, D., Cook, J., Ong, K., Walker, L., Side, L. E., Porteous, M. E., Davidson, R., Hodgson, S., Frost, D., Adlard, J., Izatt, L., Eeles, R., Ellis, S., Tischkowitz, M., Godwin, A. K., Meindl, A., Gehrig, A., Dworniczak, B., Sutter, C., Engel, C., Niederacher, D., Steinemann, D., Hahnen, E., Hauke, J., Rhiem, K., Kast, K., Arnold, N., Ditsch, N., Wang-Gohrke, S., Wappenschmidt, B., Wand, D., Lasset, C., Stoppa-Lyonnet, D., Belotti, M., Damiola, F., Barjhoux, L., Mazoyer, S., Van Heetvelde, M., Poppe, B., De Leeneer, K., Claes, K. M., de la Hoya, M., Garcia-Barberan, V., Caldes, T., Perez Segura, P., Kiiski, J. I., Aittomaeki, K., Khan, S., Nevanlinna, H., van Asperen, C. J., Vaszko, T., Kasler, M., Olah, E., Balmana, J., Gutierrez-Enriquez, S., Diez, O., Teule, A., Izquierdo, A., Darder, E., Brunet, J., Del Valle, J., Feliubadalo, L., Pujana, M., Lazaro, C., Arason, A., Agnarsson, B. A., Johannsson, O., Barkardottir, R. B., Alducci, E., Tognazzo, S., Montagna, M., Teixeira, M. R., Pinto, P., Spurdle, A. B., Holland, H., Lee, J., Lee, M., Lee, J., Kim, S., Kang, E., Kim, Z., Sharma, P., Rebbeck, T. R., Vijai, J., Robson, M., Lincoln, A., Musinsky, J., Gaddam, P., Tan, Y. Y., Berger, A., Singer, C. F., Loud, J. T., Greene, M. H., Mulligan, A., Glendon, G., Andrulis, I. L., Toland, A., Senter, L., Bojesen, A., Nielsen, H., Skytte, A., Sunde, L., Jensen, U., Pedersen, I., Krogh, L., Kruse, T. A., Caligo, M. A., Yoon, S., Teo, S., von Wachenfeldt, A., Huo, D., Nielsen, S. M., Olopade, O. I., Nathanson, K. L., Domchek, S. M., Lorenchick, C., Jankowitz, R. C., Campbell, I., James, P., Mitchell, G., Orr, N., Park, S., Thomassen, M., Offit, K., Couch, F. J., Simard, J., Easton, D. F., Chenevix-Trench, G., Schmutzler, R. K., Antoniou, A. C., Ottini, L., EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators 2017; 35 (20): 2240-+

    Abstract

    Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

    View details for PubMedID 28448241

    View details for PubMedCentralID PMC5501359

  • Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Kuchenbaecker, K. B., McGuffog, L., Barrowdale, D., Lee, A., Soucy, P., Dennis, J., Domchek, S. M., Robson, M., Spurdle, A. B., Ramus, S. J., Mavaddat, N., Terry, M., Neuhausen, S. L., Schmutzler, R., Simard, J., Pharoah, P. P., Offit, K., Couch, F. J., Chenevix-Trench, G., Easton, D. F., Antoniou, A. C. 2017; 109 (7)

    Abstract

    Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR?=?1.27, 95% confidence interval [CI] = 1.23 to 1.31, P?=? 8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR?=?1.22, 95% CI?=?1.17 to 1.28, P?=? 7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

    View details for DOI 10.1093/jnci/djw302

    View details for Web of Science ID 000405496200004

    View details for PubMedID 28376175

    View details for PubMedCentralID PMC5408990

  • Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Feng, Y., Rhie, S., Huo, D., Ruiz-Narvaez, E. A., Haddad, S. A., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Zheng, Y., Yao, S., Han, Y., Ogundiran, T. O., Rebbeck, T. R., Adebamowo, C., Ojengbede, O., Falusi, A. G., Hennis, A., Nemesure, B., Ambs, S., Blot, W., Cai, Q., Signorello, L., Nathanson, K. L., Lunetta, K. L., Sucheston-Campbell, L. E., Bensen, J. T., Chanock, S. J., Le Marchand, L., Olshan, A. F., Kolonel, L. N., Conti, D. V., Coetzee, G. A., Stram, D. O., Olopade, O. I., Palmer, J. R., Haiman, C. A. 2017; 26 (7): 1016?26

    Abstract

    Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry.Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT).Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality.Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry.Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016-26. ©2017 AACR.

    View details for PubMedID 28377418

    View details for PubMedCentralID PMC5500414

  • Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Kuchenbaecker, K. B., Hopper, J. L., Barnes, D. R., Phillips, K., Mooij, T. M., Roos-Blom, M., Jervis, S., van Leeuwen, F. E., Milne, R. L., Andrieu, N., Goldgar, D. E., Terry, M., Rookus, M. A., Easton, D. F., Antoniou, A. C., BRCA1 BRCA2 Cohort Consortium 2017; 317 (23): 2402?16

    Abstract

    The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates.To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location.Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years.BRCA1/2 mutations, family cancer history, and mutation location.Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer.Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ?2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001).These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

    View details for PubMedID 28632866

  • Pubertal development in girls by breast cancer family history: the LEGACY girls cohort BREAST CANCER RESEARCH Terry, M., Keegan, T. M., Houghton, L. C., Goldberg, M., Andrulis, I. L., Daly, M. B., Buys, S. S., Wei, Y., Whittemore, A. S., Protacio, A., Bradbury, A. R., Chung, W. K., Knight, J. A., John, E. M. 2017; 19: 69

    Abstract

    Pubertal milestones, such as onset of breast development and menstruation, play an important role in breast cancer etiology. It is unclear if these milestones are different in girls with a first- or second-degree breast cancer family history (BCFH).In the LEGACY Girls Study (n?=?1040), we examined whether three mother/guardian-reported pubertal milestones (having reached Tanner Stage 2 or higher (T2+) for breast and pubic hair development, and having started menstruation) differed by BCFH. We also examined whether associations between body size and race/ethnicity and pubertal milestones were modified by BCFH. We used mother/guardian reports as the primary measure of pubertal milestones, but also conducted sensitivity analyses using clinical Tanner measurements available for a subcohort (n?=?204). We analyzed cross-sectional baseline data with logistic regression models for the entire cohort, and longitudinal data with Weibull survival models for the subcohort of girls that were aged 5-7 years at baseline (n?=?258).BCFH was modestly, but not statistically significantly, associated with Breast T2+ (odds ratio (OR)?=?1.36, 95% confidence interval (CI)?=?0.88-2.10), with a stronger association seen in the subcohort of girls with clinical breast Tanner staging (OR?=?2.20, 95% CI?=?0.91-5.32). In a longitudinal analysis of girls who were aged 5-7 years at baseline, BCFH was associated with a 50% increased rate of having early breast development (hazard ratio (HR)?=?1.49, 95% CI?=?1.0-2.21). This association increased to twofold in girls who were not overweight at baseline (HR?=?2.04, 95% CI?=?1.29-3.21). BCFH was not associated with pubic hair development and post-menarche status. The median interval between onset of breast development and menarche was longer for BCFH+ than BCFH- girls (2.3 versus 1.7 years), suggesting a slower developmental tempo for BCFH+ girls. Associations between pubertal milestones and body size and race/ethnicity were similar in girls with or without a BCFH. For example, weight was positively associated with Breast T2+ in both girls with (OR?=?1.06 per 1 kg, 95% CI?=?1.03-1.10) and without (OR?=?1.14 per 1 kg, 95% CI?=?1.04-1.24) a BCFH.These results suggest that BCFH may be related to earlier breast development and slower pubertal tempo independent of body size and race/ethnicity.

    View details for PubMedID 28595647

    View details for PubMedCentralID PMC5465536

  • Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The Breast Cancer Family Registry. Cancer Zhang, F. F., Haslam, D. E., Terry, M. B., Knight, J. A., Andrulis, I. L., Daly, M. B., Buys, S. S., John, E. M. 2017; 123 (11): 2070-2079

    Abstract

    Soy foods possess both antiestrogenic and estrogen-like properties. It remains controversial whether women diagnosed with breast cancer should be advised to eat more or less soy foods, especially for those who receive hormone therapies as part of cancer treatment.The association of dietary intake of isoflavone, the major phytoestrogen in soy, with all-cause mortality was examined in 6235 women with breast cancer enrolled in the Breast Cancer Family Registry. Dietary intake was assessed using a Food Frequency Questionnaire developed for the Hawaii-Los Angeles Multiethnic Cohort among 5178 women who reported prediagnosis diet and 1664 women who reported postdiagnosis diet. Cox proportional-hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).During a median follow-up of 113 months (approximately 9.4 years), 1224 deaths were documented. A 21% decrease was observed in all-cause mortality for women who had the highest versus lowest quartile of dietary isoflavone intake (?1.5 vs?

    View details for DOI 10.1002/cncr.30615

    View details for PubMedID 28263368

  • Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer: evidence from gene-based tests, single-marker regression, and whole-genome prediction. Breast cancer research and treatment Scannell Bryan, M., Argos, M., Andrulis, I. L., Hopper, J. L., Chang-Claude, J., Malone, K., John, E. M., Gammon, M. D., Daly, M., Terry, M. B., Buys, S. S., Huo, D., Olopade, O., Genkinger, J. M., Jasmine, F., Kibriya, M. G., Chen, L., Ahsan, H. 2017

    Abstract

    Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor.We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods.No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association.Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.

    View details for DOI 10.1007/s10549-017-4287-4

    View details for PubMedID 28503721

  • Genetic modifiers of CHEK2*1100delC-associated breast cancer risk GENETICS IN MEDICINE Muranen, T. A., Greco, D., Blomqvist, C., Aittomaki, K., Khan, S., Hogervorst, F., Verhoef, S., Pharoah, P. D., Dunning, A. M., Shah, M., Luben, R., Bojesen, S. E., Nordestgaard, B. G., Schoemaker, M., Swerdlow, A., Garcia-Closas, M., Figueroa, J., Doerk, T., Bogdanova, N. V., Hall, P., Li, J., Khusnutdinova, E., Bermisheva, M., Kristensen, V., Borresen-Dale, A., Peto, J., Silva, I. d., Couch, F. J., Olson, J. E., Hillemans, P., Park-Simon, T., Brauch, H., Hamann, U., Burwinkel, B., Marme, F., Meindl, A., Schmutzler, R. K., Cox, A., Cross, S. S., Sawyer, E. J., Tomlinson, I., Lambrechts, D., Moisse, M., Lindblom, A., Margolin, S., Hollestelle, A., Martens, J. W., Fasching, P. A., Beckmann, M. W., Andrulis, I. L., Knight, J. A., Anton-Culver, H., Ziogas, A., Giles, G. G., Milne, R. L., Brenner, H., Arndt, V., Mannermaa, A., Kosma, V., Chang-Claude, J., Rudolph, A., Devilee, P., Seynaeve, C., Hopper, J. L., Southey, M. C., John, E. M., Whittemore, A. S., Bolla, M. K., Wang, Q., Michailidou, K., Dennis, J., Easton, D. F., Schmidt, M. K., Nevanlinna, H. 2017; 19 (5): 599-603

    Abstract

    CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.

    View details for DOI 10.1038/gim.2016.147

    View details for Web of Science ID 000401247400017

    View details for PubMedCentralID PMC5382131

  • Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer NATURE GENETICS Phelan, C. M., Kuchenbaecker, K. B., Tyrer, J. P., Kar, S. P., Lawrenson, K., Winham, S. J., Dennis, J., Pirie, A., Riggan, M. J., Chornokur, G., Earp, M. A., Lyra, P. C., Lee, J. M., Coetzee, S., Beesley, J., McGuffog, L., Soucy, P., Dicks, E., Lee, A., Barrowdale, D., Lecarpentier, J., Leslie, G., Aalfs, C. M., Aben, K. K., Adams, M., Adlard, J., Andrulis, I. L., Anton-Culver, H., Antonenkova, N., Aravantinos, G., Arnold, N., Arun, B. K., Arver, B., Azzollini, J., Balmana, J., Banerjee, S. N., Barjhoux, L., Barkardottir, R. B., Bean, Y., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M. Q., Birrer, M. J., Bjorge, L., Black, A., Blankstein, K., Blok, M. J., Bodelon, C., Bogdanova, N., Bojesen, A., Bonanni, B., Borg, A., Bradbury, A. R., Brenton, J. D., Brewer, C., Brinton, L., Broberg, P., Brooks-Wilson, A., Bruinsma, F., Brunet, J., Buecher, B., Butzow, R., Buys, S. S., Caldes, T., Caligo, M. A., Campbell, I., Cannioto, R., Carney, M. E., Cescon, T., Chan, S. B., Chang-Claude, J., Chanock, S., Chen, X. Q., Chiew, Y., Chiquette, J., Chung, W. K., Claes, K. B., Conner, T., Cook, L. S., Cook, J., Cramer, D. W., Cunningham, J. M., D'Aloisio, A. A., Daly, M. B., Damiola, F., Damirovna, S. D., Dansonka-Mieszkowska, A., Dao, F., Davidson, R., deFazio, A., Delnatte, C., Doheny, K. F., Diez, O., Ding, Y. C., Doherty, J. A., Domchek, S. M., Dorfling, C. M., Dork, T., Dossus, L., Duran, M., Durst, M., Dworniczak, B., Eccles, D., Edwards, T., Eeles, R., Eilber, U., Ejlertsen, B., Ekici, A. B., Ellis, S., Elvira, M., Eng, K. H., Engel, C., Evans, D. G., Fasching, P. A., Ferguson, S., Ferrer, S. F., Flanagan, J. M., Fogarty, Z. C., Fortner, R. T., Fostira, F., Foulkes, W. D., Fountzilas, G., Fridley, B. L., Friebel, T. M., friedman, e., Frost, D., Ganz, P. A., Garber, J., Garcia, M. J., Garcia-Barberan, V., Gehrig, A., Gentry-Maharaj, A., Gerdes, A., Giles, G. G., Glasspool, R., Glendon, G., Godwin, A. K., Goldgar, D. E., Goranova, T., Gore, M., Greene, M. H., Gronwald, J., Gruber, S., Hahnen, E., Haiman, C. A., Hakansson, N., Hamann, U., Hansen, T. v., Harrington, P. A., Harris, H. R., Hauke, J., Hein, A., Henderson, A., Hildebrandt, M. A., Hillemanns, P., Hodgson, S., Hogdall, C. K., Hogdall, E., Hogervorst, F. B., Holland, H., Hooning, M. J., Hosking, K., Huang, R., Hulick, P. J., Hung, J., Hunter, D. J., Huntsman, D. G., Huzarski, T., Imyanitov, E. N., Isaacs, C., Iversen, E. S., Izatt, L., Izquierdo, A., Jakubowska, A., James, P., Janavicius, R., Jernetz, M., Jensen, A., Jensen, U. B., John, E. M., Johnatty, S., Jones, M. E., Kannisto, P., Karlan, B. Y., Karnezis, A., Kast, K., Kennedy, C. J., Khusnutdinova, E., Kiemeney, L. A., Kiiski, J. I., Kim, S., Kjaer, S. K., Kobel, M., Kopperud, R. K., Kruse, T. A., Kupryjanczyk, J., Kwong, A., Laitman, Y., Lambrechts, D., Larranaga, N., Larson, M. C., Lazaro, C., Le, N. D., Le Marchand, L., Lee, J. W., Lele, S. B., Leminen, A., Leroux, D., Lester, J., Lesueur, F., Levine, D. A., Liang, D., Liebrich, C., Lilyquist, J., Lipworth, L., Lissowska, J., Lu, K. H., Lubinski, J., Luccarini, C., Lundvall, L., Mai, P. L., Mendoza-Fandino, G., Manoukian, S., Massuger, L. F., May, T., Mazoyer, S., McAlpine, J. N., McGuire, V., McLaughlin, J. R., McNeish, I., Meijers-Heijboer, H., Meindl, A., Menon, U., Mensenkamp, A. R., Merritt, M. A., Milne, R. L., Mitchell, G., Modugno, F., Moes-Sosnowska, J., Moffitt, M., Montagna, M., Moysich, K. B., Mulligan, A. M., Musinsky, J., Nathanson, K. L., Nedergaard, L., Ness, R. B., Neuhausen, S. L., Nevanlinna, H., Niederacher, D., Nussbaum, R. L., Odunsi, K., Olah, E., Olopade, O. I., Olsson, H., Olswold, C., O'Malley, D. M., Ong, K., Onland-Moret, N. C., Orr, N., Orsulic, S., Osorio, A., Palli, D., Papi, L., Park-Simon, T., Paul, J., Pearce, C. L., Pedersen, I. S., Peeters, P. H., Peissel, B., Peixoto, A., Pejovic, T., Pelttari, L. M., Permuth, J. B., Peterlongo, P., Pezzani, L., Pfeiler, G., Phillips, K., Piedmonte, M., Pike, M. C., Piskorz, A. M., Poblete, S. R., Pocza, T., Poole, E. M., Poppe, B., Porteous, M. E., Prieur, F., Prokofyeva, D., Pugh, E., Pujana, M. A., Pujol, P., Radice, P., Rantala, J., Rappaport-Fuerhauser, C., Rennert, G., Rhiem, K., Rice, P., Richardson, A., Robson, M., Rodriguez, G. C., Rodriguez-Antona, C., Romm, J., Rookus, M. A., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Salvesen, H. B., Sandler, D. P., Schoemaker, M. J., Senter, L., Setiawan, V. W., Severi, G., Sharma, P., Shelford, T., Siddiqui, N., Side, L. E., Sieh, W., Singer, C. F., Sobol, H., Song, H., Southey, M. C., Spurdle, A. B., Stadler, Z., Steinemann, D., Stoppa-Lyonnet, D., Sucheston-Campbell, L. E., Sukiennicki, G., Sutphen, R., Sutter, C., Swerdlow, A. J., Szabo, C. I., Szafron, L., Tan, Y. Y., Taylor, J. A., Tea, M., Teixeira, M. R., Teo, S., Terry, K. L., Thompson, P. J., Thomsen, L. C., Thull, D. L., Tihomirova, L., Tinker, A. V., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tone, A., Trabert, B., Travis, R. C., Trichopoulou, A., Tung, N., Tworoger, S. S., van Altena, A. M., Van Den Berg, D., van der Hout, A. H., van der Luijt, R. B., Van Heetvelde, M., van Nieuwenhuysen, E., Van Rensburg, E. J., Vanderstichele, A., Varon-Mateeva, R., Vega, A., Edwards, D. V., Vergote, I., Vierkant, R. A., Vijai, J., Vratimos, A., Walker, L., Walsh, C., Wand, D., Wang-Gohrke, S., Wappenschmidt, B., Webb, P. M., Weinberg, C. R., Weitzel, J. N., Wentzensen, N., Whittemore, A. S., Wijnen, J. T., Wilkens, L. R., Wolk, A., Woo, M., Wu, X., Wu, A. H., Yang, H., Yannoukakos, D., Ziogas, A., Zorn, K. K., Narod, S. A., Easton, D. F., Amos, C. I., Schildkraut, J. M., Ramus, S. J., Ottini, L., Goodman, M. T., Park-, S. K., Kelemen, L. E., Risch, H. A., Thomassen, M., Offit, K., Simard, J., Schmutzler, R. K., Hazelett, D., Monteiro, A. N., Couch, F. J., Berchuck, A., Chenevix-Trench, G., Goode, E. L., Sellers, T. A., Gayther, S. A., Antoniou, A. C., Pharoah, P. D. 2017; 49 (5): 680-?

    Abstract

    To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

    View details for DOI 10.1038/ng.3826

    View details for PubMedID 28346442

  • The Interaction between Genetic Ancestry and Breast Cancer Risk Factors among Hispanic Women: The Breast Cancer Health Disparities Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hines, L. M., Sedjo, R. L., Byers, T., John, E. M., Fejerman, L., Stern, M. C., Baumgartner, K. B., Giuliano, A. R., Torres-Mejia, G., Wolff, R. K., Harrall, K. K., Slattery, M. L. 2017; 26 (5): 692?701

    Abstract

    Background: Hispanic women have lower breast cancer incidence rates than non-Hispanic white (NHW) women. To what extent genetic versus nongenetic factors account for this difference is unknown.Methods: Using logistic regression, we evaluated the interactive influences of established risk factors and ethnicity (self-identified and identified by ancestral informative markers) on breast cancer risk among 2,326 Hispanic and 1,854 NHW postmenopausal women from the United States and Mexico in the Breast Cancer Health Disparities Study.Results: The inverse association between the percentage of Native American (NA) ancestry and breast cancer risk was only slightly attenuated after adjusting for known risk factors [lowest versus highest quartile: odds ratio (OR) =1.39, 95% confidence interval (CI) = 1.00-1.92 among U.S. Hispanics; OR = 1.92 (95% CI, 1.29-2.86) among Mexican women]. The prevalence of several risk factors, as well as the associations with certain factors and breast cancer risk, differed according to genetic admixture. For example, higher body mass index (BMI) was associated with reduced risk among women with lower NA ancestry only [BMI <25 versus >30: OR = 0.65 (95% CI, 0.44-0.98) among U.S. Hispanics; OR = 0.53 (95% CI, 0.29-0.97) among Mexicans]. The average number of risk factors among cases was inversely related to the percentage of NA ancestry.Conclusions: The lower NA ancestry groups were more likely to have the established risk factors, with the exception of BMI. Although the majority of factors were associated with risk in the expected directions among all women, BMI had an inverse association among Hispanics with lower NA ancestry.Impact: These data suggest that the established risk factors are less relevant for breast cancer development among women with more NA ancestry. Cancer Epidemiol Biomarkers Prev; 26(5); 692-701. ©2016 AACR.

    View details for PubMedID 27932594

    View details for PubMedCentralID PMC5413419

  • Racial/Ethnic Differences in the Impact of Neighborhood Social and Built Environment on Breast Cancer Risk: The Neighborhoods and Breast Cancer Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Conroy, S. M., Shariff-Marco, S., Koo, J., Yang, J., Keegan, T. M., Sangaramoorthy, M., Hertz, A., Nelson, D. O., Cockburn, M., Satariano, W. A., Yen, I. H., Ponce, N. A., John, E. M., Gomez, S. 2017; 26 (4): 541?52

    Abstract

    Background: Neighborhood socioeconomic status (nSES) has been found to be associated with breast cancer risk. It remains unclear whether this association applies across racial/ethnic groups independent of individual-level factors and is attributable to other neighborhood characteristics.Methods: We examined the independent and joint associations of education and nSES with odds of breast cancer. Residential addresses were geocoded for 2,838 cases and 3,117 controls and linked to nSES and social and built environment characteristics. We estimated ORs and 95% confidence intervals (CI) using multilevel logistic regression controlling for individual-level breast cancer risk factors and assessed the extent to which nSES associations were due to neighborhood characteristics.Results: Women living in the highest versus lowest nSES quintile had a nearly 2-fold greater odds of breast cancer, with elevated odds (adjusted ORs, 95% CI) for non-Hispanic whites (NHWs; 2.27; 1.45-3.56), African Americans (1.74; 1.07-2.83), U.S.-born Hispanics (1.82; 1.19-2.79), and foreign-born Hispanics (1.83; 1.06-3.17). Considering education and nSES jointly, ORs were increased for low education/high nSES NHWs (1.83; 1.14-2.95), high education/high nSES NHWs (1.64; 1.06-2.54), and high education/high nSES foreign-born Hispanics (2.17; 1.52-3.09) relative to their race/ethnicity/nativity-specific low education/low nSES counterparts. Adjustment for urban and mixed-land use characteristics attenuated the nSES associations for most racial/ethnic/nativity groups except NHWs.Conclusions: Our study provides empirical evidence for a role of neighborhood environments in breast cancer risk, specifically social and built environment attributes.Impact: Considering the role of neighborhood characteristics among diverse populations may offer insights to understand racial/ethnic disparities in breast cancer risk. Cancer Epidemiol Biomarkers Prev; 26(4); 541-52. ©2017 AACR.

    View details for PubMedID 28196846

    View details for PubMedCentralID PMC5380527

  • Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium PLOS GENETICS Ng, M. Y., Graff, M., Lu, Y., Justice, A. E., Mudgal, P., Liu, C., Young, K., Yanek, L. R., Feitosa, M. F., Wojczynski, M. K., Rand, K., Brody, J. A., Cade, B. E., Dimitrov, L., Duan, Q., Guo, X., Lange, L. A., Nalls, M. A., Okut, H., Tajuddin, S. M., Tayo, B. O., Vedantam, S., Bradfield, J. P., Chen, G., Chen, W., Chesi, A., Irvin, M. R., Padhukasahasram, B., Smith, J. A., Zheng, W., Allison, M. A., Ambrosone, C. B., Bandera, E. V., Bartz, T. M., Berndt, S. I., Bernstein, L., Blot, W. J., Bottinger, E. P., Carpten, J., Chanock, S. J., Chen, Y., Conti, D. V., Cooper, R. S., Fornage, M., Freedman, B. I., Garcia, M., Goodman, P. J., Hsu, Y. H., Hu, J., Huff, C. D., Ingles, S. A., John, E. M., Kittles, R., Klein, E., Li, J., McKnight, B., Nayak, U., Nemesure, B., Ogunniyi, A., Olshan, A., Press, M. F., Rohde, R., Rybicki, B. A., Salako, B., Sanderson, M., Shao, Y., Siscovick, D. S., Stanford, J. L., Stevens, V. L., Stram, A., Strom, S. S., Vaidya, D., Witte, J. S., Yao, J., Zhu, X., Ziegler, R. G., Zonderman, A. B., Adeyemo, A., Ambs, S., Cushman, M., Faul, J. D., Hakonarson, H., Levin, A. M., Nathanson, K. L., Ware, E. B., Weir, D. R., Zhao, W., Zhi, D., Arnett, D. K., Grant, S. A., Kardia, S. R., Oloapde, O. I., Rao, D. C., Rotimi, C. N., Sale, M. M., Williams, L., Zemel, B. S., Becker, D. M., Borecki, I. B., Evans, M. K., Harris, T. B., Hirschhorn, J. N., Li, Y., Patel, S. R., Psaty, B. M., Rotter, J. I., Wilson, J. G., Bowden, D. W., Cupples, L., Haiman, C. A., Loos, R. F., North, K. E., Bone Mineral Density Childhood Stu 2017; 13 (4): e1006719

    Abstract

    Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ? 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

    View details for PubMedID 28430825

  • Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers EUROPEAN JOURNAL OF HUMAN GENETICS Walker, L., Marquart, L., Pearson, J., Wiggins, G., O'Mara, T., Parsons, M. T., Barrowdale, D., McGuffog, L., Dennis, J., Benitez, J., Slavin, T. P., Radice, P., Frost, D., Godwin, A. K., Meindl, A., Schmutzler, R., Isaacs, C., Peshkin, B. N., Caldes, T., Hogervorst, F. L., Lazaro, C., Jakubowska, A., Montagna, M., Chen, X., Offit, K., Hulick, P. J., Andrulis, I. L., Lindblom, A., Nussbaum, R. L., Nathanson, K. L., Chenevix-Trench, G., Antoniou, A. C., Couch, F. J., Spurdle, A. B., BCFR, EMBRACE, GEMO Study Collaborators, HEBON, KConFAB Investigators 2017; 25 (4): 432?38

    Abstract

    Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P<0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk=0.50, P=0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers.

    View details for DOI 10.1038/ejhg.2016.203

    View details for Web of Science ID 000395996200010

    View details for PubMedID 28145423

    View details for PubMedCentralID PMC5386423

  • A functionally significant SNP in TP53 and breast cancer risk in African-American women NPJ BREAST CANCER Murphy, M. E., Liu, S., Yao, S., Huo, D., Liu, Q., Dolfi, S. C., Hirshfield, K. M., Hong, C., Hu, Q., Olshan, A. F., Ogundiran, T. O., Adebamowo, C., Domchek, S. M., Nathanson, K. L., Nemesure, B., Ambs, S., Blot, W. J., Feng, Y., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Haiman, C. A., Olopade, O. I., Lunetta, K. L., Palmer, J. R., Ambrosone, C. B. 2017; 3: 5

    Abstract

    A coding region polymorphism exists in the TP53 gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08-2.76; p-value?=?0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.

    View details for PubMedID 28649645

  • Non-invasive optical spectroscopic monitoring of breast development during puberty BREAST CANCER RESEARCH Lilge, L., Terry, M. B., Walter, J., Pinnaduwage, D., Glendon, G., Hanna, D., Tammemagi, M., Bradbury, A., Buys, S., Daly, M., John, E. M., Knight, J. A., Andrulis, I. L. 2017; 19

    Abstract

    Tanner staging (TS), a five-stage classification indicating no breast tissue (TS1) to full breast development (TS5), is used both in health research and clinical care to assess the onset of breast development (TS2) and duration in each stage. Currently, TS is measured both visually and through palpation but non-invasive methods will improve comparisons across settings.We used optical spectroscopy (OS) measures from 102 girls at the Ontario site of the LEGACY girls study (average age 12 years, range 10.0-15.4 years) to determine whether breast tissue optical properties map to each TS. We further examined whether these properties differed by age, body mass index (BMI), and breast cancer risk score (BCRS) by examining the major principal components (PC).Age and BMI increased linearly with increasing TS. Eight PCs explained 99.9% of the variation in OS data. Unlike the linear increase with age and BMI, OS components had distinct patterns by TS: the onset of breast development (TS1 to TS2) was marked by elevation of PC3 scores indicating an increase in adipose tissue and decrease in signal from the pectoral muscle; transition to TS3 was marked by elevation of PC6 and PC7 and decline of PC2 scores indicating an increase in glandular or dense tissue; and transition to TS4+ by decline of PC2 scores representing a further increase in glandular tissue relative to adipose tissue. Of the eight PCs, three component scores (PC4, PC5, and PC8) remained in the best-fitting model of BCRS, suggesting different levels of collagen in the breast tissue by BCRS.Our results suggest that serial measures of OS, a non-invasive assessment of breast tissue characteristics, can be used as an objective outcome that does not rely on visual inspection or palpation, for studying drivers of breast development.

    View details for DOI 10.1186/s13058-017-0805-x

    View details for Web of Science ID 000393623100001

    View details for PubMedID 28166807

  • Projecting Individualized Absolute Invasive Breast Cancer Risk in US Hispanic Women JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Banegas, M. P., John, E. M., Slattery, M. L., Gomez, S. L., Yu, M., LaCroix, A. Z., Pee, D., Chlebowski, R. T., Hines, L. M., Thompson, C. A., Gail, M. H. 2017; 109 (2)

    Abstract

    There is no model to estimate absolute invasive breast cancer risk for Hispanic women.The San Francisco Bay Area Breast Cancer Study (SFBCS) provided data on Hispanic breast cancer case patients (533?US-born, 553 foreign-born) and control participants (464?US-born, 947 foreign-born). These data yielded estimates of relative risk (RR) and attributable risk (AR) separately for US-born and foreign-born women. Nativity-specific absolute risks were estimated by combining RR and AR information with nativity-specific invasive breast cancer incidence and competing mortality rates from the California Cancer Registry and Surveillance, Epidemiology, and End Results program to develop the Hispanic risk model (HRM). In independent data, we assessed model calibration through observed/expected (O/E) ratios, and we estimated discriminatory accuracy with the area under the receiver operating characteristic curve (AUC) statistic.The US-born HRM included age at first full-term pregnancy, biopsy for benign breast disease, and family history of breast cancer; the foreign-born HRM also included age at menarche. The HRM estimated lower risks than the National Cancer Institute's Breast Cancer Risk Assessment Tool (BCRAT) for US-born Hispanic women, but higher risks in foreign-born women. In independent data from the Women's Health Initiative, the HRM was well calibrated for US-born women (observed/expected [O/E] ratio = 1.07, 95% confidence interval [CI] = 0.81 to 1.40), but seemed to overestimate risk in foreign-born women (O/E ratio = 0.66, 95% CI?=?0.41 to 1.07). The AUC was 0.564 (95% CI?=?0.485 to 0.644) for US-born and 0.625 (95% CI?=?0.487 to 0.764) for foreign-born women.The HRM is the first absolute risk model that is based entirely on data specific to Hispanic women by nativity. Further studies in Hispanic women are warranted to evaluate its validity.

    View details for DOI 10.1093/jnci/djw215

    View details for Web of Science ID 000396507600006

    View details for PubMedID 28003316

  • Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab GENETICS IN MEDICINE Li, H., Feng, B., Miron, A., Chen, X., Beesley, J., Bimeh, E., Barrowdale, D., John, E. M., Daly, M. B., Andrulis, I. L., Buys, S. S., Kraft, P., Thorne, H., Chenevix-Trench, G., Southey, M. C., Antoniou, A. C., James, P. A., Terry, M. B., Phillips, K., Hopper, J. L., Mitchell, G., Goldgar, D. E. 2017; 19 (1): 30-35

    Abstract

    This study examined the utility of sets of single-nucleotide polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC).We derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the Breast Cancer Family Registry and Kathleen Cuningham Consortium Foundation for Research into Familial Breast Cancer familial BC cohorts. We compared scores for women based on cancer status at baseline; 2,599 women unaffected at enrollment were followed-up for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone.The mean PRS at baseline was 2.25 (SD, 0.35) for affected women and was 2.17 (SD, 0.35) for unaffected women from combined cohorts (P < 10(-6)). During follow-up, 205 BC cases occurred. The hazard ratios for continuous PRS (per SD) and upper versus lower quintiles were 1.38 (95% confidence interval: 1.22-1.56) and 3.18 (95% confidence interval: 1.84-5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered.Including BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women.Genet Med 19 1, 30-35.

    View details for DOI 10.1038/gim.2016.43

    View details for Web of Science ID 000391911100005

    View details for PubMedCentralID PMC5107177

  • Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab. Genetics in medicine Li, H., Feng, B., Miron, A., Chen, X., Beesley, J., Bimeh, E., Barrowdale, D., John, E. M., Daly, M. B., Andrulis, I. L., Buys, S. S., Kraft, P., Thorne, H., Chenevix-Trench, G., Southey, M. C., Antoniou, A. C., James, P. A., Terry, M. B., Phillips, K., Hopper, J. L., Mitchell, G., Goldgar, D. E. 2017; 19 (1): 30-35

    Abstract

    This study examined the utility of sets of single-nucleotide polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC).We derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the Breast Cancer Family Registry and Kathleen Cuningham Consortium Foundation for Research into Familial Breast Cancer familial BC cohorts. We compared scores for women based on cancer status at baseline; 2,599 women unaffected at enrollment were followed-up for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone.The mean PRS at baseline was 2.25 (SD, 0.35) for affected women and was 2.17 (SD, 0.35) for unaffected women from combined cohorts (P < 10(-6)). During follow-up, 205 BC cases occurred. The hazard ratios for continuous PRS (per SD) and upper versus lower quintiles were 1.38 (95% confidence interval: 1.22-1.56) and 3.18 (95% confidence interval: 1.84-5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered.Including BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women.Genet Med 19 1, 30-35.

    View details for DOI 10.1038/gim.2016.43

    View details for PubMedID 27171545

  • Assessing biological and technological variability in protein levels measured in pre-diagnostic plasma samples of women with breast cancer. Biomarker research Yeh, C. Y., Adusumilli, R., Kullolli, M., Mallick, P., John, E. M., Pitteri, S. J. 2017; 5: 30

    Abstract

    Quantitative proteomics allows for the discovery and functional investigation of blood-based pre-diagnostic biomarkers for early cancer detection. However, a major limitation of proteomic investigations in biomarker studies remains the biological and technical variability in the analysis of complex clinical samples. Moreover, unlike 'omics analogues such as genomics and transcriptomics, proteomics has yet to achieve reproducibility and long-term stability on a unified technological platform. Few studies have thoroughly investigated protein variability in pre-diagnostic samples of cancer patients across multiple platforms.We obtained ten blood plasma "case" samples collected up to 2 years prior to breast cancer diagnosis. Each case sample was paired with a matched control plasma from a full biological sister without breast cancer. We measured protein levels using both mass-spectrometry and antibody-based technologies to: (1) assess the technical considerations in different protein assays when analyzing limited clinical samples, and (2) evaluate the statistical power of potential diagnostic analytes.Although we found inherent technical variation in the three assays used, we detected protein dependent biological signal from the limited samples. The three assay types yielded 32 proteins with statistically significantly (p < 1E-01) altered expression levels between cases and controls, with no proteins retaining statistical significance after false discovery correction.Technical, practical, and study design considerations are essential to maximize information obtained in limited pre-diagnostic samples of cancer patients. This study provides a framework that estimates biological effect sizes critical for consideration in designing studies for pre-diagnostic blood-based biomarker detection.

    View details for PubMedID 29075496

  • Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population. Breast cancer research : BCR Reiner, A. S., Lynch, C. F., Sisti, J. S., John, E. M., Brooks, J. D., Bernstein, L., Knight, J. A., Hsu, L., Concannon, P., Mellemkjćr, L., Tischkowitz, M., Haile, R. W., Shen, R., Malone, K. E., Woods, M., Liang, X., Morrow, M., Bernstein, J. L. 2017; 19 (1): 83

    Abstract

    Previous population-based studies have described first primary breast cancer tumor characteristics and their association with contralateral breast cancer (CBC) risk. However, information on influential covariates such as treatment, family history of breast cancer, and BRCA1/2 mutation carrier status was not available. In a large, population-based, case-control study, we evaluated whether tumor characteristics of the first primary breast cancer are associated with risk of developing second primary asynchronous CBC, overall and in subgroups of interest, including among BRCA1/2 mutation non-carriers, women who are not treated with tamoxifen, and women without a breast cancer family history.The Women's Environmental Cancer and Radiation Epidemiology Study is a population-based case-control study of 1521 CBC cases and 2212 individually-matched controls with unilateral breast cancer. Detailed information about breast cancer risk factors, treatment for and characteristics of first tumors, including estrogen receptor (ER) and progesterone receptor (PR) status, was obtained by telephone interview and medical record abstraction. Multivariable risk ratios (RRs) and 95% confidence intervals (CIs) were estimated in conditional logistic regression models, adjusting for demographics, treatment, and personal medical and family history. A subset of women was screened for BRCA1/2 mutations.Lobular histology of the first tumor was associated with a 30% increase in CBC risk (95% CI 1.0-1.6). Compared to women with ER+/PR+ first tumors, those with ER-/PR- tumors had increased risk of CBC (RR?=?1.4, 95% CI 1.1-1.7). Notably, women with ER-/PR- first tumors were more likely to develop CBC with the ER-/PR- phenotype (RR?=?5.4, 95% CI 3.0-9.5), and risk remained elevated in multiple subgroups: BRCA1/2 mutation non-carriers, women younger than 45 years of age, women without a breast cancer family history, and women who were not treated with tamoxifen.Having a hormone receptor negative first primary breast cancer is associated with increased risk of CBC. Women with ER-/PR- primary tumors were more likely to develop ER-/PR- CBC, even after excluding BRCA1/2 mutation carriers. Hormone receptor status, which is routinely evaluated in breast tumors, may be used clinically to determine treatment protocols and identify patients who may benefit from increased surveillance for CBC.

    View details for PubMedID 28724391

    View details for PubMedCentralID PMC5517810

  • Assessing biological and technological variability in protein levels measured in pre-diagnostic plasma samples of women with breast cancer Biomarker Research Yeh, C. Y., Adusumilli, R., Kullolli, M., Mallick, P., John, E. M., Pitteri, S. J. 2017; 5: 30

    Abstract

    Quantitative proteomics allows for the discovery and functional investigation of blood-based pre-diagnostic biomarkers for early cancer detection. However, a major limitation of proteomic investigations in biomarker studies remains the biological and technical variability in the analysis of complex clinical samples. Moreover, unlike 'omics analogues such as genomics and transcriptomics, proteomics has yet to achieve reproducibility and long-term stability on a unified technological platform. Few studies have thoroughly investigated protein variability in pre-diagnostic samples of cancer patients across multiple platforms.We obtained ten blood plasma "case" samples collected up to 2 years prior to breast cancer diagnosis. Each case sample was paired with a matched control plasma from a full biological sister without breast cancer. We measured protein levels using both mass-spectrometry and antibody-based technologies to: (1) assess the technical considerations in different protein assays when analyzing limited clinical samples, and (2) evaluate the statistical power of potential diagnostic analytes.Although we found inherent technical variation in the three assays used, we detected protein dependent biological signal from the limited samples. The three assay types yielded 32 proteins with statistically significantly (p < 1E-01) altered expression levels between cases and controls, with no proteins retaining statistical significance after false discovery correction.Technical, practical, and study design considerations are essential to maximize information obtained in limited pre-diagnostic samples of cancer patients. This study provides a framework that estimates biological effect sizes critical for consideration in designing studies for pre-diagnostic blood-based biomarker detection.

    View details for DOI 10.1186/s40364-017-0110-y

    View details for PubMedCentralID PMC5645980

  • Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3 BREAST CANCER RESEARCH AND TREATMENT Hamdi, Y., Soucy, P., Kuchenbaeker, K. B., Pastinen, T., Droit, A., Lemacon, A., Adlard, J., Aittomaki, K., Andrulis, I. L., Arason, A., Arnold, N., Arun, B. K., Azzollini, J., Bane, A., Barjhoux, L., Barrowdale, D., Benitez, J., Berthet, P., Blok, M. J., Bobolis, K., Bonadona, V., Bonanni, B., Bradbury, A. R., Brewer, C., Buecher, B., Buys, S. S., Caligo, M. A., Chiquette, J., Chung, W. K., Claes, K. B., Daly, M. B., Damiola, F., Davidson, R., de la Hoya, M., De Leeneer, K., Diez, O., Ding, Y. C., Dolcetti, R., Domchek, S. M., Dorfling, C. M., Eccles, D., Eeles, R., Einbeigi, Z., Ejlertsen, B., Engel, C., Evans, D. G., Feliubadalo, L., Foretova, L., Fostira, F., Foulkes, W. D., Fountzilas, G., friedman, e., Frost, D., Ganschow, P., Ganz, P. A., Garber, J., Gayther, S. A., Gerdes, A., Glendon, G., Godwin, A. K., Goldgar, D. E., Greene, M. H., Gronwald, J., Hahnen, E., Hamann, U., Hansen, T. v., Hart, S., Hays, J. L., Hogervorst, F. B., Hulick, P. J., Imyanitov, E. N., Isaacs, C., Izatt, L., Jakubowska, A., James, P., Janavicius, R., Jensen, U. B., John, E. M., Joseph, V., Just, W., Kaczmarek, K., Karlan, B. Y., Kets, C. M., Kirk, J., Kriege, M., Laitman, Y., Laurent, M., Lazaro, C., Leslie, G., Lester, J., Lesueur, F., Liljegren, A., Loman, N., Loud, J. T., Manoukian, S., Mariani, M., Mazoyer, S., McGuffog, L., Meijers-Heijboer, H. E., Meindl, A., Miller, A., Montagna, M., Mulligan, A. M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nussbaum, R. L., Olah, E., Olopade, O. I., Ong, K., Oosterwijk, J. C., Osorio, A., Papi, L., Park, S. K., Pedersen, I. S., Peissel, B., Segura, P. P., Peterlongo, P., Phelan, C. M., Radice, P., Rantala, J., Rappaport-Fuerhauser, C., Rennert, G., Richardson, A., Robson, M., Rodriguez, G. C., Rookus, M. A., Schmutzler, R. K., Sevenet, N., Shah, P. D., Singer, C. F., Slavin, T. P., Snape, K., Sokolowska, J., Sonderstrup, I. M., Southey, M., Spurdle, A. B., Stadler, Z., Stoppa-Lyonnet, D., Sukiennicki, G., Sutter, C., Tan, Y., Tea, M., Teixeira, M. R., Teule, A., Teo, S., Terry, M. B., Thomassen, M., Tihomirova, L., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tung, N., van den Ouweland, A. M., van der Luijt, R. B., van Engelen, K., Van Rensburg, E. J., Varon-Mateeva, R., Wappenschmidt, B., Wijnen, J. T., Rebbeck, T., Chenevix-Trench, G., Offit, K., Couch, F. J., Nord, S., Easton, D. F., Antoniou, A. C., Simard, J. 2017; 161 (1): 117-134

    Abstract

    Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10(-6)). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

    View details for DOI 10.1007/s10549-016-4018-2

    View details for Web of Science ID 000392188500012

    View details for PubMedCentralID PMC5222911

  • Pre-diagnostic breastfeeding, adiposity, and mortality among parous Hispanic and non-Hispanic white women with invasive breast cancer: the Breast Cancer Health Disparities Study BREAST CANCER RESEARCH AND TREATMENT Connor, A. E., Visvanathan, K., Baumgartner, K. B., Baumgartner, R. N., Boone, S. D., Hines, L. M., Wolff, R. K., John, E. M., Slattery, M. L. 2017; 161 (2): 321-331

    Abstract

    U.S. Hispanic women have high rates of parity, breastfeeding, and obesity. It is unclear whether these reproductive factors are associated with breast cancer (BC) mortality. We examined the associations between breastfeeding, parity, adiposity and BC-specific and overall mortality in Hispanic and non-Hispanic white (NHW) BC cases.The study population included 2921 parous women (1477 Hispanics, 1444 NHWs) from the Breast Cancer Health Disparities Study with invasive BC diagnosed between 1995 and 2004. Information on reproductive history and lifestyle factors was collected by in-person interview. Overall and stratified Cox proportional hazard regression models by ethnicity, parity, and body mass index (BMI) at age 30 years were used to calculate hazard ratios (HR) and 95% confidence intervals (CI).After a median follow-up time of 11.2 years, a total of 679 deaths occurred. Pre-diagnostic breastfeeding was associated with a 16% reduction in mortality (HR 0.84; 95% 0.72-0.99) irrespective of ethnicity. Parity significantly modified the association between breastfeeding duration and mortality (p interaction = 0.05), with longer breastfeeding duration associated with lower risk among women who had ?2 births (p trend = 0.02). Breastfeeding duration was associated with reduced risk of both BC-specific and overall mortality among women with BMI <25 kg/m2, while positive associations were observed among women with BMI ?25 kg/m2 (p interactions <0.01).Pre-diagnostic breastfeeding was inversely associated with risk of mortality after BC, particularly in women of low parity or normal BMI. These results provide another reason to encourage breastfeeding and weight management among young women.

    View details for DOI 10.1007/s10549-016-4048-9

    View details for Web of Science ID 000392385100013

    View details for PubMedID 27837379

  • A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Rand, K. A., Song, C., Dean, E., Serie, D. J., Curtin, K., Sheng, X., Hu, D., Huff, C. A., Bernal-Mizrachi, L., Tomasson, M. H., Ailawadhi, S., Singhal, S., Pawlish, K., Peters, E. S., Bock, C. H., Stram, A., Van den Berg, D. J., Edlund, C. K., Conti, D. V., Zimmerman, T., Hwang, A. E., Huntsman, S., Graff, J., Nooka, A., Kong, Y., Pregja, S. L., Berndt, S. I., Blot, W. J., Carpten, J., Casey, G., Chu, L., Diver, W. R., Stevens, V. L., Lieber, M. R., Goodman, P. J., Hennis, A. J., Hsing, A. W., Mehta, J., Kittles, R. A., Kolb, S., Klein, E. A., Leske, C., Murphy, A. B., Nemesure, B., Neslund-Dudas, C., Strom, S. S., Vij, R., Rybicki, B. A., Stanford, J. L., Signorello, L. B., Witte, J. S., Ambrosone, C. B., Bhatti, P., John, E. M., Bernstein, L., Zheng, W., Olshan, A. F., Hu, J. J., Ziegler, R. G., Nyante, S. J., Bandera, E. V., Birmann, B. M., Ingles, S. A., Press, M. F., Atanackovic, D., Glenn, M. J., Cannon-Albright, L. A., Jones, B., Tricot, G., Martin, T. G., Kumar, S. K., Wolf, J. L., Halverson, S. L., Rothman, N., Brooks-Wilson, A. R., Rajkumar, S. V., Kolonel, L. N., Chanock, S. J., Slager, S. L., Severson, R. K., Janakiraman, N., Terebelo, H. R., Brown, E. E., De Roos, A. J., Mohrbacher, A. F., Colditz, G. A., Giles, G. G., Spinelli, J. J., Chiu, B. C., Munshi, N. C., Anderson, K. C., Levy, J., Zonder, J. A., Orlowski, R. Z., Lonial, S., Camp, N. J., Vachon, C. M., Ziv, E., Stram, D. O., Hazelett, D. J., Haiman, C. A., Cozen, W. 2016; 25 (12): 1609-1618

    Abstract

    Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma.We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality.We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10(-7)) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-?B pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles.A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.

    View details for PubMedID 27587788

  • Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women BREAST CANCER RESEARCH Rebbeck, T. R., Friebel, T. M., Mitra, N., Wan, F., Chen, S., Andrulis, I. L., Apostolou, P., Arnold, N., Arun, B. K., Barrowdale, D., Benitez, J., Berger, R., Berthet, P., Borg, A., Buys, S. S., Caldes, T., Carter, J., Chiquette, J., Claes, K. M., Couch, F. J., Cybulski, C., Daly, M. B., de la Hoya, M., Diez, O., Domchek, S. M., Nathanson, K. L., Durda, K., Ellis, S., Evans, D., Foretova, L., Friedman, E., Frost, D., Ganz, P. A., Garber, J., Glendon, G., Godwin, A. K., Greene, M. H., Gronwald, J., Hahnen, E., Hallberg, E., Hamann, U., Hansen, T. O., Imyanitov, E. N., Isaacs, C., Jakubowska, A., Janavicius, R., Jaworska-Bieniek, K., John, E. M., Karlan, B. Y., Kaufman, B., Kwong, A., Laitman, Y., Lasset, C., Lazaro, C., Lester, J., Loman, N., Lubinski, J., Manoukian, S., Mitchell, G., Montagna, M., Neuhausen, S. L., Nevanlinna, H., Niederacher, D., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O. I., Park, S., Piedmonte, M., Radice, P., Rappaport-Fuerhauser, C., Rookus, M. A., Seynaeve, C., Simard, J., Singer, C. F., Soucy, P., Southey, M., Stoppa-Lyonnet, D., Sukiennicki, G., Szabo, C. I., Tancredi, M., Teixeira, M. R., Teo, S., Terry, M., Thomassen, M., Tihomirova, L., Tischkowitz, M., Toland, A., Toloczko-Grabarek, A., Tung, N., van Rensburg, E. J., Villano, D., Wang-Gohrke, S., Wappenschmidt, B., Weitzel, J. N., Zidan, J., Zorn, K. K., McGuffog, L., Easton, D., Chenevix-Trench, G., Antoniou, A. C., Ramus, S. J., EMBRACE, HEBON, KConFab Investigators 2016; 18: 112

    Abstract

    Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p?=?0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p?=?0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p?=?0.231), but was on average 4.5 years younger in TH than in SH2 (p?

    View details for PubMedID 27836010

    View details for PubMedCentralID PMC5106833

  • Body mass index, weight change, and risk of second primary breast cancer in the WECARE study: influence of estrogen receptor status of the first breast cancer CANCER MEDICINE Brooks, J. D., John, E. M., Mellemkjaer, L., Lynch, C. F., Knight, J. A., Malone, K. E., Reiner, A. S., Bernstein, L., Liang, X., Shore, R. E., Stovall, M., Bernstein, J. L., WECARE Study Collaborative Grp 2016; 5 (11): 3282?91

    View details for DOI 10.1002/cam4.890

    View details for Web of Science ID 000388370000028

  • Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer HUMAN MOLECULAR GENETICS Huo, D., Feng, Y., Haddad, S., Zheng, Y., Yao, S., Han, Y., Ogundiran, T. O., Adebamowo, C., Ojengbede, O., Falusi, A. G., Zheng, W., Blot, W., Cai, Q., Signorello, L., John, E. M., Bernstein, L., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Ruiz-Narvaez, E. A., Sucheston-Campbell, L. E., Bensen, J. T., Simon, M. S., Hennis, A., Nemesure, B., Leske, M., Ambs, S., Chen, L. S., Qian, F., Gamazon, E. R., Lunetta, K. L., Cox, N. J., Chanock, S. J., Kolonel, L. N., Olshan, A. F., Ambrosone, C. B., Olopade, O. I., Palmer, J. R., Haiman, C. A. 2016; 25 (21): 4835?46

    Abstract

    Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina?s HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5?Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR]=1.29, 95% CI: 1.18-1.40; P?=?1.8?×?10???8). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR?=?1.30; P?=?2.4?×?10???10) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR?=?1.34; P?=?2.2?×?10???8) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cancer.

    View details for PubMedID 28171663

    View details for PubMedCentralID PMC5975608

  • Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3. Breast cancer research and treatment Hamdi, Y., Soucy, P., Kuchenbaeker, K. B., Pastinen, T., Droit, A., Lemaçon, A., Adlard, J., Aittomäki, K., Andrulis, I. L., Arason, A., Arnold, N., Arun, B. K., Azzollini, J., Bane, A., Barjhoux, L., Barrowdale, D., Benitez, J., Berthet, P., Blok, M. J., Bobolis, K., Bonadona, V., Bonanni, B., Bradbury, A. R., Brewer, C., Buecher, B., Buys, S. S., Caligo, M. A., Chiquette, J., Chung, W. K., Claes, K. B., Daly, M. B., Damiola, F., Davidson, R., de la Hoya, M., De Leeneer, K., Diez, O., Ding, Y. C., Dolcetti, R., Domchek, S. M., Dorfling, C. M., Eccles, D., Eeles, R., Einbeigi, Z., Ejlertsen, B., Engel, C., Gareth Evans, D., Feliubadalo, L., Foretova, L., Fostira, F., Foulkes, W. D., Fountzilas, G., friedman, e., Frost, D., Ganschow, P., Ganz, P. A., Garber, J., Gayther, S. A., Gerdes, A., Glendon, G., Godwin, A. K., Goldgar, D. E., Greene, M. H., Gronwald, J., Hahnen, E., Hamann, U., Hansen, T. v., Hart, S., Hays, J. L., Hogervorst, F. B., Hulick, P. J., Imyanitov, E. N., Isaacs, C., Izatt, L., Jakubowska, A., James, P., Janavicius, R., Jensen, U. B., John, E. M., Joseph, V., Just, W., Kaczmarek, K., Karlan, B. Y., Kets, C. M., Kirk, J., Kriege, M., Laitman, Y., Laurent, M., Lazaro, C., Leslie, G., Lester, J., Lesueur, F., Liljegren, A., Loman, N., Loud, J. T., Manoukian, S., Mariani, M., Mazoyer, S., McGuffog, L., Meijers-Heijboer, H. E., Meindl, A., Miller, A., Montagna, M., Mulligan, A. M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nussbaum, R. L., Olah, E., Olopade, O. I., Ong, K., Oosterwijk, J. C., Osorio, A., Papi, L., Park, S. K., Pedersen, I. S., Peissel, B., Segura, P. P., Peterlongo, P., Phelan, C. M., Radice, P., Rantala, J., Rappaport-Fuerhauser, C., Rennert, G., Richardson, A., Robson, M., Rodriguez, G. C., Rookus, M. A., Schmutzler, R. K., Sevenet, N., Shah, P. D., Singer, C. F., Slavin, T. P., Snape, K., Sokolowska, J., Sřnderstrup, I. M., Southey, M., Spurdle, A. B., Stadler, Z., Stoppa-Lyonnet, D., Sukiennicki, G., Sutter, C., Tan, Y., Tea, M., Teixeira, M. R., Teulé, A., Teo, S., Terry, M. B., Thomassen, M., Tihomirova, L., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tung, N., van den Ouweland, A. M., van der Luijt, R. B., van Engelen, K., Van Rensburg, E. J., Varon-Mateeva, R., Wappenschmidt, B., Wijnen, J. T., Rebbeck, T., Chenevix-Trench, G., Offit, K., Couch, F. J., Nord, S., Easton, D. F., Antoniou, A. C., Simard, J. 2016: -?

    Abstract

    Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10(-6)). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

    View details for PubMedID 27796716

  • Genetic modifiers of CHEK2*1100delC-associated breast cancer risk. Genetics in medicine Muranen, T. A., Greco, D., Blomqvist, C., Aittomäki, K., Khan, S., Hogervorst, F., Verhoef, S., Pharoah, P. D., Dunning, A. M., Shah, M., Luben, R., Bojesen, S. E., Nordestgaard, B. G., Schoemaker, M., Swerdlow, A., García-Closas, M., Figueroa, J., Dörk, T., Bogdanova, N. V., Hall, P., Li, J., Khusnutdinova, E., Bermisheva, M., Kristensen, V., Borresen-Dale, A., Investigators, N., Peto, J., dos Santos Silva, I., Couch, F. J., Olson, J. E., Hillemans, P., Park-Simon, T., Brauch, H., Hamann, U., Burwinkel, B., Marme, F., Meindl, A., Schmutzler, R. K., Cox, A., Cross, S. S., Sawyer, E. J., Tomlinson, I., Lambrechts, D., Moisse, M., Lindblom, A., Margolin, S., Hollestelle, A., Martens, J. W., Fasching, P. A., Beckmann, M. W., Andrulis, I. L., Knight, J. A., Investigators, k., Anton-Culver, H., Ziogas, A., Giles, G. G., Milne, R. L., Brenner, H., Arndt, V., Mannermaa, A., Kosma, V., Chang-Claude, J., Rudolph, A., Devilee, P., Seynaeve, C., Hopper, J. L., Southey, M. C., John, E. M., Whittemore, A. S., Bolla, M. K., Wang, Q., Michailidou, K., Dennis, J., Easton, D. F., Schmidt, M. K., Nevanlinna, H. 2016

    Abstract

    CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.

    View details for DOI 10.1038/gim.2016.147

    View details for PubMedID 27711073

  • Genetic variants in microRNA and microRNA biogenesis pathway genes and breast cancer risk among women of African ancestry. Human genetics Qian, F., Feng, Y., Zheng, Y., Ogundiran, T. O., Ojengbede, O., Zheng, W., Blot, W., Ambrosone, C. B., John, E. M., Bernstein, L., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Nathanson, K. L., Hennis, A., Nemesure, B., Ambs, S., Kolonel, L. N., Olopade, O. I., Haiman, C. A., Huo, D. 2016; 135 (10): 1145-1159

    Abstract

    MicroRNAs (miRNA) regulate breast biology by binding to specific RNA sequences, leading to RNA degradation and inhibition of translation of their target genes. While germline genetic variations may disrupt some of these interactions between miRNAs and their targets, studies assessing the relationship between genetic variations in the miRNA network and breast cancer risk are still limited, particularly among women of African ancestry. We systematically put together a list of 822 and 10,468 genetic variants among primary miRNA sequences and 38 genes in the miRNA biogenesis pathway, respectively; and examined their association with breast cancer risk in the ROOT consortium which includes women of African ancestry. Findings were replicated in an independent consortium. Logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI). For overall breast cancer risk, three single-nucleotide polymorphisms (SNPs) in miRNA biogenesis genes DROSHA rs78393591 (OR = 0.69, 95 % CI: 0.55-0.88, P = 0.003), ESR1 rs523736 (OR = 0.88, 95 % CI: 0.82-0.95, P = 3.99 × 10(-4)), and ZCCHC11 rs114101502 (OR = 1.33, 95 % CI: 1.11-1.59, P = 0.002), and one SNP in primary miRNA sequence (rs116159732 in miR-6826, OR = 0.74, 95 % CI: 0.63-0.89, P = 0.001) were found to have significant associations in both discovery and validation phases. In a subgroup analysis, two SNPs were associated with risk of estrogen receptor (ER)-negative breast cancer, and three SNPs were associated with risk of ER-positive breast cancer. Several variants in miRNA and miRNA biogenesis pathway genes were associated with breast cancer risk. Risk associations varied by ER status, suggesting potential new mechanisms in etiology.

    View details for DOI 10.1007/s00439-016-1707-1

    View details for PubMedID 27380242

    View details for PubMedCentralID PMC5021583

  • Admixture Mapping of African-American Women in the AMBER Consortium Identifies New Loci for Breast Cancer and Estrogen-Receptor Subtypes FRONTIERS IN GENETICS Ruiz-Narvaez, E. A., Sucheston-Campbell, L., Bensen, J. T., Yao, S., Haddad, S., Haiman, C. A., Bandera, E. V., John, E. M., Bernstein, L., Hu, J. J., Ziegler, R. G., Deming, S. L., Olshan, A. F., Ambrosone, C. B., Palmer, J. R., Lunetta, K. L. 2016; 7: 170

    Abstract

    Recent genetic admixture coupled with striking differences in incidence of estrogen receptor (ER) breast cancer subtypes, as well as severity, between women of African and European ancestry, provides an excellent rationale for performing admixture mapping in African American women with breast cancer risk. We performed the largest breast cancer admixture mapping study with in African American women to identify novel genomic regions associated with the disease. We conducted a genome-wide admixture scan using 2,624 autosomal ancestry informative markers (AIMs) in 3,629 breast cancer cases (including 1,968 ER-positive, 1093 ER-negative, and 601 triple-negative) and 4,658 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a collaborative study of four large geographically different epidemiological studies of breast cancer in African American women. We used an independent case-control study to test for SNP association in regions with genome-wide significant admixture signals. We found two novel genome-wide significant regions of excess African ancestry, 4p16.1 and 17q25.1, associated with ER-positive breast cancer. Two regions known to harbor breast cancer variants, 10q26 and 11q13, were also identified with excess of African ancestry. Fine-mapping of the identified genome-wide significant regions suggests the presence of significant genetic associations with ER-positive breast cancer in 4p16.1 and 11q13. In summary, we identified three novel genomic regions associated with breast cancer risk by ER status, suggesting that additional previously unidentified variants may contribute to the racial differences in breast cancer risk in the African American population.

    View details for PubMedID 27708667

  • Association of lifestyle and demographic factors with estrogenic and glucocorticogenic activity in Mexican American women CARCINOGENESIS Fejerman, L., Sanchez, S. S., Thomas, R., Tachachartvanich, P., Riby, J., Gomez, S. L., John, E. M., Smith, M. T. 2016; 37 (9): 904?11

    Abstract

    Breast cancer risk is higher in US-born than in foreign-born Hispanics/Latinas and also increases with greater length of US residency. It is only partially known what factors contribute to these patterns of risk. To gain new insights, we tested the association between lifestyle and demographic variables and breast cancer status, with measures of estrogenic (E) and glucocorticogenic (G) activity in Mexican American women. We used Chemical-Activated LUciferase gene eXpression assays to measure E and G activity in total plasma from 90 Mexican American women, without a history of breast cancer at the time of recruitment, from the San Francisco Bay Area Breast Cancer Study. We tested associations of nativity, lifestyle and sociodemographic factors with E and G activity using linear regression models. We did not find a statistically significant difference in E or G activity by nativity. However, in multivariable models, E activity was associated with Indigenous American ancestry (19% decrease in E activity per 10% increase in ancestry, P = 0.014) and with length of US residency (28% increase in E activity for every 10 years, P = 0.035). G activity was associated with breast cancer status (women who have developed breast cancer since recruitment into the study had 21% lower G activity than those who have not, P = 0.054) and alcohol intake (drinkers had 25% higher G activity than non-drinkers, P = 0.015). These associations suggest that previously reported breast cancer risk factors such as genetic ancestry and alcohol intake might in part be associated with breast cancer risk through mechanisms linked to the endocrine system.

    View details for PubMedID 27412823

    View details for PubMedCentralID PMC5008251

  • Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers. Journal of clinical oncology Schmidt, M. K., Hogervorst, F., van Hien, R., Cornelissen, S., Broeks, A., Adank, M. A., Meijers, H., Waisfisz, Q., Hollestelle, A., Schutte, M., van den Ouweland, A., Hooning, M., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Antoniou, A. C., Arndt, V., Bermisheva, M., Bogdanova, N. V., Bolla, M. K., Brauch, H., Brenner, H., Brüning, T., Burwinkel, B., Chang-Claude, J., Chenevix-Trench, G., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Dunning, A. M., Fasching, P. A., Figueroa, J., Fletcher, O., Flyger, H., Galle, E., García-Closas, M., Giles, G. G., Haeberle, L., Hall, P., Hillemanns, P., Hopper, J. L., Jakubowska, A., John, E. M., Jones, M., Khusnutdinova, E., Knight, J. A., Kosma, V., Kristensen, V., Lee, A., Lindblom, A., Lubinski, J., Mannermaa, A., Margolin, S., Meindl, A., Milne, R. L., Muranen, T. A., Newcomb, P. A., Offit, K., Park-Simon, T., Peto, J., Pharoah, P. D., Robson, M., Rudolph, A., Sawyer, E. J., Schmutzler, R. K., Seynaeve, C., Soens, J., Southey, M. C., Spurdle, A. B., Surowy, H., Swerdlow, A., Tollenaar, R. A., Tomlinson, I., Trentham-Dietz, A., Vachon, C., Wang, Q., Whittemore, A. S., Ziogas, A., van der Kolk, L., Nevanlinna, H., Dörk, T., Bojesen, S., Easton, D. F. 2016; 34 (23): 2750-2760

    Abstract

    CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC.CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies.Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom.These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.

    View details for DOI 10.1200/JCO.2016.66.5844

    View details for PubMedID 27269948

  • Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent PLOS MEDICINE Guo, Y., Andersen, S. W., Shu, X., Michailidou, K., Bolla, M. K., Wang, Q., Garcia-Closas, M., Milne, R. L., Schmidt, M. K., Chang-Claude, J., Dunning, A., Bojesen, S. E., Ahsan, H., Aittomaki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Bogdanova, N. V., Bonanni, B., Borresen-Dale, A., Brand, J., Brauch, H., Brenner, H., Bruening, T., Burwinkel, B., Casey, G., Chenevix-Trench, G., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Devilee, P., Doerk, T., Dumont, M., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fostira, F., Gammon, M., Giles, G. G., Guenel, P., Haiman, C. A., Hamann, U., Hooning, M. J., Hopper, J. L., Jakubowska, A., Jasmine, F., Jenkins, M., John, E. M., Johnson, N., Jones, M. E., Kabisch, M., Kibriya, M., Knight, J. A., Koppert, L. B., Kosma, V., Kristensen, V., Le Marchand, L., Lee, E., Li, J., Lindblom, A., Luben, R., Lubinski, J., Malone, K. E., Mannermaa, A., Margolin, S., Marme, F., McLean, C., Meijers-Heijboer, H., Meindl, A., Neuhausen, S. L., Nevanlinna, H., Neven, P., Olson, J. E., Perez, J. I., Perkins, B., Peterlongo, P., Phillips, K., Pylkas, K., Rudolph, A., Santella, R., Sawyer, E. J., Schmutzler, R. K., Seynaeve, C., Shah, M., Shrubsole, M. J., Southey, M. C., Swerdlow, A. J., Toland, A. E., Tomlinson, I., Torres, D., Truong, T., Ursin, G., van der Luijt, R. B., Verhoef, S., Whittemore, A. S., Winqvist, R., Zhao, H., Zhao, S., Hall, P., Simard, J., Kraft, P., Pharoah, P., Hunter, D., Easton, D. F., Zheng, W. 2016; 13 (8)

    Abstract

    Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases? = ?46,325, controls? = ?42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]? = ?0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32?×?10-10). The associations were similar for both premenopausal (OR?? = ??0.44, 95% CI:0.31-0.62, p? = ?9.91?×?10-8) and postmenopausal breast cancer (OR? = ?0.57, 95%?CI: 0.46-0.71, p? = ?1.88?×?10-8). This association was replicated in the data from the DRIVE consortium (OR? = ?0.72, 95%?CI: 0.60-0.84, p?? = ??1.64?×?10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p?

    View details for DOI 10.1371/journal.pmed.1002105

    View details for Web of Science ID 000383357400022

    View details for PubMedCentralID PMC4995025

  • Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent. PLoS medicine Guo, Y., Warren Andersen, S., Shu, X., Michailidou, K., Bolla, M. K., Wang, Q., Garcia-Closas, M., Milne, R. L., Schmidt, M. K., Chang-Claude, J., Dunning, A., Bojesen, S. E., Ahsan, H., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Bogdanova, N. V., Bonanni, B., Břrresen-Dale, A., Brand, J., Brauch, H., Brenner, H., Brüning, T., Burwinkel, B., Casey, G., Chenevix-Trench, G., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Devilee, P., Dörk, T., Dumont, M., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fostira, F., Gammon, M., Giles, G. G., Guénel, P., Haiman, C. A., Hamann, U., Hooning, M. J., Hopper, J. L., Jakubowska, A., Jasmine, F., Jenkins, M., John, E. M., Johnson, N., Jones, M. E., Kabisch, M., Kibriya, M., Knight, J. A., Koppert, L. B., Kosma, V., Kristensen, V., Le Marchand, L., Lee, E., Li, J., Lindblom, A., Luben, R., Lubinski, J., Malone, K. E., Mannermaa, A., Margolin, S., Marme, F., McLean, C., Meijers-Heijboer, H., Meindl, A., Neuhausen, S. L., Nevanlinna, H., Neven, P., Olson, J. E., Perez, J. I., Perkins, B., Peterlongo, P., Phillips, K., Pylkäs, K., Rudolph, A., Santella, R., Sawyer, E. J., Schmutzler, R. K., Seynaeve, C., Shah, M., Shrubsole, M. J., Southey, M. C., Swerdlow, A. J., Toland, A. E., Tomlinson, I., Torres, D., Truong, T., Ursin, G., van der Luijt, R. B., Verhoef, S., Whittemore, A. S., Winqvist, R., Zhao, H., Zhao, S., Hall, P., Simard, J., Kraft, P., Pharoah, P., Hunter, D., Easton, D. F., Zheng, W. 2016; 13 (8)

    Abstract

    Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases? = ?46,325, controls? = ?42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]? = ?0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32?×?10-10). The associations were similar for both premenopausal (OR?? = ??0.44, 95% CI:0.31-0.62, p? = ?9.91?×?10-8) and postmenopausal breast cancer (OR? = ?0.57, 95%?CI: 0.46-0.71, p? = ?1.88?×?10-8). This association was replicated in the data from the DRIVE consortium (OR? = ?0.72, 95%?CI: 0.60-0.84, p?? = ??1.64?×?10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p?

    View details for DOI 10.1371/journal.pmed.1002105

    View details for PubMedID 27551723

  • Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers PLOS ONE Vigorito, E., Kuchenbaecker, K. B., Beesley, J., Adlard, J., Agnarsson, B. A., Andrulis, I. L., Arun, B. K., Barjhoux, L., Belotti, M., Benitez, J., Berger, A., Bojesen, A., Bonanni, B., Brewer, C., Caldes, T., Caligo, M. A., Campbell, I., Chan, S. B., Claes, K. M., Cohn, D. E., Cook, J., Daly, M. B., Damiola, F., Davidson, R., de Pauw, A., Delnatte, C., Diez, O., Domchek, S. M., Dumont, M., Durda, K., Dworniczak, B., Easton, D. F., Eccles, D., Ardnor, C., Eeles, R., Ejlertsen, B., Ellis, S., Evans, D., Feliubadalo, L., Fostira, F., Foulkes, W. D., Friedman, E., Frost, D., Gaddam, P., Ganz, P. A., Garber, J., Garcia-Barberan, V., Gauthier-Villars, M., Gehrig, A., Gerdes, A., Giraud, S., Godwin, A. K., Goldgar, D. E., Hake, C. R., Hansen, T. O., Healey, S., Hodgson, S., Hogervorst, F. L., Houdayer, C., Hulick, P. J., Imyanitov, E. N., Isaacs, C., Izatt, L., Izquierdo, A., Jacobs, L., Jakubowska, A., Janavicius, R., Jaworska-Bieniek, K., Jensen, U., John, E. M., Vijai, J., Karlan, B. Y., Kast, K., Khan, S., Kwong, A., Laitman, Y., Lester, J., Lesueur, F., Liljegren, A., Lubinski, J., Mai, P. L., Manoukian, S., Mazoyer, S., Meindl, A., Mensenkamp, A. R., Montagna, M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Niederacher, D., Olah, E., Olopade, O. I., Ong, K., Osorio, A., Park, S., Paulsson-Karlsson, Y., Pedersen, I., Peissel, B., Peterlongo, P., Pfeiler, G., Phelan, C. M., Piedmonte, M., Poppe, B., Angel Pujana, M., Radice, P., Rennert, G., Rodriguez, G. C., Rookus, M. A., Ross, E. A., Schmutzler, R., Simard, J., Singer, C. F., Slavin, T. P., Soucy, P., Southey, M., Steinemann, D., Stoppa-Lyonnet, D., Sukiennicki, G., Sutter, C., Szabo, C. I., Tea, M., Teixeira, M. R., Teo, S., Terry, M., Thomassen, M., Tibiletti, M., Tihomirova, L., Tognazzo, S., van Rensburg, E. J., Varesco, L., Varon-Mateeva, R., Vratimos, A., Weitzel, J. N., McGuffog, L., Kirk, J., Toland, A., Hamann, U., Lindor, N., Ramus, S. J., Greene, M. H., Couch, F. J., Offit, K., Pharoah, P. P., Chenevix-Trench, G., Antoniou, A. C., Kconfab Investigators 2016; 11 (7): e0158801

    Abstract

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

    View details for PubMedID 27463617

  • Systemic therapy for breast cancer and risk of subsequent contralateral breast cancer in the WECARE Study BREAST CANCER RESEARCH Langballe, R., Mellemkjaer, L., Malone, K. E., Lynch, C. F., John, E. M., Knight, J. A., Bernstein, L., Brooks, J., Andersson, M., Reiner, A. S., Liang, X., Woods, M., Concannon, P. J., Bernstein, J. L., WECARE Study Collaborative Grp 2016; 18
  • The Effect of Patient and Contextual Characteristics on Racial/Ethnic Disparity in Breast Cancer Mortality CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Sposto, R., Keegan, T. H., Vigen, C., Kwan, M. L., Bernstein, L., John, E. M., Cheng, I., Yang, J., Koo, J., Kurian, A. W., Caan, B. J., Lu, Y., Monroe, K. R., Shariff-Marco, S., Gomez, S. L., Wu, A. H. 2016; 25 (7): 1064-1072

    Abstract

    Racial/ethnic disparity in breast cancer-specific mortality in the U.S. is well documented. We examined whether accounting for racial/ethnic differences in the prevalence of clinical, patient, and lifestyle and contextual factors that are associated with breast cancer-specific mortality can explain this disparity.The California Breast Cancer Survivorship Consortium combined interview data from six California-based breast cancer studies with cancer registry data to create a large racially diverse cohort of women with primary invasive breast cancer. We examined the contribution of variables in a previously reported Cox regression baseline model plus additional contextual, physical activity, body size, and comorbidity variables to the racial/ethnic disparity in breast cancer-specific mortality.The cohort comprised 12,098 women. Fifty-four percent were non-Latina Whites, 17% African Americans, 17% Latinas, and 12% Asian Americans. In a model adjusting only for age and study, breast cancer-specific hazard ratios relative to Whites were 1.69 (95% CI 1.46 - 1.96), 1.00 (0.84 - 1.19), and 0.52 (0.33 - 0.85) for African Americans, Latinas, and Asian Americans respectively. Adjusting for baseline-model variables decreased disparity primarily by reducing the hazard ratio for African Americans to 1.13 (0.96 - 1.33). The most influential variables were related to disease characteristics, neighborhood socioeconomic status, and smoking status at diagnosis. Other variables had negligible impact on disparity.While contextual, physical activity, body size, and comorbidity variables may influence breast cancer-specific mortality, they do not explain racial/ethnic mortality disparity.Other factors besides those investigated here may explain the existing racial/ethnic disparity in mortality.

    View details for DOI 10.1158/1055-9965.EPI-15-1326

    View details for PubMedID 27197297

  • Comparison of Clinical, Maternal, and Self Pubertal Assessments: Implications for Health Studies PEDIATRICS Terry, M. B., Goldberg, M., Schechter, S., Houghton, L. C., White, M. L., O'Toole, K., Chung, W. K., Daly, M. B., Keegan, T. H., Andrulis, I. L., Bradbury, A. R., Schwartz, L., Knight, J. A., John, E. M., Buys, S. S. 2016; 138 (1)

    Abstract

    Most epidemiologic studies of puberty have only 1 source of pubertal development information (maternal, self or clinical). Interpretation of results across studies requires data on reliability and validity across sources.The LEGACY Girls Study, a 5-site prospective study of girls aged 6 to 13 years (n = 1040) collected information on breast and pubic hair development from mothers (for all daughters) and daughters (if ?10 years) according to Tanner stage (T1-5) drawings. At 2 LEGACY sites, girls (n = 282) were also examined in the clinic by trained professionals. We assessed agreement (?) and validity (sensitivity and specificity) with the clinical assessment (gold standard) for both the mothers' and daughters' assessment in the subcohort of 282. In the entire cohort, we examined the agreement between mothers and daughters.Compared with clinical assessment, sensitivity of maternal assessment for breast development was 77.2 and specificity was 94.3. In girls aged ?11 years, self-assessment had higher sensitivity and specificity than maternal report. Specificity for both mothers and self, but not sensitivity, was significantly lower for overweight girls. In the overall cohort, maternal and daughter agreement for breast development and pubic hair development (T2+ vs T1) were similar (0.66, [95% confidence interval 0.58-0.75] and 0.69 [95% confidence interval 0.61-0.77], respectively), but declined with age. Mothers were more likely to report a lower Tanner stage for both breast and pubic hair compared with self-assessments.These differences in validity should be considered in studies measuring pubertal changes longitudinally when they do not have access to clinical assessments.

    View details for DOI 10.1542/peds.2015-4571

    View details for Web of Science ID 000378853100029

    View details for PubMedID 27279647

  • Prostate Cancer Susceptibility in Men of African Ancestry at 8q24. Journal of the National Cancer Institute Han, Y., Rand, K. A., Hazelett, D. J., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Stanford, J. L., Zheng, W., Schumacher, F. R., Berndt, S. I., Wang, Z., Xu, J., Rohland, N., Reich, D., Tandon, A., Pasaniuc, B., Allen, A., Quinque, D., Mallick, S., Notani, D., Rosenfeld, M. G., Jayani, R. S., Kolb, S., Gapstur, S. M., Stevens, V. L., Pettaway, C. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., John, E. M., Murphy, A. B., Signorello, L. B., Carpten, J., Leske, M. C., Wu, S., Hennis, A. J., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Witte, J. S., Casey, G., Lubwama, A., Pooler, L. C., Sheng, X., Coetzee, G. A., Cook, M. B., Chanock, S. J., Stram, D. O., Watya, S., Blot, W. J., Conti, D. V., Henderson, B. E., Haiman, C. A. 2016; 108 (7)

    Abstract

    The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.

    View details for DOI 10.1093/jnci/djv431

    View details for PubMedID 26823525

  • ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry PLOS ONE Renault, A., Lesueur, F., Coulombe, Y., Gobeil, S., Soucy, P., Hamdi, Y., Desjardins, S., Le Calvez-Kelm, F., Vallee, M., Voegele, C., Hopper, J. L., Andrulis, I. L., Southey, M. C., John, E. M., Masson, J., Tavtigian, S. V., Simard, J. 2016; 11 (6)

    Abstract

    Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer.

    View details for DOI 10.1371/journal.pone.0156820

    View details for Web of Science ID 000377561000040

    View details for PubMedID 27270457

    View details for PubMedCentralID PMC4896418

  • Cohort Profile: The Breast Cancer Prospective Family Study Cohort (ProF-SC) INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Terry, M. B., Phillips, K., Daly, M. B., John, E. M., Andrulis, I. L., Buys, S. S., Goldgar, D. E., Knight, J. A., Whittemore, A. S., Chung, W. K., Apicella, C., Hopper, J. L. 2016; 45 (3): 683-692

    View details for DOI 10.1093/ije/dyv118

    View details for PubMedID 26174520

  • Multigene testing of moderate-risk genes: be mindful of the missense JOURNAL OF MEDICAL GENETICS Young, E. L., Feng, B. J., Stark, A. W., Damiola, F., Durand, G., Forey, N., Francy, T. C., Gammon, A., Kohlmann, W. K., Kaphingst, K. A., McKay-Chopin, S., Nguyen-Dumont, T., Oliver, J., Paquette, A. M., Pertesi, M., Robinot, N., Rosenthal, J. S., Vallee, M., Voegele, C., Hopper, J. L., Southey, M. C., Andrulis, I. L., John, E. M., Hashibe, M., Gertz, J., Le Calvez-Kelm, F., Lesueur, F., Goldgar, D. E., Tavtigian, S. V., Breast Canc Family Registry 2016; 53 (6): 366?76

    Abstract

    Moderate-risk genes have not been extensively studied, and missense substitutions in them are generally returned to patients as variants of uncertain significance lacking clearly defined risk estimates. The fraction of early-onset breast cancer cases carrying moderate-risk genotypes and quantitative methods for flagging variants for further analysis have not been established.We evaluated rare missense substitutions identified from a mutation screen of ATM, CHEK2, MRE11A, RAD50, NBN, RAD51, RINT1, XRCC2 and BARD1 in 1297 cases of early-onset breast cancer and 1121 controls via scores from Align-Grantham Variation Grantham Deviation (GVGD), combined annotation dependent depletion (CADD), multivariate analysis of protein polymorphism (MAPP) and PolyPhen-2. We also evaluated subjects by polygenotype from 18 breast cancer risk SNPs. From these analyses, we estimated the fraction of cases and controls that reach a breast cancer OR?2.5 threshold.Analysis of mutation screening data from the nine genes revealed that 7.5% of cases and 2.4% of controls were carriers of at least one rare variant with an average OR?2.5. 2.1% of cases and 1.2% of controls had a polygenotype with an average OR?2.5.Among early-onset breast cancer cases, 9.6% had a genotype associated with an increased risk sufficient to affect clinical management recommendations. Over two-thirds of variants conferring this level of risk were rare missense substitutions in moderate-risk genes. Placement in the estimated OR?2.5 group by at least two of these missense analysis programs should be used to prioritise variants for further study. Panel testing often creates more heat than light; quantitative approaches to variant prioritisation and classification may facilitate more efficient clinical classification of variants.

    View details for PubMedID 26787654

    View details for PubMedCentralID PMC4893078

  • The LEGACY Girls Study: Growth and Development in the Context of Breast Cancer Family History. Epidemiology John, E. M., Terry, M. B., Keegan, T. H., Bradbury, A. R., Knight, J. A., Chung, W. K., Frost, C. J., Lilge, L., Patrick-Miller, L., Schwartz, L. A., Whittemore, A. S., Buys, S. S., Daly, M. B., Andrulis, I. L. 2016; 27 (3): 438-448

    Abstract

    Although the timing of pubertal milestones has been associated with breast cancer risk, few studies of girls' development include girls at increased breast cancer risk due to their family history.The Lessons in Epidemiology and Genetics of Adult Cancer from Youth (LEGACY) Girls Study was initiated in 2011 in the USA and Canada to assess the relation between early life exposures and intermediate markers of breast cancer risk (e.g., pubertal development, breast tissue characteristics) and to investigate psychosocial well being and health behaviors in the context of family history. We describe the methods used to establish and follow a cohort of 1,040 girls ages 6-13 years at baseline, half with a breast cancer family history, and the collection of questionnaire data (family history, early life exposures, growth and development, psychosocial and behavioral), anthropometry, biospecimens, and breast tissue characteristics using optical spectroscopy.During this initial 5-year phase of the study, follow-up visits are conducted every 6 months for repeated data and biospecimen collection. Participation in baseline components was high (98% for urine, 97.5% for blood or saliva, and 98% for anthropometry). At enrollment, 77% of girls were premenarcheal and 49% were at breast Tanner stage T1.This study design allows thorough examination of events affecting girls' growth and development and how they differ across the spectrum of breast cancer risk. A better understanding of early life breast cancer risk factors will be essential to enhance prevention across the lifespan for those with and without a family history of the disease.

    View details for DOI 10.1097/EDE.0000000000000456

    View details for PubMedID 26829160

  • Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry CANCER CAUSES & CONTROL Zhao, Z., Wen, W., Michailidou, K., Bolla, M. K., Wang, Q., Zhang, B., Long, J., Shu, X., Schmidt, M. K., Milne, R. L., Garcia-Closas, M., Chang-Claude, J., Lindstrom, S., Bojesen, S. E., Ahsan, H., Aittomaki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Blomqvist, C., Bogdanova, N. V., Borresen-Dale, A., Brand, J., Brauch, H., Brenner, H., Burwinkel, B., Cai, Q., Casey, G., Chenevix-Trench, G., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Doerk, T., Dumont, M., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fostira, F., Gammon, M., Giles, G. G., Guenel, P., Haiman, C. A., Hamann, U., Harrington, P., Hartman, M., Hooning, M. J., Hopper, J. L., Jakubowska, A., Jasmine, F., John, E. M., Johnson, N., Kabisch, M., Khan, S., Kibriya, M., Knight, J. A., Kosma, V., Kriege, M., Kristensen, V., Le Marchand, L., Lee, E., Li, J., Lindblom, A., Lophatananon, A., Luben, R., Lubinski, J., Malone, K. E., Mannermaa, A., Manoukian, S., Margolin, S., Marme, F., McLean, C., Meijers-Heijboer, H., Meindl, A., Miao, H., Muir, K., Neuhausen, S. L., Nevanlinna, H., Neven, P., Olson, J. E., Perkins, B., Peterlongo, P., Phillips, K., Pylkas, K., Rudolph, A., Santella, R., Sawyer, E. J., Schmutzler, R. K., Schoemaker, M., Shah, M., Shrubsole, M., Southey, M. C., Swerdlow, A. J., Toland, A. E., Tomlinson, I., Torres, D., Therese Truong, T., Ursin, G., van der Luijt, R. B., Verhoef, S., Wang-Gohrke, S., Whittemore, A. S., Winqvist, R., Zamora, M. P., Zhao, H., Dunning, A. M., Simard, J., Hall, P., Kraft, P., Pharoah, P., Hunter, D., Easton, D. F., Zheng, W. 2016; 27 (5): 679-693

    Abstract

    Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies.The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04).We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

    View details for DOI 10.1007/s10552-016-0741-6

    View details for PubMedID 27053251

  • Ethnic differences in the relationships between diabetes, early age adiposity and mortality among breast cancer survivors: the Breast Cancer Health Disparities Study BREAST CANCER RESEARCH AND TREATMENT Connor, A. E., Visvanathan, K., Baumgartner, K. B., Baumgartner, R. N., Boone, S. D., Hines, L. M., Wolff, R. K., John, E. M., Slattery, M. L. 2016; 157 (1): 167-178

    Abstract

    The contribution of type 2 diabetes and obesity on mortality in breast cancer (BC) patients has not been well studied among Hispanic women, in whom these exposures are highly prevalent. In a multi-center population-based study, we examined the associations between diabetes, multiple obesity measures, and mortality in 1180 Hispanic and 1298 non-Hispanic white (NHW) women who were diagnosed with incident invasive BC from the San Francisco Bay Area, New Mexico, Utah, Colorado, and Arizona. Adjusted hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards regression models. The median follow-up time from BC diagnosis to death was 10.8 years. In ethnic-stratified results, the association for BC-specific mortality among Hispanics was significantly increased (HR 1.85 95 % CI 1.11, 3.09), but the ethnic interaction was not statistically significant. In contrast, obesity at age 30 increased BC-specific mortality risk in NHW women (HR 2.33 95 % CI 1.36, 3.97) but not Hispanics (p-interaction = 0.045). Although there were no ethnic differences for all-cause mortality, diabetes, obesity at age 30, and post-diagnostic waist-hip ratio were significantly associated with all-cause mortality in all women. This study provides evidence that diabetes and adiposity, both modifiable, are prognostic factors among Hispanic and NHW BC patients.

    View details for DOI 10.1007/s10549-016-3810-3

    View details for Web of Science ID 000376303100016

    View details for PubMedID 27116186

  • No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing JOURNAL OF MEDICAL GENETICS Easton, D. F., Lesueur, F., Decker, B., Michailidou, K., Li, J., Allen, J., Luccarini, C., Pooley, K. A., Shah, M., Bolla, M. K., Wang, Q., Dennis, J., Ahmad, J., Thompson, E. R., Damiola, F., Pertesi, M., Voegele, C., Mebirouk, N., Robinot, N., Durand, G., Forey, N., Luben, R. N., Ahmed, S., Aittomaki, K., Anton-Culver, H., Arndt, V., Baynes, C., Beckman, M. W., Benitez, J., Van Den Berg, D., Blot, W. J., Bogdanova, N. V., Bojesen, S. E., Brenner, H., Chang-Claude, J., Chia, K. S., Choi, J., Conroy, D. M., Cox, A., Cross, S. S., Czene, K., Darabi, H., Devilee, P., Eriksson, M., Fasching, P. A., Figueroa, J., Flyger, H., Fostira, F., Garcia-Closas, M., Giles, G. G., Glendon, G., Gonzalez-Neira, A., Guenel, P., Haiman, C. A., Hall, P., Hart, S. N., Hartman, M., Hooning, M. J., Hsiung, C., Ito, H., Jakubowska, A., James, P. A., John, E. M., Johnson, N., Jones, M., Kabisch, M., Kang, D., Kosma, V., Kristensen, V., Lambrechts, D., Li, N., Lindblom, A., Long, J., Lophatananon, A., Lubinski, J., Mannermaa, A., Manoukian, S., Margolin, S., Matsuo, K., Meindl, A., Mitchell, G., Muir, K., Nevelsteen, I., van den Ouweland, A., Peterlongo, P., Phuah, S. Y., Pylkas, K., Rowley, S. M., Sangrajrang, S., Schmutzler, R. K., Shen, C., Shu, X., Southey, M. C., Surowy, H., Swerdlow, A., Teo, S. H., Tollenaar, R. A., Tomlinson, I., Torres, D., Truong, T., Vachon, C., Verhoef, S., Wong-Brown, M., Zheng, W., Zheng, Y., Nevanlinna, H., Scott, R. J., Andrulis, I. L., Wu, A. H., Hopper, J. L., Couch, F. J., Winqvist, R., Burwinkel, B., Sawyer, E. J., Schmidt, M. K., Rudolph, A., Doerk, T., Brauch, H., Hamann, U., Neuhausen, S. L., Milne, R. L., Fletcher, O., Pharoah, P. D., Campbell, I. G., Dunning, A. M., Le Calvez-Kelm, F., Goldgar, D. E., Tavtigian, S. V., Chenevix-Trench, G. 2016; 53 (5): 298-309

    Abstract

    BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48?144 cases and 43?607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13?213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

    View details for DOI 10.1136/jmedgenet-2015-103529

    View details for Web of Science ID 000375274900003

    View details for PubMedID 26921362

    View details for PubMedCentralID PMC4938802

  • Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170 NATURE GENETICS Dunning, A. M., Michailidou, K., Kuchenbaecker, K. B., Thompson, D., French, J. D., Beesley, J., Healey, C. S., Kar, S., Pooley, K. A., Lopez-Knowles, E., Dicks, E., Barrowdale, D., Sinnott-Armstrong, N. A., Sallari, R. C., Hillman, K. M., Kaufmann, S., Sivakumaran, H., Marjaneh, M. M., Lee, J. S., Hills, M., Jarosz, M., Drury, S., Canisius, S., Bolla, M. K., Dennis, J., Wang, Q., Hopper, J. L., Southey, M. C., Broeks, A., Schmidt, M. K., Lophatananon, A., Muir, K., Beckmann, M. W., Fasching, P. A., Dos-Santos-Silva, I., Peto, J., Sawyer, E. J., Tomlinson, I., Burwinkel, B., Marme, F., Guenel, P., Truong, T., Bojesen, S. E., Flyger, H., Gonzalez-Neira, A., Perez, J. I., Anton-Culver, H., Eunjung, L., Arndt, V., Brenner, H., Meindl, A., Schmutzler, R. K., Brauch, H., Hamann, U., Aittomaki, K., Blomqvist, C., Ito, H., Matsuo, K., Bogdanova, N., Dork, T., Lindblom, A., Margolin, S., Kosma, V., Mannermaa, A., Tseng, C., Wu, A. H., Lambrechts, D., Wildiers, H., Chang-Claude, J., Rudolph, A., Peterlongo, P., Radice, P., Olson, J. E., Giles, G. G., Milne, R. L., Haiman, C. A., Henderson, B. E., Goldberg, M. S., Teo, S. H., Yip, C. H., Nord, S., Borresen-Dale, A., Kristensen, V., Long, J., Zheng, W., Pylkas, K., Winqvist, R., Andrulis, I. L., Knight, J. A., Devilee, P., Seynaeve, C., Figueroa, J., Sherman, M. E., Czene, K., Darabi, H., Hollestelle, A., van den Ouweland, A. M., Humphreys, K., Gao, Y., Shu, X., Cox, A., Cross, S. S., Blot, W., Cai, Q., Ghoussaini, M., Perkins, B. J., Shah, M., Choi, J., Kang, D., Lee, S. C., Hartman, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Brennan, P., Sangrajrang, S., Ambrosone, C. B., Toland, A. E., Shen, C., Wu, P., Orr, N., Swerdlow, A., McGuffog, L., Healey, S., Lee, A., Kapuscinski, M., John, E. M., Terry, M. B., Daly, M. B., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., Van Rensburg, E. J., Neuhausen, S. L., Ejlertsen, B., Hansen, T. v., Osorio, A., Benitez, J., Rando, R., Weitzel, J. N., Bonanni, B., Peissel, B., Manoukian, S., Papi, L., Ottini, L., Konstantopoulou, I., Apostolou, P., Garber, J., Rashid, M. U., Frost, D., Izatt, L., Ellis, S., Godwin, A. K., Arnold, N., Niederacher, D., Rhiem, K., Bogdanova-Markov, N., Sagne, C., Stoppa-Lyonnet, D., Damiola, F., Sinilnikova, O. M., Mazoyer, S., Isaacs, C., Claes, K. B., De Leeneer, K., de la Hoya, M., Caldes, T., Nevanlinna, H., Khan, S., Mensenkamp, A. R., Hooning, M. J., Rookus, M. A., Kwong, A., Olah, E., Diez, O., Brunet, J., Pujana, M. A., Gronwald, J., Huzarski, T., Barkardottir, R. B., Laframboise, R., Soucy, P., Montagna, M., Agata, S., Teixeira, M. R., Park, S. K., Lindor, N., Couch, F. J., Tischkowitz, M., Foretova, L., Vijai, J., Offit, K., Singer, C. F., Rappaport, C., Phelan, C. M., Greene, M. H., Mai, P. L., Rennert, G., Imyanitov, E. N., Hulick, P. J., Phillips, K., Piedmonte, M., Mulligan, A. M., Glendon, G., Bojesen, A., Thomassen, M., Caligo, M. A., Yoon, S., friedman, e., Laitman, Y., Borg, A., von Wachenfeldt, A., Ehrencrona, H., Rantala, J., Olopade, O. I., Ganz, P. A., Nussbaum, R. L., Gayther, S. A., Nathanson, K. L., Domchek, S. M., Arun, B. K., Mitchell, G., Karlan, B. Y., Lester, J., Maskarinec, G., Woolcott, C., Scott, C., Stone, J., Apicella, C., Tamimi, R., Luben, R., Khaw, K., Helland, A., Haakensen, V., Dowsett, M., Pharoah, P. D., Simard, J., Hall, P., Garcia-Closas, M., Vachon, C., Chenevix-Trench, G., Antoniou, A. C., Easton, D. F., Edwards, S. L. 2016; 48 (4): 374-?

    Abstract

    We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor ?) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

    View details for DOI 10.1038/ng.3521

    View details for Web of Science ID 000372908800009

    View details for PubMedCentralID PMC4938803

  • Red meat, poultry, and fish intake and breast cancer risk among Hispanic and Non-Hispanic white women: The Breast Cancer Health Disparities Study. Cancer causes & control Kim, A. E., Lundgreen, A., Wolff, R. K., Fejerman, L., John, E. M., Torres-Mejía, G., Ingles, S. A., Boone, S. D., Connor, A. E., Hines, L. M., Baumgartner, K. B., Giuliano, A., Joshi, A. D., Slattery, M. L., Stern, M. C. 2016; 27 (4): 527-543

    Abstract

    There is suggestive but limited evidence for a relationship between meat intake and breast cancer (BC) risk. Few studies included Hispanic women. We investigated the association between meats and fish intake and BC risk among Hispanic and NHW women.The study included NHW (1,982 cases and 2,218 controls) and the US Hispanics (1,777 cases and 2,218 controls) from two population-based case-control studies. Analyses considered menopausal status and percent Native American ancestry. We estimated pooled ORs combining harmonized data from both studies, and study- and race-/ethnicity-specific ORs that were combined using fixed or random effects models, depending on heterogeneity levels.When comparing highest versus lowest tertile of intake, among NHW we observed an association between tuna intake and BC risk (pooled OR 1.25; 95 % CI 1.05-1.50; trend p = 0.006). Among Hispanics, we observed an association between BC risk and processed meat intake (pooled OR 1.42; 95 % CI 1.18-1.71; trend p < 0.001), and between white meat (OR 0.80; 95 % CI 0.67-0.95; trend p = 0.01) and BC risk, driven by poultry. All these findings were supported by meta-analysis using fixed or random effect models and were restricted to estrogen receptor-positive tumors. Processed meats and poultry were not associated with BC risk among NHW women; red meat and fish were not associated with BC risk in either race/ethnic groups.Our results suggest the presence of ethnic differences in associations between meat and BC risk that may contribute to BC disparities.

    View details for DOI 10.1007/s10552-016-0727-4

    View details for PubMedID 26898200

    View details for PubMedCentralID PMC4821634

  • Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nature genetics Dunning, A. M., Michailidou, K., Kuchenbaecker, K. B., Thompson, D., French, J. D., Beesley, J., Healey, C. S., Kar, S., Pooley, K. A., Lopez-Knowles, E., Dicks, E., Barrowdale, D., Sinnott-Armstrong, N. A., Sallari, R. C., Hillman, K. M., Kaufmann, S., Sivakumaran, H., Moradi Marjaneh, M., Lee, J. S., Hills, M., Jarosz, M., Drury, S., Canisius, S., Bolla, M. K., Dennis, J., Wang, Q., Hopper, J. L., Southey, M. C., Broeks, A., Schmidt, M. K., Lophatananon, A., Muir, K., Beckmann, M. W., Fasching, P. A., Dos-Santos-Silva, I., Peto, J., Sawyer, E. J., Tomlinson, I., Burwinkel, B., Marme, F., Guénel, P., Truong, T., Bojesen, S. E., Flyger, H., González-Neira, A., Perez, J. I., Anton-Culver, H., Eunjung, L., Arndt, V., Brenner, H., Meindl, A., Schmutzler, R. K., Brauch, H., Hamann, U., Aittomäki, K., Blomqvist, C., Ito, H., Matsuo, K., Bogdanova, N., Dörk, T., Lindblom, A., Margolin, S., Kosma, V., Mannermaa, A., Tseng, C., Wu, A. H., Lambrechts, D., Wildiers, H., Chang-Claude, J., Rudolph, A., Peterlongo, P., Radice, P., Olson, J. E., Giles, G. G., Milne, R. L., Haiman, C. A., Henderson, B. E., Goldberg, M. S., Teo, S. H., Yip, C. H., Nord, S., Borresen-Dale, A., Kristensen, V., Long, J., Zheng, W., Pylkäs, K., Winqvist, R., Andrulis, I. L., Knight, J. A., Devilee, P., Seynaeve, C., Figueroa, J., Sherman, M. E., Czene, K., Darabi, H., Hollestelle, A., van den Ouweland, A. M., Humphreys, K., Gao, Y., Shu, X., Cox, A., Cross, S. S., Blot, W., Cai, Q., Ghoussaini, M., Perkins, B. J., Shah, M., Choi, J., Kang, D., Lee, S. C., Hartman, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Brennan, P., Sangrajrang, S., Ambrosone, C. B., Toland, A. E., Shen, C., Wu, P., Orr, N., Swerdlow, A., McGuffog, L., Healey, S., Lee, A., Kapuscinski, M., John, E. M., Terry, M. B., Daly, M. B., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., Van Rensburg, E. J., Neuhausen, S. L., Ejlertsen, B., Hansen, T. v., Osorio, A., Benitez, J., Rando, R., Weitzel, J. N., Bonanni, B., Peissel, B., Manoukian, S., Papi, L., Ottini, L., Konstantopoulou, I., Apostolou, P., Garber, J., Rashid, M. U., Frost, D., Izatt, L., Ellis, S., Godwin, A. K., Arnold, N., Niederacher, D., Rhiem, K., Bogdanova-Markov, N., Sagne, C., Stoppa-Lyonnet, D., Damiola, F., Sinilnikova, O. M., Mazoyer, S., Isaacs, C., Claes, K. B., De Leeneer, K., de la Hoya, M., Caldes, T., Nevanlinna, H., Khan, S., Mensenkamp, A. R., Hooning, M. J., Rookus, M. A., Kwong, A., Olah, E., Diez, O., Brunet, J., Pujana, M. A., Gronwald, J., Huzarski, T., Barkardottir, R. B., Laframboise, R., Soucy, P., Montagna, M., Agata, S., Teixeira, M. R., Park, S. K., Lindor, N., Couch, F. J., Tischkowitz, M., Foretova, L., Vijai, J., Offit, K., Singer, C. F., Rappaport, C., Phelan, C. M., Greene, M. H., Mai, P. L., Rennert, G., Imyanitov, E. N., Hulick, P. J., Phillips, K., Piedmonte, M., Mulligan, A. M., Glendon, G., Bojesen, A., Thomassen, M., Caligo, M. A., Yoon, S., friedman, e., Laitman, Y., Borg, A., von Wachenfeldt, A., Ehrencrona, H., Rantala, J., Olopade, O. I., Ganz, P. A., Nussbaum, R. L., Gayther, S. A., Nathanson, K. L., Domchek, S. M., Arun, B. K., Mitchell, G., Karlan, B. Y., Lester, J., Maskarinec, G., Woolcott, C., Scott, C., Stone, J., Apicella, C., Tamimi, R., Luben, R., Khaw, K., Helland, Ĺ., Haakensen, V., Dowsett, M., Pharoah, P. D., Simard, J., Hall, P., García-Closas, M., Vachon, C., Chenevix-Trench, G., Antoniou, A. C., Easton, D. F., Edwards, S. L. 2016; 48 (4): 374-386

    Abstract

    We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor ?) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

    View details for DOI 10.1038/ng.3521

    View details for PubMedID 26928228

  • Red meat, poultry, and fish intake and breast cancer risk among Hispanic and Non-Hispanic white women: The Breast Cancer Health Disparities Study CANCER CAUSES & CONTROL Kim, A. E., Lundgreen, A., Wolff, R. K., Fejerman, L., John, E. M., Torres-Mejia, G., Ingles, S. A., Boone, S. D., Connor, A. E., Hines, L. M., Baumgartner, K. B., Giuliano, A., Joshi, A. D., Slattery, M. L., Stern, M. C. 2016; 27 (4): 527-543

    Abstract

    There is suggestive but limited evidence for a relationship between meat intake and breast cancer (BC) risk. Few studies included Hispanic women. We investigated the association between meats and fish intake and BC risk among Hispanic and NHW women.The study included NHW (1,982 cases and 2,218 controls) and the US Hispanics (1,777 cases and 2,218 controls) from two population-based case-control studies. Analyses considered menopausal status and percent Native American ancestry. We estimated pooled ORs combining harmonized data from both studies, and study- and race-/ethnicity-specific ORs that were combined using fixed or random effects models, depending on heterogeneity levels.When comparing highest versus lowest tertile of intake, among NHW we observed an association between tuna intake and BC risk (pooled OR 1.25; 95 % CI 1.05-1.50; trend p = 0.006). Among Hispanics, we observed an association between BC risk and processed meat intake (pooled OR 1.42; 95 % CI 1.18-1.71; trend p < 0.001), and between white meat (OR 0.80; 95 % CI 0.67-0.95; trend p = 0.01) and BC risk, driven by poultry. All these findings were supported by meta-analysis using fixed or random effect models and were restricted to estrogen receptor-positive tumors. Processed meats and poultry were not associated with BC risk among NHW women; red meat and fish were not associated with BC risk in either race/ethnic groups.Our results suggest the presence of ethnic differences in associations between meat and BC risk that may contribute to BC disparities.

    View details for DOI 10.1007/s10552-016-0727-4

    View details for Web of Science ID 000372554500007

    View details for PubMedCentralID PMC4821634

  • Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer NATURE COMMUNICATIONS Couch, F. J., Kuchenbaecker, K. B., Michailidou, K., Mendoza-Fandino, G. A., Nord, S., Lilyquist, J., Olswold, C., Hallberg, E., Agata, S., Ahsan, H., Aittomaeki, K., Ambrosone, C., Andrulis, I. L., Anton-Culver, H., Arndt, V., Arun, B. K., Arver, B., Barile, M., Barkardottir, R. B., Barrowdale, D., Beckmann, L., Beckmann, M. W., Benitez, J., Blank, S. V., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Bonanni, B., Brauch, H., Brenner, H., Burwinkel, B., Buys, S. S., Caldes, T., Caligo, M. A., Canzian, F., Carpenter, J., Chang-Claude, J., Chanock, S. J., Chung, W. K., Claes, K. B., Cox, A., Cross, S. S., Cunningham, J. M., Czene, K., Daly, M. B., Damiola, F., Darabi, H., de la Hoya, M., Devilee, P., Diez, O., Ding, Y. C., Dolcetti, R., Domchek, S. M., Dorfling, C. M., Dos-Santos-Silva, I., Dumont, M., Dunning, A. M., Eccles, D. M., Ehrencrona, H., Ekici, A. B., Eliassen, H., Ellis, S., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Foersti, A., Fostira, F., Foulkes, W. D., Friebel, T., friedman, e., Frost, D., Gabrielson, M., Gammon, M. D., Ganz, P. A., Gapstur, S. M., Garber, J., Gaudet, M. M., Gayther, S. A., Gerdes, A., Ghoussaini, M., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Greene, M. H., Gronwald, J., Guenel, P., Gunter, M., Haeberle, L., Haiman, C. A., Hamann, U., Hansen, T. v., Hart, S., Healey, S., Heikkinen, T., Henderson, B. E., Herzog, J., Hogervorst, F. B., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Humphreys, K., Hunter, D. J., Huzarski, T., Imyanitov, E. N., Isaacs, C., Jakubowska, A., James, P., Janavicius, R., Jensen, U. B., John, E. M., Jones, M., Kabisch, M., Kar, S., Karlan, B. Y., Khan, S., Khaw, K., Kibriya, M. G., Knight, J. A., Ko, Y., Konstantopoulou, I., Kosma, V., Kristensen, V., Kwong, A., Laitman, Y., Lambrechts, D., Lazaro, C., Lee, E., Le Marchand, L., Lester, J., Lindblom, A., Lindor, N., Lindstrom, S., Liu, J., Long, J., Lubinski, J., Mai, P. L., Makalic, E., Malone, K. E., Mannermaa, A., Manoukian, S., Margolin, S., Marme, F., Martens, J. W., McGuffog, L., Meindl, A., Miller, A., Milne, R. L., Miron, P., Montagna, M., Mazoyer, S., Mulligan, A. M., Muranen, T. A., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nordestgaard, B. G., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O. I., Olson, J. E., Osorio, A., Park, S. K., Peeters, P. H., Peissel, B., Peterlongo, P., Peto, J., Phelan, C. M., Pilarski, R., Poppe, B., Pylkaes, K., Radice, P., Rahman, N., Rantala, J., Rappaport, C., Rennert, G., Richardson, A., Robson, M., Romieu, I., Rudolph, A., Rutgers, E. J., Sanchez, M., Santella, R. M., Sawyer, E. J., Schmidt, D. F., Schmidt, M. K., Schmutzler, R. K., Schumacher, F., Scott, R., Senter, L., Sharma, P., Simard, J., Singer, C. F., Sinilnikova, O. M., Soucy, P., Southey, M., Steinemann, D., Stenmark-Askmalm, M., Stoppa-Lyonnet, D., Swerdlow, A., Szabo, C. I., Tamimi, R., Tapper, W., Teixeira, M. R., Teo, S., Terry, M. B., Thomassen, M., Thompson, D., Tihomirova, L., Toland, A. E., Tollenaar, R. A., Tomlinson, I., Truong, T., Tsimiklis, H., Teule, A., Tumino, R., Tung, N., Turnbull, C., Ursin, G., van Deurzen, C. H., Van Rensburg, E. J., Varon-Mateeva, R., Wang, Z., Wang-Gohrke, S., Weiderpass, E., Weitzel, J. N., Whittemore, A., Wildiers, H., Winqvist, R., Yang, X. R., Yannoukakos, D., Yao, S., Zamora, M. P., Zheng, W., Hall, P., Kraft, P., Vachon, C., Slager, S., Chenevix-Trench, G., Pharoah, P. D., Monteiro, A. A., Garcia-Closas, M., Easton, D. F., Antoniou, A. C. 2016; 7

    Abstract

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ?11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

    View details for DOI 10.1038/ncomms11375

    View details for Web of Science ID 000374894400001

    View details for PubMedCentralID PMC4853421

  • Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation NATURE COMMUNICATIONS Gusev, A., Shi, H., Kichaev, G., Pomerantz, M., Li, F., Long, H. W., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Zheng, W., Pettaway, C. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., John, E. M., Murphy, A. B., Signorello, L. B., Carpten, J., Leske, M. C., Wu, S., Hennis, A. J., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Witte, J. S., Casey, G., Kaggwa, S., Cook, M. B., Stram, D. O., Blot, W. J., Eeles, R. A., Easton, D., Kote-Jarai, Z., Al Olama, A. A., Benlloch, S., Muir, K., Giles, G. G., Southey, M. C., FitzGerald, L. M., Gronberg, H., Wiklund, F., Aly, M., Henderson, B. E., Schleutker, J., Wahlfors, T., Tammela, T. L., Nordestgaard, B. G., Key, T. J., Travis, R. C., Neal, D. E., Donovan, J. L., Hamdy, F. C., Pharoah, P., Pashayan, N., Khaw, K., Stanford, J. L., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Maier, C., Vogel, W., Luedeke, M., Herkommer, K., Kibel, A. S., Cybulski, C., Wokolorczyk, D., Kluzniak, W., Cannon-Albright, L., Teerlink, C., Brenner, H., Dieffenbach, A. K., Arndt, V., Park, J. Y., Sellers, T. A., Lin, H., Slavov, C., Kaneva, R., Mitev, V., Batra, J., Spurdle, A., Clements, J. A., Teixeira, M. R., Pandha, H., Michael, A., Paulo, P., Maia, S., Kierzek, A., Conti, D. V., Albanes, D., Berg, C., Berndt, S. I., Campa, D., Crawford, E. D., Diver, W. R., Gapstur, S. M., Gaziano, J. M., Giovannucci, E., Hoover, R., Hunter, D. J., Johansson, M., Kraft, P., Le Marchand, L., Lindstrom, S., Navarro, C., Overvad, K., Riboli, E., Siddiq, A., Stevens, V. L., Trichopoulos, D., Vineis, P., Yeager, M., Trynka, G., Raychaudhuri, S., Schumacher, F. R., Price, A. L., Freedman, M. L., Haiman, C. A., Pasaniuc, B., Cook, M., Guy, M., Govindasami, K., Leongamornlert, D., Sawyer, E. J., Wilkinson, R., Saunders, E. J., Tymrakiewicz, M., Dadaev, T., Morgan, A., Fisher, C., Hazel, S., Livni, N., Lophatananon, A., Pedersen, J., Hopper, J. L., Adolfson, J., Stattin, P., Johansson, J., Cavalli-Bjoerkman, C., Karlsson, A., Broms, M., Auvinen, A., Kujala, P., Maeaettaenen, L., Murtola, T., Taari, K., Weischer, M., Nielsen, S. F., Klarskov, P., Roder, A., Iversen, P., Wallinder, H., Gustafsson, S., Cox, A., Brown, P., George, A., Marsden, G., Lane, A., Davis, M., Zheng, W., Signorello, L. B., Blot, W. J., Tillmans, L., Riska, S., Wang, L., Rinckleb, A., Lubiski, J., Stegmaier, C., Pow-Sang, J., Park, H., Radlein, S., Rincon, M., Haley, J., Zachariah, B., Kachakova, D., Popov, E., Mitkova, A., Vlahova, A., Dikov, T., Christova, S., Heathcote, P., Wood, G., Malone, G., Saunders, P., Eckert, A., Yeadon, T., Kerr, K., Collins, A., Turner, M., Srinivasan, S., Kedda, M., Alexander, K., Omara, T., Wu, H., Henrique, R., Pinto, P., Santos, J., Barros-Silva, J. 2016; 7

    Abstract

    Although genome-wide association studies have identified over 100 risk loci that explain ?33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

    View details for DOI 10.1038/ncomms10979

    View details for PubMedID 27052111

  • Validation of self-reported comorbidity status of breast cancer patients with medical records: the California Breast Cancer Survivorship Consortium (CBCSC). Cancer causes & control Vigen, C., Kwan, M. L., John, E. M., Gomez, S. L., Keegan, T. H., Lu, Y., Shariff-Marco, S., Monroe, K. R., Kurian, A. W., Cheng, I., Caan, B. J., Lee, V. S., Roh, J. M., Bernstein, L., Sposto, R., Wu, A. H. 2016; 27 (3): 391-401

    Abstract

    To compare information from self-report and electronic medical records for four common comorbidities (diabetes, hypertension, myocardial infarction, and other heart diseases).We pooled data from two multiethnic studies (one case-control and one survivor cohort) enrolling 1,936 women diagnosed with breast cancer, who were members of Kaiser Permanente Northern California.Concordance varied by comorbidity; kappa values ranged from 0.50 for other heart diseases to 0.87 for diabetes. Sensitivities for comorbidities from self-report versus medical record were similar for racial/ethnic minorities and non-Hispanic Whites, and did not vary by age, neighborhood socioeconomic status, or education. Women with a longer history of comorbidity or who took medications for the comorbidity were more likely to report the condition. Hazard ratios for all-cause mortality were not consistently affected by source of comorbidity information; the hazard ratio was lower for diabetes, but higher for the other comorbidities when medical record versus self-report was used. Model fit was better when the medical record versus self-reported data were used.Comorbidities are increasingly recognized to influence the survival of patients with breast or other cancers. Potential effects of misclassification of comorbidity status should be considered in the interpretation of research results.

    View details for DOI 10.1007/s10552-016-0715-8

    View details for PubMedID 26797455

  • Cigarette Smoking and Breast Cancer Risk in Hispanic and Non-Hispanic White Women: The Breast Cancer Health Disparities Study. Journal of women's health (2002) Connor, A. E., Baumgartner, K. B., Baumgartner, R. N., Pinkston, C. M., Boone, S. D., John, E. M., Torres-Mejía, G., Hines, L. M., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2016; 25 (3): 299-310

    Abstract

    Few epidemiological studies have included Hispanics with the evaluation of the effects of cigarette smoking and breast cancer. We examined the relationship between cigarette smoking, ethnicity, and breast cancer risk using data from the Breast Cancer Health Disparities Study (BCHDS).The BCHDS is a consortium of three population-based case-control studies, including U.S. non-Hispanic whites (NHWs) (1,525 cases; 1,593 controls), U.S. Hispanics/Native Americans (1,265 cases; 1,495 controls), and Mexican women (990 cases; 1,049 controls). Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).Breast cancer risk was elevated among Mexican former smokers (OR 1.43, 95% CI 1.04-1.96) and among those who smoked ?31 years (OR 1.95, 95% CI 1.13-3.35), compared to never smokers. In addition, Mexican former smokers with a history of alcohol consumption had increased breast cancer risk (OR 2.30, 95% CI 1.01-5.21). Among NHW premenopausal women, breast cancer risk was increased for smoking ?20 cigarettes per day (OR 1.61, 95% CI 1.07-2.41).Our findings suggest the possibility of ethnic differences with the associations between cigarette smoking and breast cancer risk.

    View details for DOI 10.1089/jwh.2015.5502

    View details for PubMedID 26682495

    View details for PubMedCentralID PMC4790199

  • Cigarette Smoking and Breast Cancer Risk in Hispanic and Non-Hispanic White Women: The Breast Cancer Health Disparities Study JOURNAL OF WOMENS HEALTH Connor, A. E., Baumgartner, K. B., Baumgartner, R. N., Pinkston, C. M., Boone, S. D., John, E. M., Torres-Mejia, G., Hines, L. M., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2016; 25 (3): 299-310

    Abstract

    Few epidemiological studies have included Hispanics with the evaluation of the effects of cigarette smoking and breast cancer. We examined the relationship between cigarette smoking, ethnicity, and breast cancer risk using data from the Breast Cancer Health Disparities Study (BCHDS).The BCHDS is a consortium of three population-based case-control studies, including U.S. non-Hispanic whites (NHWs) (1,525 cases; 1,593 controls), U.S. Hispanics/Native Americans (1,265 cases; 1,495 controls), and Mexican women (990 cases; 1,049 controls). Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).Breast cancer risk was elevated among Mexican former smokers (OR 1.43, 95% CI 1.04-1.96) and among those who smoked ?31 years (OR 1.95, 95% CI 1.13-3.35), compared to never smokers. In addition, Mexican former smokers with a history of alcohol consumption had increased breast cancer risk (OR 2.30, 95% CI 1.01-5.21). Among NHW premenopausal women, breast cancer risk was increased for smoking ?20 cigarettes per day (OR 1.61, 95% CI 1.07-2.41).Our findings suggest the possibility of ethnic differences with the associations between cigarette smoking and breast cancer risk.

    View details for DOI 10.1089/jwh.2015.5502

    View details for Web of Science ID 000372173200015

    View details for PubMedCentralID PMC4790199

  • Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2 BREAST CANCER RESEARCH Silvestri, V., Barrowdale, D., Mulligan, A., Neuhausen, S. L., Fox, S., Karlan, B. Y., Mitchell, G., James, P., Thull, D. L., Zorn, K. K., Carter, N. J., Nathanson, K. L., Dornchek, S. M., Rebbeck, T. R., Ramus, S. J., Nussbaum, R. L., Olopade, O. I., Rantala, J., Yoon, S., Caligo, M. A., Spugnesi, L., Bojesen, A., Pedersen, I., Thomassen, M., Jensen, U., Toland, A., Senter, L., Andrulis, I. L., Glendon, G., Hulick, P. J., Irnyanitov, E. N., Greene, M. H., Mai, P. L., Singer, C. F., Rappaport-Fuerhauser, C., Kramer, G., Vijai, J., Offit, K., Robson, M., Lincoln, A., Jacobs, L., Machackova, E., Foretova, L., Navratilova, M., Vasickova, P., Couch, F. J., Hallberg, E., Ruddy, K. J., Sharma, P., Kim, S., Teixeira, M. R., Pinte, P., Montagna, M., Matricardi, L., Arason, A., Johannsson, O., Barkardottir, R. B., Jakubowska, A., Lubinski, J., Izquierdo, A., Angel Pujana, M., Balmana, J., Diez, O., Ivady, G., Papp, J., Olah, E., Kwong, A., Nevanlinna, H., Aittomaki, K., Perez Segura, P., Caldes, T., Van Maerken, T., Poppe, B., Claes, K. M., Isaacs, C., Elan, C., Lasset, C., Stoppa-Lyonnet, D., Barjhoux, L., Belotti, M., Meindl, A., Gehrig, A., Sutter, C., Enger, C., Niederacher, D., Steinemann, D., Hahnen, E., Kast, K., Arnold, N., Varon-Mateeva, R., Wand, D., Godwin, A. K., Evans, D., Frost, D., Perkins, J., Adlard, J., Izatt, L., Platte, R., Eeles, R., Ellis, S., Hamann, U., Garber, J., Fostira, F., Fountzilas, G., Pasini, B., Giannini, G., Rizzolo, P., Russo, A., Cortesi, L., Papi, L., Varesco, L., Palli, D., Zanna, I., Savarese, A., Radice, P., Manoukian, S., Peissel, B., Barile, M., Bonanni, B., Viel, A., Pensotti, V., Tommasi, S., Peterlongo, P., Weitzel, J. N., Osorio, A., Benitez, J., McGuffog, L., Healey, S., Gerdes, A., Ejlertsen, B., Hansen, T. O., Steele, L., Ding, Y., Tung, N., Janavicius, R., Goldgar, D. E., Buys, S. S., Daly, M. B., Bane, A., Terry, M., John, E. M., Southey, M., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Ottini, L., kConFab Investigators, Hereditary Breast Ovarian Canc Res, EMBRACE 2016; 18: 15

    Abstract

    BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs).We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database.Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P?=?0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend?=?2?×?10(-5)) and higher grade (P for trend?=?0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend?=?4?×?10(-12)).On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

    View details for PubMedID 26857456

    View details for PubMedCentralID PMC4746828

  • BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Meeks, H. D., Song, H., Michailidou, K., Bolla, M. K., Dennis, J., Wang, Q., Barrowdale, D., Frost, D., McGuffog, L., Ellis, S., Feng, B., Buys, S. S., Hopper, J. L., Southey, M. C., Tesoriero, A., James, P. A., Bruinsma, F., Campbell, I. G., Broeks, A., Schmidt, M. K., Hogervorst, F. B., Beckman, M. W., Fasching, P. A., Fletcher, O., Johnson, N., Sawyer, E. J., Riboli, E., Banerjee, S., Menon, U., Tomlinson, I., Burwinkel, B., Hamann, U., Marme, F., Rudolph, A., Janavicius, R., Tihomirova, L., Tung, N., Garber, J., Cramer, D., Terry, K. L., Poole, E. M., Tworoger, S. S., Dorfling, C. M., Van Rensburg, E. J., Godwin, A. K., Guenel, P., Truong, T., Stoppa-Lyonnet, D., Damiola, F., Mazoyer, S., Sinilnikova, O. M., Isaacs, C., Maugard, C., Bojesen, S. E., Flyger, H., Gerdes, A., Hansen, T. v., Jensen, A., Kjaer, S. K., Hogdall, C., Hogdall, E., Pedersen, I. S., Thomassen, M., Benitez, J., Gonzalez-Neira, A., Osorio, A., de la Hoya, M., Perez Segura, P., Diez, O., Lazaro, C., Brunet, J., Anton-Culver, H., Eunjung, L., John, E. M., Neuhausen, S. L., Ding, Y. C., Castillo, D., Weitzel, J. N., Ganz, P. A., Nussbaum, R. L., Chan, S. B., Karlan, B. Y., Lester, J., Wu, A., Gayther, S., Ramus, S. J., Sieh, W., Whittermore, A. S., Monteiro, A. N., Phelan, C. M., Terry, M. B., Piedmonte, M., Offit, K., Robson, M., Levine, D., Moysich, K. B., Cannioto, R., Olson, S. H., Daly, M. B., Nathanson, K. L., Domchek, S. M., Lu, K. H., Liang, D., Hildebrant, M. A., Ness, R., Modugno, F., Pearce, L., Goodman, M. T., Thompson, P. J., Brenner, H., Butterbach, K., Meindl, A., Hahnen, E., Wappenschmidt, B., Brauch, H., Bruening, T., Blomqvist, C., Khan, S., Nevanlinna, H., Pelttari, L. M., Aittomaeki, K., Butzow, R., Bogdanova, N. V., Doerk, T., Lindblom, A., Margolin, S., Rantala, J., Kosma, V., Mannermaa, A., Lambrechts, D., Neven, P., Claes, K. B., Van Maerken, T., Chang-Claude, J., Flesch-Janys, D., Heitz, F., Varon-Mateeva, R., Peterlongo, P., Radice, P., Viel, A., Barile, M., Peissel, B., Manoukian, S., Montagna, M., Oliani, C., Peixoto, A., Teixeira, M. R., Collavoli, A., Hallberg, E., Olson, J. E., Goode, E. L., Hart, S. N., Shimelis, H., Cunningham, J. M., Giles, G. G., Milne, R. L., Healey, S., Tucker, K., Haiman, C. A., Henderson, B. E., Goldberg, M. S., Tischkowitz, M., Simard, J., Soucy, P., Eccles, D. M., Le, N., Borresen-Dale, A., Kristensen, V., Salvesen, H. B., Bjorge, L., Bandera, E. V., Risch, H., Zheng, W., Beeghly-Fadiel, A., Cai, H., Pylkas, K., Tollenaar, R. A., van der Ouweland, A. M., Andrulis, I. L., Knight, J. A., Narod, S., Devilee, P., Winqvist, R., Figueroa, J., Greene, M. H., Mai, P. L., Loud, J. T., Garcia-Closas, M., Schoemaker, M. J., Czene, K., Darabi, H., McNeish, I., Siddiquil, N., Glasspool, R., Kwong, A., Park, S. K., Teo, S. H., Yoon, S., Matsuo, K., Hosono, S., Woo, Y. L., Gao, Y., Foretova, L., Singer, C. F., Rappaport-Feurhauser, C., friedman, e., Laitman, Y., Rennert, G., Imyanitov, E. N., Hulick, P. J., Olopade, O. I., Senter, L., Olah, E., Doherty, J. A., Schildkraut, J., Koppert, L. B., Kiemeney, L. A., Massuger, L. F., Cook, L. S., Pejovic, T., Li, J., Borg, A., Ofverholm, A., Rossing, M. A., Wentzensen, N., Henriksson, K., Cox, A., Cross, S. S., Pasini, B. J., Shah, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Gronwald, J., Agnarsson, B. A., Kupryjanczyk, J., Moes-Sosnowska, J., Fostira, F., Konstantopoulou, I., Slager, S., Jones, M., Antoniou, A. C., Berchuck, A., Swerdlow, A., Chenevix-Trench, G., Dunning, A. M., Pharoah, P. D., Hall, P., Easton, D. F., Couch, F. J., Spurdle, A. B., Goldgar, D. E. 2016; 108 (2)

    Abstract

    The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided.The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed.Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

    View details for DOI 10.1093/jnci/djv315

    View details for Web of Science ID 000371153900007

    View details for PubMedID 26586665

    View details for PubMedCentralID PMC4907358

  • Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nature communications Lawrenson, K., Kar, S., McCue, K., Kuchenbaeker, K., Michailidou, K., Tyrer, J., Beesley, J., Ramus, S. J., Li, Q., Delgado, M. K., Lee, J. M., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Arun, B. K., Arver, B., Bandera, E. V., Barile, M., Barkardottir, R. B., Barrowdale, D., Beckmann, M. W., Benitez, J., Berchuck, A., Bisogna, M., Bjorge, L., Blomqvist, C., Blot, W., Bogdanova, N., Bojesen, A., Bojesen, S. E., Bolla, M. K., Bonanni, B., Břrresen-Dale, A., Brauch, H., Brennan, P., Brenner, H., Bruinsma, F., Brunet, J., Buhari, S. A., Burwinkel, B., Butzow, R., Buys, S. S., Cai, Q., Caldes, T., Campbell, I., Canniotto, R., Chang-Claude, J., Chiquette, J., Choi, J., Claes, K. B., Cook, L. S., Cox, A., Cramer, D. W., Cross, S. S., Cybulski, C., Czene, K., Daly, M. B., Damiola, F., Dansonka-Mieszkowska, A., Darabi, H., Dennis, J., Devilee, P., Diez, O., Doherty, J. A., Domchek, S. M., Dorfling, C. M., Dörk, T., Dumont, M., Ehrencrona, H., Ejlertsen, B., Ellis, S., Engel, C., Lee, E., Evans, D. G., Fasching, P. A., Feliubadalo, L., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Foretova, L., Fostira, F., Foulkes, W. D., Fridley, B. L., friedman, e., Frost, D., Gambino, G., Ganz, P. A., Garber, J., García-Closas, M., Gentry-Maharaj, A., Ghoussaini, M., Giles, G. G., Glasspool, R., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., González-Neira, A., Goode, E. L., Goodman, M. T., Greene, M. H., Gronwald, J., Guénel, P., Haiman, C. A., Hall, P., Hallberg, E., Hamann, U., Hansen, T. v., Harrington, P. A., Hartman, M., Hassan, N., Healey, S., Heitz, F., Herzog, J., Hřgdall, E., Hřgdall, C. K., Hogervorst, F. B., Hollestelle, A., Hopper, J. L., Hulick, P. J., Huzarski, T., Imyanitov, E. N., Isaacs, C., Ito, H., Jakubowska, A., Janavicius, R., Jensen, A., John, E. M., Johnson, N., Kabisch, M., Kang, D., Kapuscinski, M., Karlan, B. Y., Khan, S., Kiemeney, L. A., Kjaer, S. K., Knight, J. A., Konstantopoulou, I., Kosma, V., Kristensen, V., Kupryjanczyk, J., Kwong, A., de la Hoya, M., Laitman, Y., Lambrechts, D., Le, N., De Leeneer, K., Lester, J., Levine, D. A., Li, J., Lindblom, A., Long, J., Lophatananon, A., Loud, J. T., Lu, K., Lubinski, J., Mannermaa, A., Manoukian, S., Le Marchand, L., Margolin, S., Marme, F., Massuger, L. F., Matsuo, K., Mazoyer, S., McGuffog, L., McLean, C., McNeish, I., Meindl, A., Menon, U., Mensenkamp, A. R., Milne, R. L., Montagna, M., Moysich, K. B., Muir, K., Mulligan, A. M., Nathanson, K. L., Ness, R. B., Neuhausen, S. L., Nevanlinna, H., Nord, S., Nussbaum, R. L., Odunsi, K., Offit, K., Olah, E., Olopade, O. I., Olson, J. E., Olswold, C., O'Malley, D., Orlow, I., Orr, N., Osorio, A., Park, S. K., Pearce, C. L., Pejovic, T., Peterlongo, P., Pfeiler, G., Phelan, C. M., Poole, E. M., Pylkäs, K., Radice, P., Rantala, J., Rashid, M. U., Rennert, G., Rhenius, V., Rhiem, K., Risch, H. A., Rodriguez, G., Rossing, M. A., Rudolph, A., Salvesen, H. B., Sangrajrang, S., Sawyer, E. J., Schildkraut, J. M., Schmidt, M. K., Schmutzler, R. K., Sellers, T. A., Seynaeve, C., Shah, M., Shen, C., Shu, X., Sieh, W., Singer, C. F., Sinilnikova, O. M., Slager, S., Song, H., Soucy, P., Southey, M. C., Stenmark-Askmalm, M., Stoppa-Lyonnet, D., Sutter, C., Swerdlow, A., Tchatchou, S., Teixeira, M. R., Teo, S. H., Terry, K. L., Terry, M. B., Thomassen, M., Tibiletti, M. G., Tihomirova, L., Tognazzo, S., Toland, A. E., Tomlinson, I., Torres, D., Truong, T., Tseng, C., Tung, N., Tworoger, S. S., Vachon, C., van den Ouweland, A. M., van Doorn, H. C., Van Rensburg, E. J., van't Veer, L. J., Vanderstichele, A., Vergote, I., Vijai, J., Wang, Q., Wang-Gohrke, S., Weitzel, J. N., Wentzensen, N., Whittemore, A. S., Wildiers, H., Winqvist, R., Wu, A. H., Yannoukakos, D., Yoon, S., Yu, J., Zheng, W., Zheng, Y., Khanna, K. K., Simard, J., Monteiro, A. N., French, J. D., Couch, F. J., Freedman, M. L., Easton, D. F., Dunning, A. M., Pharoah, P. D., Edwards, S. L., Chenevix-Trench, G., Antoniou, A. C., Gayther, S. A. 2016; 7: 12675-?

    Abstract

    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

    View details for DOI 10.1038/ncomms12675

    View details for PubMedID 27601076

  • Systemic therapy for breast cancer and risk of subsequent contralateral breast cancer in the WECARE Study. Breast cancer research : BCR Langballe, R., Mellemkjćr, L., Malone, K. E., Lynch, C. F., John, E. M., Knight, J. A., Bernstein, L., Brooks, J., Andersson, M., Reiner, A. S., Liang, X., Woods, M., Concannon, P. J., Bernstein, J. L. 2016; 18 (1): 65

    Abstract

    Treatment with tamoxifen or chemotherapy reduces the risk of contralateral breast cancer (CBC). However, it is uncertain how long the protection lasts and whether the protective effect is modified by patient, tumor, or treatment characteristics.The population-based WECARE Study included 1521 cases with CBC and 2212 age- and year of first diagnosis-matched controls with unilateral breast cancer recruited during two phases in the USA, Canada, and Denmark. Women were diagnosed with a first breast cancer before age 55 years during 1985-2008. Abstraction of medical records provided detailed treatment information, while information on risk factors was obtained during telephone interviews. Risk ratios (RRs) and 95 % confidence intervals (CIs) for CBC were obtained from multivariable conditional logistic regression models.Compared with never users of tamoxifen, the RR of CBC was lower for current users of tamoxifen (RR?=?0.73; 95 % CI?=?0.55-0.97) and for past users within 3 years of last use (RR?=?0.73; 95 % CI?=?0.53-1.00). There was no evidence of an increased risk of estrogen receptor-negative CBC associated with ever use of tamoxifen or use for 4.5 or more years. Use of chemotherapy (ever versus never use) was associated with a significantly reduced RR of developing CBC 1-4 years (RR?=?0.59; 95 % CI?=?0.45-0.77) and 5-9 years (RR?=?0.73; 95 % CI?=?0.56-0.95) after first breast cancer diagnosis. RRs of CBC associated with tamoxifen or with chemotherapy use were independent of age, family history of breast cancer, body mass index and tumor characteristics of the first breast cancer with the exception that the RR of CBC was lower for lobular histology compared with other histologies.Our findings are consistent with previous studies showing that treatment with tamoxifen or chemotherapy is associated with a lower risk of CBC although the risk reduction appears to last for a limited time period after treatment is completed.

    View details for PubMedID 27400983

  • Body mass index, weight change, and risk of second primary breast cancer in the WECARE study: influence of estrogen receptor status of the first breast cancer. Cancer medicine Brooks, J. D., John, E. M., Mellemkjaer, L., Lynch, C. F., Knight, J. A., Malone, K. E., Reiner, A. S., Bernstein, L., Liang, X., Shore, R. E., Stovall, M., Bernstein, J. L. 2016; 5 (11): 3282?91

    Abstract

    Studies examining the relationship between body mass index (BMI) and risk of contralateral breast cancer (CBC) have reported mixed findings. We previously showed that obese postmenopausal women with estrogen receptor (ER)-negative breast cancer have a fivefold higher risk of CBC compared with normal weight women. In the current analysis, we reexamined this relationship in the expanded Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study, focusing on the impact of menopausal status and ER status of the first breast cancer. The WECARE Study is a population-based case-control study of young women with CBC (cases, N = 1386) and with unilateral breast cancer (controls, N = 2045). Rate ratios (RR) and 95% confidence intervals (CI) were calculated to assess the relationship between BMI and risk of CBC stratified by menopausal and ER status. Positive associations with obesity and weight gain were limited to women who became postmenopausal following their first primary breast cancer. Among those with an ER-negative first breast cancer, obesity (vs. normal weight) at first diagnosis was associated with an increased risk of CBC (RR = 1.9, 95% CI: 1.02, 3.4). Also, weight gain of ?10 kg after first diagnosis was associated with an almost twofold increased risk of CBC (RR = 1.9, 95% CI: 0.99, 3.8). These results suggest that women with an ER-negative first primary cancer who are obese at first primary diagnosis or who experience a large weight gain afterward may benefit from heightened surveillance. Future studies are needed to address the impact of weight loss interventions on risk of CBC.

    View details for PubMedID 27700016

  • Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer. Nature communications Couch, F. J., Kuchenbaecker, K. B., Michailidou, K., Mendoza-Fandino, G. A., Nord, S., Lilyquist, J., Olswold, C., Hallberg, E., Agata, S., Ahsan, H., Aittomäki, K., Ambrosone, C., Andrulis, I. L., Anton-Culver, H., Arndt, V., Arun, B. K., Arver, B., Barile, M., Barkardottir, R. B., Barrowdale, D., Beckmann, L., Beckmann, M. W., Benitez, J., Blank, S. V., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Bonanni, B., Brauch, H., Brenner, H., Burwinkel, B., Buys, S. S., Caldes, T., Caligo, M. A., Canzian, F., Carpenter, J., Chang-Claude, J., Chanock, S. J., Chung, W. K., Claes, K. B., Cox, A., Cross, S. S., Cunningham, J. M., Czene, K., Daly, M. B., Damiola, F., Darabi, H., de la Hoya, M., Devilee, P., Diez, O., Ding, Y. C., Dolcetti, R., Domchek, S. M., Dorfling, C. M., Dos-Santos-Silva, I., Dumont, M., Dunning, A. M., Eccles, D. M., Ehrencrona, H., Ekici, A. B., Eliassen, H., Ellis, S., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Försti, A., Fostira, F., Foulkes, W. D., Friebel, T., friedman, e., Frost, D., Gabrielson, M., Gammon, M. D., Ganz, P. A., Gapstur, S. M., Garber, J., Gaudet, M. M., Gayther, S. A., Gerdes, A., Ghoussaini, M., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., González-Neira, A., Greene, M. H., Gronwald, J., Guénel, P., Gunter, M., Haeberle, L., Haiman, C. A., Hamann, U., Hansen, T. v., Hart, S., Healey, S., Heikkinen, T., Henderson, B. E., Herzog, J., Hogervorst, F. B., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Humphreys, K., Hunter, D. J., Huzarski, T., Imyanitov, E. N., Isaacs, C., Jakubowska, A., James, P., Janavicius, R., Jensen, U. B., John, E. M., Jones, M., Kabisch, M., Kar, S., Karlan, B. Y., Khan, S., Khaw, K., Kibriya, M. G., Knight, J. A., Ko, Y., Konstantopoulou, I., Kosma, V., Kristensen, V., Kwong, A., Laitman, Y., Lambrechts, D., Lazaro, C., Lee, E., Le Marchand, L., Lester, J., Lindblom, A., Lindor, N., Lindstrom, S., Liu, J., Long, J., Lubinski, J., Mai, P. L., Makalic, E., Malone, K. E., Mannermaa, A., Manoukian, S., Margolin, S., Marme, F., Martens, J. W., McGuffog, L., Meindl, A., Miller, A., Milne, R. L., Miron, P., Montagna, M., Mazoyer, S., Mulligan, A. M., Muranen, T. A., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nordestgaard, B. G., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O. I., Olson, J. E., Osorio, A., Park, S. K., Peeters, P. H., Peissel, B., Peterlongo, P., Peto, J., Phelan, C. M., Pilarski, R., Poppe, B., Pylkäs, K., Radice, P., Rahman, N., Rantala, J., Rappaport, C., Rennert, G., Richardson, A., Robson, M., Romieu, I., Rudolph, A., Rutgers, E. J., Sanchez, M., Santella, R. M., Sawyer, E. J., Schmidt, D. F., Schmidt, M. K., Schmutzler, R. K., Schumacher, F., Scott, R., Senter, L., Sharma, P., Simard, J., Singer, C. F., Sinilnikova, O. M., Soucy, P., Southey, M., Steinemann, D., Stenmark-Askmalm, M., Stoppa-Lyonnet, D., Swerdlow, A., Szabo, C. I., Tamimi, R., Tapper, W., Teixeira, M. R., Teo, S., Terry, M. B., Thomassen, M., Thompson, D., Tihomirova, L., Toland, A. E., Tollenaar, R. A., Tomlinson, I., Truong, T., Tsimiklis, H., Teulé, A., Tumino, R., Tung, N., Turnbull, C., Ursin, G., van Deurzen, C. H., Van Rensburg, E. J., Varon-Mateeva, R., Wang, Z., Wang-Gohrke, S., Weiderpass, E., Weitzel, J. N., Whittemore, A., Wildiers, H., Winqvist, R., Yang, X. R., Yannoukakos, D., Yao, S., Zamora, M. P., Zheng, W., Hall, P., Kraft, P., Vachon, C., Slager, S., Chenevix-Trench, G., Pharoah, P. D., Monteiro, A. A., García-Closas, M., Easton, D. F., Antoniou, A. C. 2016; 7: 11375-?

    Abstract

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ?11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

    View details for DOI 10.1038/ncomms11375

    View details for PubMedID 27117709

  • Energy homeostasis genes and survival after breast cancer diagnosis: the Breast Cancer Health Disparities Study CANCER CAUSES & CONTROL Pellatt, A. J., Lundgreen, A., Wolff, R. K., Hines, L., John, E. M., Slattery, M. L. 2016; 27 (1): 47-57

    Abstract

    The leptin-signaling pathway and other genes involved in energy homeostasis (EH) have been examined in relation to breast cancer risk as well as to obesity. We test the hypothesis that genetic variation in EH genes influences survival after diagnosis with breast cancer and that body mass index (BMI) will modify that risk.We evaluated associations between 10 EH genes and survival among 1,186 non-Hispanic white and 1,155 Hispanic/Native American women diagnosed with breast cancer. Percent Native American (NA) ancestry was determined from 104 ancestry-informative markers. Adaptive rank truncation product (ARTP) was used to determine gene and pathway significance.The overall EH pathway was marginally significant for all-cause mortality among women with low NA ancestry (P(ARTP) = 0.057). Within the pathway, ghrelin(GHRL) and leptin receptor (LEPR) were significantly associated with all-cause mortality (P(ARTP) = 0.035 and 0.007, respectively). The EH pathway was significantly associated with breast cancer-specific mortality among women with low NA ancestry (P(ARTP) = 0.038). Three genes cholecystokinin (CCK), GHRL, and LEPR were significantly associated with breast cancer-specific mortality among women with low NA ancestry (P(ARTP) = 0.046,0.015, and 0.046, respectively), while neuropeptide Y (NPY) was significantly associated with breast cancer-specific mortality among women with higher NA ancestry(P(ARTP) = 0.038). BMI did not modify these associations.Our data support our hypothesis that certain EH genes influence survival after diagnosis with breast cancer; associations appear to be most important among women with low NA ancestry.

    View details for DOI 10.1007/s10552-015-0681-6

    View details for Web of Science ID 000368151600005

    View details for PubMedCentralID PMC4833710

  • Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. Breast cancer research Zeng, C., Guo, X., Long, J., Kuchenbaecker, K. B., Droit, A., Michailidou, K., Ghoussaini, M., Kar, S., Freeman, A., Hopper, J. L., Milne, R. L., Bolla, M. K., Wang, Q., Dennis, J., Agata, S., Ahmed, S., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arason, A., Arndt, V., Arun, B. K., Arver, B., Bacot, F., Barrowdale, D., Baynes, C., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Blomqvist, C., Blot, W. J., Bogdanova, N. V., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brand, J. S., Brauch, H., Brennan, P., Brenner, H., Broeks, A., Brüning, T., Burwinkel, B., Buys, S. S., Cai, Q., Caldes, T., Campbell, I., Carpenter, J., Chang-Claude, J., Choi, J., Claes, K. B., Clarke, C., Cox, A., Cross, S. S., Czene, K., Daly, M. B., de la Hoya, M., De Leeneer, K., Devilee, P., Diez, O., Domchek, S. M., Doody, M., Dorfling, C. M., Dörk, T., Dos-Santos-Silva, I., Dumont, M., Dwek, M., Dworniczak, B., Egan, K., Eilber, U., Einbeigi, Z., Ejlertsen, B., Ellis, S., Frost, D., Lalloo, F., Fasching, P. A., Figueroa, J., Flyger, H., Friedlander, M., friedman, e., Gambino, G., Gao, Y., Garber, J., García-Closas, M., Gehrig, A., Damiola, F., Lesueur, F., Mazoyer, S., Stoppa-Lyonnet, D., Giles, G. G., Godwin, A. K., Goldgar, D. E., González-Neira, A., Greene, M. H., Guénel, P., Haeberle, L., Haiman, C. A., Hallberg, E., Hamann, U., Hansen, T. v., Hart, S., Hartikainen, J. M., Hartman, M., Hassan, N., Healey, S., Hogervorst, F. B., Verhoef, S., Hendricks, C. B., Hillemanns, P., Hollestelle, A., Hulick, P. J., Hunter, D. J., Imyanitov, E. N., Isaacs, C., Ito, H., Jakubowska, A., Janavicius, R., Jaworska-Bieniek, K., Jensen, U. B., John, E. M., Joly Beauparlant, C., Jones, M., Kabisch, M., Kang, D., Karlan, B. Y., Kauppila, S., Kerin, M. J., Khan, S., Khusnutdinova, E., Knight, J. A., Konstantopoulou, I., Kraft, P., Kwong, A., Laitman, Y., Lambrechts, D., Lazaro, C., Le Marchand, L., Lee, C. N., Lee, M. H., Lester, J., Li, J., Liljegren, A., Lindblom, A., Lophatananon, A., Lubinski, J., Mai, P. L., Mannermaa, A., Manoukian, S., Margolin, S., Marme, F., Matsuo, K., McGuffog, L., Meindl, A., Menegaux, F., Montagna, M., Muir, K., Mulligan, A. M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Newcomb, P. A., Nord, S., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O. I., Olswold, C., Osorio, A., Papi, L., Park-Simon, T., Paulsson-Karlsson, Y., Peeters, S., Peissel, B., Peterlongo, P., Peto, J., Pfeiler, G., Phelan, C. M., Presneau, N., Radice, P., Rahman, N., Ramus, S. J., Rashid, M. U., Rennert, G., Rhiem, K., Rudolph, A., Salani, R., Sangrajrang, S., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Schoemaker, M. J., Schürmann, P., Seynaeve, C., Shen, C., Shrubsole, M. J., Shu, X., Sigurdson, A., Singer, C. F., Slager, S., Soucy, P., Southey, M., Steinemann, D., Swerdlow, A., Szabo, C. I., Tchatchou, S., Teixeira, M. R., Teo, S. H., Terry, M. B., Tessier, D. C., Teulé, A., Thomassen, M., Tihomirova, L., Tischkowitz, M., Toland, A. E., Tung, N., Turnbull, C., van den Ouweland, A. M., Van Rensburg, E. J., Ven den Berg, D., Vijai, J., Wang-Gohrke, S., Weitzel, J. N., Whittemore, A. S., Winqvist, R., Wong, T. Y., Wu, A. H., Yannoukakos, D., Yu, J., Pharoah, P. D., Hall, P., Chenevix-Trench, G., Dunning, A. M., Simard, J., Couch, F. J., Antoniou, A. C., Easton, D. F., Zheng, W. 2016; 18 (1): 64-?

    Abstract

    Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR)?=?1.09, 95 % confidence interval (CI)?=?1.06-1.12; P?=?3?×?10(-9)), rs805510 (OR?=?1.08, 95 % CI?=?1.04-1.12, P?=?2?×?10(-5)), and rs1871152 (OR?=?1.04, 95 % CI?=?1.02-1.06; P?=?2?×?10(-4)) identified in the general populations, and rs113824616 (P?=?7?×?10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P?

    View details for DOI 10.1186/s13058-016-0718-0

    View details for PubMedID 27459855

  • Reproductive factors, tumor estrogen receptor status and contralateral breast cancer risk: results from the WECARE study SPRINGERPLUS Sisti, J. S., Bernstein, J. L., Lynch, C. F., Reiner, A. S., Mellemkjaer, L., Brooks, J. D., Knight, J. A., Bernstein, L., Malone, K. E., Woods, M., Liang, X., John, E. M., WECARE Study Collaborative Grp 2015; 4
  • Intersection of Race/Ethnicity and Socioeconomic Status in Mortality After Breast Cancer JOURNAL OF COMMUNITY HEALTH Shariff-Marco, S., Yang, J., John, E. M., Kurian, A. W., Cheng, I., Leung, R., Koo, J., Monroe, K. R., Henderson, B. E., Bernstein, L., Lu, Y., Kwan, M. L., Sposto, R., Vigen, C. L., Wu, A. H., Keegan, T. H., Gomez, S. L. 2015; 40 (6): 1287-1299

    Abstract

    We investigated social disparities in breast cancer (BC) mortality, leveraging data from the California Breast Cancer Survivorship Consortium. The associations of race/ethnicity, education, and neighborhood SES (nSES) with all-cause and BC-specific mortality were assessed among 9372 women with BC (diagnosed 1993-2007 in California with follow-up through 2010) from four racial/ethnic groups [African American, Asian American, Latina, and non-Latina (NL) White] using Cox proportional hazards models. Compared to NL White women with high-education/high-nSES, higher all-cause mortality was observed among NL White women with high-education/low-nSES [hazard ratio (HR) (95 % confidence interval) 1.24 (1.08-1.43)], and African American women with low-nSES, regardless of education [high education HR 1.24 (1.03-1.49); low-education HR 1.19 (0.99-1.44)]. Latina women with low-education/high-nSES had lower all-cause mortality [HR 0.70 (0.54-0.90)] and non-significant lower mortality was observed for Asian American women, regardless of their education and nSES. Similar patterns were seen for BC-specific mortality. Individual- and neighborhood-level measures of SES interact with race/ethnicity to impact mortality after BC diagnosis. Considering the joint impacts of these social factors may offer insights to understanding inequalities by multiple social determinants of health.

    View details for DOI 10.1007/s10900-015-0052-y

    View details for PubMedID 26072260

  • Diet quality of cancer survivors and noncancer individuals: Results from a national survey CANCER Zhang, F., Liu, S., John, E. M., Must, A., Demark-Wahnefried, W. 2015; 121 (23): 4212?21

    Abstract

    Patterns of poor nutritional intake may exacerbate the elevated morbidity experienced by cancer survivors. It remains unclear whether cancer survivors adhere to existing dietary guidelines and whether survivors' diets differ from those of individuals without cancer over the long term.The authors evaluated dietary intake and quality in 1533 adult cancer survivors who participated in the National Health and Nutrition Examination Survey from 1999 to 2010 compared with dietary intake and quality in 3075 individuals who had no history of cancer and were matched to the cancer survivors by age, sex, and race/ethnicity. Dietary intake was assessed using 24-hour dietary recalls. The 2010 Healthy Eating Index (HEI-2010) was used to evaluate diet quality.The mean?±?standard deviation HEI-2010 total score was 47.2?±?0.5 in the cancer survivors and 48.3?±?0.4 in the noncancer group (P?=?.03). Compared with the noncancer group, cancer survivors had a significantly lower score for empty calories (13.6 vs 14.4; P?=?.001), which corresponded to worse adherence to dietary intake of calories from solid fats, alcohol, and added sugars. Cancer survivors also had significantly lower dietary intake of fiber than the noncancer group (15.0 vs 15.9 g per day; P?=?.02). In relation to recommended intake, survivors' mean dietary intake of vitamin D, vitamin E, potassium, fiber, and calcium was 31%, 47%, 55%, 60%, and 73%, respectively; whereas their mean dietary intake of saturated fat and sodium was 112% and 133%, respectively, of the recommended intake.Cancer survivors had poor adherence to the US Department of Agriculture 2010 Dietary Guidelines for Americans, and their intake patterns were worse than those in the general population for empty calories and fiber.

    View details for PubMedID 26624564

    View details for PubMedCentralID PMC4667562

  • Associations between ALOX, COX, and CRP polymorphisms and breast cancer among Hispanic and non-Hispanic white women: The breast cancer health disparities study MOLECULAR CARCINOGENESIS Connor, A. E., Baumgartner, R. N., Baumgartner, K. B., Pinkston, C. M., Boone, S. D., John, E. M., Torres-Mejia, G., Hines, L. M., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2015; 54 (12): 1541-1553

    Abstract

    Chronic inflammation is suggested to be associated with specific cancer sites, including breast cancer. Recent research has focused on the roles of genes involved in the leukotriene/lipoxygenase and prostaglandin/cyclooxygenase pathways in breast cancer etiology. We hypothesized that genes in ALOX/COX pathways and CRP polymorphisms would be associated with breast cancer risk and mortality in our sample of Hispanic/Native American (NA) (1430 cases, 1599 controls) and non-Hispanic white (NHW) (2093 cases, 2610 controls) women. A total of 104 Ancestral Informative Markers was used to distinguish European and NA ancestry. The adaptive rank truncated product (ARTP) method was used to determine the significance of associations for each gene and the inflammation pathway with breast cancer risk and by NA ancestry. Overall, the pathway was associated with breast cancer risk (PARTP = 0.01). Two-way interactions with NA ancestry (P(adj) ?< 0.05) were observed for ALOX12 (rs2292350, rs2271316) and PTGS1 (rs10306194). We observed increases in breast cancer risk in stratified analyses by tertiles of polyunsaturated fat intake for ALOX12 polymorphisms; the largest increase in risk was among women in the highest tertile with ALOX12 rs9904779CC (Odds Ratio (OR), 1.49; 95% Confidence Interval (CI) 1.14-1.94, P(adj) = 0.01). In a sub-analysis stratified by NSAIDs use, two-way interactions with NSAIDs use were found for ALOX12 rs9904779 (P(adj) ?= 0.02), rs434473 (P(adj )?= 0.02), and rs1126667 (P(adj) ?=? 0.01); ORs for ALOX12 polymorphisms ranged from 1.55 to 1.64 among regular users. Associations were not observed with breast cancer mortality. These findings could support advances in the discovery of new pathways related to inflammation for breast cancer treatment.

    View details for DOI 10.1002/mc.22228

    View details for Web of Science ID 000363480000002

    View details for PubMedID 25339205

  • Energy homeostasis genes and breast cancer risk: The influence of ancestry, body size, and menopausal status, the breast cancer health disparities study CANCER EPIDEMIOLOGY Slattery, M. L., Lundgreen, A., Hines, L., Wolff, R. K., Torres-Mejia, G., Baumgartner, K. N., John, E. M. 2015; 39 (6): 1113?22

    Abstract

    Obesity and breast cancer risk is multifaceted and genes associated with energy homeostasis may modify this relationship.We evaluated 10 genes that have been associated with obesity and energy homeostasis to determine their association with breast cancer risk in Hispanic/Native American (2111 cases, 2597 controls) and non-Hispanic white (1481 cases, 1585 controls) women.Cholecystokinin (CCK) rs747455 and proopiomelanocortin (POMC) rs6713532 and rs7565877 (for low Indigenous American (IA) ancestry); CCK rs8192472 and neuropeptide Y (NYP) rs16141 and rs14129 (intermediate IA ancestry); and leptin receptor (LEPR) rs11585329 (high IA ancestry) were strongly associated with multiple indicators of body size. There were no significant associations with breast cancer risk between genes and SNPs overall. However, LEPR was significantly associated with breast cancer risk among women with low IA ancestry (PARTP=0.024); POMC was significantly associated with breast cancer risk among women with intermediate (PARTP=0.015) and high (PARTP=0.012) IA ancestry. The overall pathway was statistically significant for pre-menopausal women with low IA ancestry (PARTP=0.05), as was cocaine and amphetamine regulated transcript protein (CARTPT) (PARTP=0.014) and ghrelin (GHRL) (PARTP=0.007). POMC was significantly associated with breast cancer risk among post-menopausal women with higher IA ancestry (PARTP=0.005). Three SNPs in LEPR (rs6704167, rs17412175, and rs7626141), and adiponectin (ADIPOQ); rs822391) showed significant 4-way interactions (GxExMenopausexAncestry) for multiple indicators of body size among pre-menopausal women.Energy homeostasis genes were associated with breast cancer risk; menopausal status, body size, and genetic ancestry influenced this relationship.

    View details for PubMedID 26395295

    View details for PubMedCentralID PMC4679560

  • Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Zhang, B., Shu, X., Delahanty, R. J., Zeng, C., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Wen, W., Long, J., Li, C., Dunning, A. M., Chang-Claude, J., Shah, M., Perkins, B. J., Czene, K., Darabi, H., Eriksson, M., Bojesen, S. E., Nordestgaard, B. G., Nielsen, S. F., Flyger, H., Lambrechts, D., Neven, P., Wildiers, H., Floris, G., Schmidt, M. K., Rookus, M. A., van den Hurk, K., de Kort, W. L., Couch, F. J., Olson, J. E., Hallberg, E., Vachon, C., Rudolph, A., Seibold, P., Flesch-Janys, D., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Nevanlinna, H., Muranen, T. A., Aittomaki, K., Blomqvist, C., Li, J., Humphreys, K., Brand, J., Guenel, P., Truong, T., Cordina-Duverger, E., Menegaux, F., Burwinkel, B., Marme, F., Yang, R., Surowy, H., Benitez, J., Pilar Zamora, M., Perez, J. I., Cox, A., Cross, S. S., Reed, M. W., Andrulis, I. L., Knight, J. A., Glendon, G., Tchatchou, S., Sawyer, E. J., Tomlinson, I., Kerin, M. J., Miller, N., Chenevix-Trench, G., Haiman, C. A., Henderson, B. E., Schumacher, F., Le Marchand, L., Lindblom, A., Margolin, S., Hooning, M. J., Martens, J. W., Tilanus-Linthorst, M. M., Collee, J. M., Hopper, J. L., Southey, M. C., Tsimiklis, H., Apicella, C., Slager, S., Toland, A. E., Ambrosone, C. B., Yannoukakos, D., Giles, G. G., Milne, R. L., McLean, C., Fasching, P. A., Haeberle, L., Ekici, A. B., Beckmann, M. W., Brenner, H., Dieffenbach, A. K., Arndt, V., Stegmaier, C., Swerdlow, A. J., Ashworth, A., Orr, N., Jones, M., Figueroa, J., Garcia-Closas, M., Brinton, L., Lissowska, J., Dumont, M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Brauch, H., Bruening, T., Ko, Y., Peterlongo, P., Manoukian, S., Bonanni, B., Radice, P., Bogdanova, N., Antonenkova, N., Doerk, T., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Devilee, P., Seynaeve, C., van Asperen, C. J., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Hamann, U., Torres, D., Schmutzler, R. K., Neuhausen, S. L., Anton-Culver, H., Kristensen, V. N., Alnaes, G. I., Pierce, B. L., Kraft, P., Peters, U., Lindstrom, S., Seminara, D., Burgess, S., Ahsan, H., Whittemore, A. S., John, E. M., Gammon, M. D., Malone, K. E., Tessier, D. C., Vincent, D., Bacot, F., Luccarini, C., Baynes, C., Ahmed, S., Maranian, M., Healey, C. S., Gonzalez-Neira, A., Pita, G., Rosario Alonso, M., Alvarez, N., Herrero, D., Pharoah, P. D., Simard, J., Hall, P., Hunter, D. J., Easton, D. F., Zheng, W. 2015; 107 (11)

    Abstract

    Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients.The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8).Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.

    View details for DOI 10.1093/jnci/djv219

    View details for Web of Science ID 000366972300027

    View details for PubMedID 26296642

    View details for PubMedCentralID PMC4643630

  • Active and passive cigarette smoking and mortality among Hispanic and non-Hispanic white women diagnosed with invasive breast cancer ANNALS OF EPIDEMIOLOGY Boone, S. D., Baumgartner, K. B., Baumgartner, R. N., Connor, A. E., John, E. M., Giuliano, A. R., Hines, L. M., Rai, S. N., Riley, E. C., Pinkston, C. M., Wolff, R. K., Slattery, M. L. 2015; 25 (11): 824-831

    Abstract

    Women who smoke at breast cancer diagnosis have higher risk of breast cancer-specific and all-cause mortality than nonsmokers; however, differences by ethnicity or prognostic factors and risk for noncancer mortality have not been evaluated.We examined associations of active and passive smoke exposure with mortality among Hispanic (n = 1020) and non-Hispanic white (n = 1198) women with invasive breast cancer in the Breast Cancer Health Disparities Study (median follow-up of 10.6 years).Risk of breast cancer-specific (HR = 1.55, 95% CI = 1.11-2.16) and all-cause (HR = 1.68, 95% CI = 1.30-2.17) mortality was increased for current smokers, with similar results stratified by ethnicity. Ever smokers had an increased risk of noncancer mortality (HR = 1.68, 95% CI = 1.12-2.51). Associations were strongest for current smokers who smoked for 20 years or more were postmenopausal, overweight and/or obese, or reported moderate and/or high alcohol consumption; however, interactions were not significant. Breast cancer-specific mortality was increased two fold for moderate and/or high recent passive smoke exposure among never smokers (HR = 2.12, 95% CI = 1.24-3.63).Findings support associations of active-smoking and passive-smoking diagnosis with risk of breast cancer-specific and all-cause mortality and ever smoking with noncancer mortality, regardless of ethnicity, and other factors. Smoking is a modifiable lifestyle factor and effective smoking cessation, and maintenance programs should be routinely recommended for women with breast cancer.

    View details for DOI 10.1016/j.annepidem.2015.08.007

    View details for Web of Science ID 000363602300004

    View details for PubMedID 26387598

  • Racial and Ethnic Disparities in the Impact of Obesity on Breast Cancer Risk and Survival: A Global Perspective ADVANCES IN NUTRITION Bandera, E. V., Maskarinec, G., Romieu, I., John, E. M. 2015; 6 (6): 803?19

    Abstract

    Obesity is a global concern, affecting both developed and developing countries. Although there are large variations in obesity and breast cancer rates worldwide and across racial/ethnic groups, most studies evaluating the impact of obesity on breast cancer risk and survival have been conducted in non-Hispanic white women in the United States or Europe. Given the known racial/ethnic differences in tumor hormone receptor subtype distribution, obesity prevalence, and risk factor profiles, we reviewed published data for women of African, Hispanic, and Asian ancestry in the United States and their countries of origin. Although the data are limited, current evidence suggests a stronger adverse effect of obesity on breast cancer risk and survival in women of Asian ancestry. For African Americans and Hispanics, the strength of the associations appears to be more comparable to that of non-Hispanic whites, particularly when accounting for subtype and menopausal status. Central obesity seems to have a stronger impact in African-American women than general adiposity as measured by body mass index. International data from countries undergoing economic transition offer a unique opportunity to evaluate the impact of rapid weight gain on breast cancer. Such studies should take into account genetic ancestry, which may help elucidate differences in associations between ethnically admixed populations. Overall, additional large studies that use a variety of adiposity measures are needed, because the current evidence is based on few studies, most with limited statistical power. Future investigations of obesity biomarkers will be useful to understand possible racial/ethnic biological differences underlying the complex association between obesity and breast cancer development and progression.

    View details for PubMedID 26567202

    View details for PubMedCentralID PMC4642425

  • Interaction between Common Breast Cancer Susceptibility Variants, Genetic Ancestry, and Nongenetic Risk Factors in Hispanic Women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Fejerman, L., Stern, M. C., John, E. M., Torres-Meja, G., Hines, L. M., Wolff, R. K., Baumgartner, K. B., Giuliano, A. R., Ziv, E., Perez-Stable, E. J., Slattery, M. L. 2015; 24 (11): 1731?38

    Abstract

    Most genetic variants associated with breast cancer risk have been discovered in women of European ancestry, and only a few genome-wide association studies (GWAS) have been conducted in minority groups. This research disparity persists in post-GWAS gene-environment interaction analyses. We tested the interaction between hormonal and lifestyle risk factors for breast cancer, and ten GWAS-identified SNPs among 2,107 Hispanic women with breast cancer and 2,587 unaffected controls, to gain insight into a previously reported gene by ancestry interaction in this population.We estimated genetic ancestry with a set of 104 ancestry-informative markers selected to discriminate between Indigenous American and European ancestry. We used logistic regression models to evaluate main effects and interactions.We found that the rs13387042-2q35(G/A) SNP was associated with breast cancer risk only among postmenopausal women who never used hormone therapy [per A allele OR: 0.94 (95% confidence intervals, 0.74-1.20), 1.20 (0.94-1.53), and 1.49 (1.28-1.75) for current, former, and never hormone therapy users, respectively, Pinteraction 0.002] and premenopausal women who breastfed >12 months [OR: 1.01 (0.72-1.42), 1.19 (0.98-1.45), and 1.69 (1.26-2.26) for never, <12 months, and >12 months breastfeeding, respectively, Pinteraction 0.014].The correlation between genetic ancestry, hormone replacement therapy use, and breastfeeding behavior partially explained a previously reported interaction between a breast cancer risk variant and genetic ancestry in Hispanic women.These results highlight the importance of understanding the interplay between genetic ancestry, genetics, and nongenetic risk factors and their contribution to breast cancer risk.

    View details for PubMedID 26364163

    View details for PubMedCentralID PMC4633366

  • Psychosocial Adjustment in School-age Girls With a Family History of Breast Cancer PEDIATRICS Bradbury, A. R., Patrick-Miller, L., Schwartz, L., Egleston, B., Sands, C. B., Chung, W. K., Glendon, G., McDonald, J. A., Moore, C., Rauch, P., Tuchman, L., Andrulis, I. L., Buys, S. S., Frost, C. J., Keegan, T. H., Knight, J. A., Terry, M. B., John, E. M., Daly, M. B. 2015; 136 (5): 927-937

    Abstract

    Understanding how young girls respond to growing up with breast cancer family histories is critical given expansion of genetic testing and breast cancer messaging. We examined the impact of breast cancer family history on psychosocial adjustment and health behaviors among >800 girls in the multicenter LEGACY Girls Study.Girls aged 6 to 13 years with a family history of breast cancer or familial BRCA1/2 mutation (BCFH+), peers without a family history (BCFH-), and their biological mothers completed assessments of psychosocial adjustment (maternal report for 6- to 13-year-olds, self-report for 10- to 13-year-olds), breast cancer-specific distress, perceived risk of breast cancer, and health behaviors (10- to 13-year-olds).BCFH+ girls had better general psychosocial adjustment than BCFH- peers by maternal report. Psychosocial adjustment and health behaviors did not differ significantly by self-report among 10- to 13-year-old girls. BCFH+ girls reported higher breast cancer-specific distress (P = .001) and were more likely to report themselves at increased breast cancer risk than BCFH- peers (38.4% vs 13.7%, P < .001), although many girls were unsure of their risk. In multivariable analyses, higher daughter anxiety was associated with higher maternal anxiety and poorer family communication. Higher daughter breast cancer-specific distress was associated with higher maternal breast cancer-specific distress.Although growing up in a family at risk for breast cancer does not negatively affect general psychosocial adjustment among preadolescent girls, those from breast cancer risk families experience greater breast cancer-specific distress. Interventions to address daughter and mother breast cancer concerns and responses to genetic or familial risk might improve psychosocial outcomes of teen daughters.

    View details for DOI 10.1542/peds.2015-0498

    View details for Web of Science ID 000363969600058

    View details for PubMedCentralID PMC4972044

  • Impact of neighborhoods and body size on survival after breast cancer diagnosis HEALTH & PLACE Shariff-Marco, S., Gomez, S. L., Sangaramoorthy, M., Yang, J., Koo, J., Hertz, A., John, E. M., Cheng, I., Keegan, T. H. 2015; 36: 162-172

    Abstract

    With data from the Neighborhoods and Breast Cancer Study, we examined the associations between body size, social and built environments, and survival following breast cancer diagnosis among 4347 women in the San Francisco Bay Area. Lower neighborhood socioeconomic status and greater neighborhood crowding were associated with higher waist-to-hip ratio (WHR). After mutual adjustment, WHR, but not neighborhood characteristics, was positively associated with overall mortality and marginally with breast cancer-specific mortality. Our findings suggest that WHR is an important modifiable prognostic factor for breast cancer survivors. Future WHR interventions should account for neighborhood characteristics that may influence WHR.

    View details for DOI 10.1016/j.healthplace.2015.10.003

    View details for PubMedID 26606455

  • Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions. Human molecular genetics Han, Y., Hazelett, D. J., Wiklund, F., Schumacher, F. R., Stram, D. O., Berndt, S. I., Wang, Z., Rand, K. A., Hoover, R. N., Machiela, M. J., Yeager, M., Burdette, L., Chung, C. C., Hutchinson, A., Yu, K., Xu, J., Travis, R. C., Key, T. J., Siddiq, A., Canzian, F., Takahashi, A., Kubo, M., Stanford, J. L., Kolb, S., Gapstur, S. M., Diver, W. R., Stevens, V. L., Strom, S. S., Pettaway, C. A., Al Olama, A. A., Kote-Jarai, Z., Eeles, R. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., Isaacs, W. B., Chen, C., Lindstrom, S., Le Marchand, L., Giovannucci, E. L., Pomerantz, M., Long, H., Li, F., Ma, J., Stampfer, M., John, E. M., Ingles, S. A., Kittles, R. A., Murphy, A. B., Blot, W. J., Signorello, L. B., Zheng, W., Albanes, D., Virtamo, J., Weinstein, S., Nemesure, B., Carpten, J., Leske, M. C., Wu, S., Hennis, A. J., Rybicki, B. A., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Witte, J. S., Casey, G., Riboli, E., Li, Q., Freedman, M. L., Hunter, D. J., Gronberg, H., Cook, M. B., Nakagawa, H., Kraft, P., Chanock, S. J., Easton, D. F., Henderson, B. E., Coetzee, G. A., Conti, D. V., Haiman, C. A. 2015; 24 (19): 5603-5618

    Abstract

    Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

    View details for DOI 10.1093/hmg/ddv269

    View details for PubMedID 26162851

  • Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study HUMAN MOLECULAR GENETICS Zhang, C., Doherty, J. A., Burgess, S., Hung, R. J., Lindstroem, S., Kraft, P., Gong, J., Amos, C. I., Sellers, T. A., Monteiro, A. N., Chenevix-Trench, G., Bickeboeller, H., Risch, A., Brennan, P., McKay, J. D., Houlston, R. S., Landi, M. T., Timofeeva, M. N., Wang, Y., Heinrich, J., Kote-Jarai, Z., Eeles, R. A., Muir, K., Wiklund, F., Gronberg, H., Berndt, S. I., Chanock, S. J., Schumacher, F., Haiman, C. A., Henderson, B. E., Al Olama, A. A., Andrulis, I. L., Hopper, J. L., Chang-Claude, J., John, E. M., Malone, K. E., Gammon, M. D., Ursin, G., Whittemore, A. S., Hunter, D. J., Gruber, S. B., Knight, J. A., Hou, L., Le Marchand, L., Newcomb, P. A., Hudson, T. J., Chan, A. T., Li, L., Woods, M. O., Ahsan, H., Pierce, B. L. 2015; 24 (18): 5356-5366

    Abstract

    Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.

    View details for DOI 10.1093/hmg/ddv252

    View details for Web of Science ID 000361317200024

    View details for PubMedCentralID PMC4550826

  • Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study. Human molecular genetics Zhang, C., Doherty, J. A., Burgess, S., Hung, R. J., Lindström, S., Kraft, P., Gong, J., Amos, C. I., Sellers, T. A., Monteiro, A. N., Chenevix-Trench, G., Bickeböller, H., Risch, A., Brennan, P., McKay, J. D., Houlston, R. S., Landi, M. T., Timofeeva, M. N., Wang, Y., Heinrich, J., Kote-Jarai, Z., Eeles, R. A., Muir, K., Wiklund, F., Grönberg, H., Berndt, S. I., Chanock, S. J., Schumacher, F., Haiman, C. A., Henderson, B. E., Amin Al Olama, A., Andrulis, I. L., Hopper, J. L., Chang-Claude, J., John, E. M., Malone, K. E., Gammon, M. D., Ursin, G., Whittemore, A. S., Hunter, D. J., Gruber, S. B., Knight, J. A., Hou, L., Le Marchand, L., Newcomb, P. A., Hudson, T. J., Chan, A. T., Li, L., Woods, M. O., Ahsan, H., Pierce, B. L. 2015; 24 (18): 5356-5366

    Abstract

    Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.

    View details for DOI 10.1093/hmg/ddv252

    View details for PubMedID 26138067

  • Contribution of the Neighborhood Environment and Obesity to Breast Cancer Survival: The California Breast Cancer Survivorship Consortium CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Cheng, I., Shariff-Marco, S., Koo, J., Monroe, K. R., Yang, J., John, E. M., Kurian, A. W., Kwan, M. L., Henderson, B. E., Bernstein, L., Lu, Y., Sposto, R., Vigen, C., Wu, A. H., Gomez, S. L., Keegan, T. H. 2015; 24 (8): 1282-1290

    Abstract

    Little is known about neighborhood attributes that may influence opportunities for healthy eating and physical activity in relation to breast cancer mortality. We used data from the California Breast Cancer Survivorship Consortium and the California Neighborhoods Data System to examine the neighborhood environment, body mass index, and mortality after breast cancer. We studied 8,995 African American, Asian American, Latina, and non-Latina White women with breast cancer. Residential addresses were linked to the CNDS to characterize neighborhoods. We used multinomial logistic regression to evaluate the associations between neighborhood factors and obesity, and Cox proportional hazards regression to examine associations between neighborhood factors and mortality. For Latinas, obesity was associated with more neighborhood crowding (Quartile 4 (Q4) vs. Q1: Odds Ratio (OR)=3.24; 95% Confidence Interval (CI): 1.50-7.00); breast cancer-specific mortality was inversely associated with neighborhood businesses (Q4 vs. Q1: Hazard Ratio (HR)=0.46; 95% CI: 0.25-0.85) and positively associated with multi-family housing (Q3 vs. Q1: HR=1.98; 95% CI: 1.20-3.26). For non-Latina Whites, lower neighborhood socioeconomic status (SES) was associated with obesity (Quintile 1 (Q1) vs. Q5: OR=2.52; 95% CI: 1.31-4.84), breast cancer-specific (Q1 vs. Q5: HR=2.75; 95% CI: 1.47-5.12), and all-cause (Q1 vs. Q5: HR=1.75; 95% CI: 1.17-2.62) mortality. For Asian Americans, no associations were seen. For African Americans, lower neighborhood SES was associated with lower mortality in a nonlinear fashion. Attributes of the neighborhood environment were associated with obesity and mortality following breast cancer diagnosis, but these associations differed across racial/ethnic groups.

    View details for DOI 10.1158/1055-9965.EPI-15-0055

    View details for PubMedID 26063477

  • Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults PLOS ONE Chen, F., He, J., Zhang, J., Chen, G. K., Thomas, V., Ambrosone, C. B., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Cai, Q., Carpten, J., Casey, G., Chanock, S. J., Cheng, I., Chu, L., Deming, S. L., Driver, W. R., Goodman, P., Hayes, R. B., Hennis, A. J., Hsing, A. W., Hu, J. J., Ingles, S. A., John, E. M., Kittles, R. A., Kolb, S., Leske, M. C., Millikan, R. C., Monroe, K. R., Murphy, A., Nemesure, B., Neslund-Dudas, C., Nyante, S., Ostrander, E. A., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schumacher, F., Stanford, J. L., Signorello, L. B., Strom, S. S., Stevens, V., Van Den Berg, D., Wang, Z., Witte, J. S., Wu, S., Yamamura, Y., Zheng, W., Ziegler, R. G., Stram, A. H., Kolonel, L. N., Le Marchand, L., Henderson, B. E., Haiman, C. A., Stram, D. O. 2015; 10 (6)

    Abstract

    Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.

    View details for DOI 10.1371/journal.pone.0131106

    View details for Web of Science ID 000358151300033

    View details for PubMedCentralID PMC4488332

  • History of Recreational Physical Activity and Survival After Breast Cancer The California Breast Cancer Survivorship Consortium AMERICAN JOURNAL OF EPIDEMIOLOGY Lu, Y., John, E. M., Sullivan-Halley, J., Vigen, C., Gomez, S. L., Kwan, M. L., Caan, B. J., Lee, V. S., Roh, J. M., Shariff-Marco, S., Keegan, T. H., Kurian, A. W., Monroe, K. R., Cheng, I., Sposto, R., Wu, A. H., Bernstein, L. 2015; 181 (12): 944-955

    Abstract

    Recent epidemiologic evidence suggests that prediagnosis physical activity is associated with survival in women diagnosed with breast cancer. However, few data exist for racial/ethnic groups other than non-Latina whites. To examine the association between prediagnosis recreational physical activity and mortality by race/ethnicity, we pooled data from the California Breast Cancer Survivorship Consortium for 3 population-based case-control studies of breast cancer patients (n = 4,608) diagnosed from 1994 to 2002 and followed up through 2010. Cox proportional hazards models provided estimates of the relative hazard ratio for mortality from all causes, breast cancer, and causes other than breast cancer associated with recent recreational physical activity (i.e., in the 10 years before diagnosis). Among 1,347 ascertained deaths, 826 (61%) were from breast cancer. Compared with women with the lowest level of recent recreational physical activity, those with the highest level had a marginally decreased risk of all-cause mortality (hazard ratio = 0.88, 95% confidence interval: 0.76, 1.01) and a statistically significant decreased risk of mortality from causes other than breast cancer (hazard ratio = 0.63, 95% confidence interval: 0.49, 0.80), and particularly from cardiovascular disease. No association was observed for breast cancer-specific mortality. These risk patterns did not differ by race/ethnicity (non-Latina white, African American, Latina, and Asian American). Our findings suggest that physical activity is beneficial for overall survival regardless of race/ethnicity.

    View details for DOI 10.1093/aje/kwu466

    View details for Web of Science ID 000356180600004

    View details for PubMedID 25925388

  • Second primary breast cancer in BRCA1 and BRCA2 mutation carriers: 10-year cumulative incidence in the Breast Cancer Family Registry BREAST CANCER RESEARCH AND TREATMENT Menes, T. S., Terry, M., Goldgar, D., Andrulis, I. L., Knight, J. A., John, E. M., Liao, Y., Southey, M., Miron, A., Chung, W., Buys, S. S. 2015; 151 (3): 653?60

    Abstract

    BReast CAncer genes 1 and 2 (BRCA1 and BRCA2) mutation carriers diagnosed with breast cancer are at increased risk of developing a second primary breast cancer. Data from high-risk clinics may be subject to different biases which can cause both over and underestimation of this risk. Using data from a large multi-institutional family registry we estimated the 10-year cumulative risk of second primary breast cancer including more complete testing information on family members. We prospectively followed 800 women diagnosed with breast cancer from the Breast Cancer Family Registry (BCFR) who were carriers of a BRCA1 or BRCA2 pathogenic mutation or a variant of unknown clinical significance. In order to limit survival and ascertainment bias, cases were limited to those diagnosed with a first primary breast cancer from 1994 to 2001 and enrolled in the BCFR within 3 years after their cancer diagnosis. We excluded women enrolled after being diagnosed with a second breast cancer. We calculated 10-year incidence of second primary breast cancers. The 10-year incidence of a second primary breast cancer was highest in BRCA1 mutation carriers (17 %; 95 % CI 11-25 %), with even higher estimates in those first diagnosed under the age of 40 (21 %; 95 % CI 13-34 %). Lower rates were found in BRCA2 mutation carriers (7 %; 95 % CI 3-15 %) and women with a variant of unknown clinical significance (6 %; 95 % CI 4-9 %). Whereas the cumulative 10-year incidence of second primary breast cancer is high in BRCA1 mutation carriers, the estimates in BRCA2 mutation carriers and women with variants of unknown clinical significance are similar to those reported in women with sporadic breast cancer.

    View details for DOI 10.1007/s10549-015-3419-y

    View details for Web of Science ID 000355658700016

    View details for PubMedID 25975955

    View details for PubMedCentralID PMC4545282

  • Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Mavaddat, N., Pharoah, P. D., Michailidou, K., Tyrer, J., Brook, M. N., Bolla, M. K., Wang, Q., Dennis, J., Dunning, A. M., Shah, M., Luben, R., Brown, J., Bojesen, S. E., Nordestgaard, B. G., Nielsen, S. F., Flyger, H., Czene, K., Darabi, H., Eriksson, M., Peto, J., Dos-Santos-Silva, I., Dudbridge, F., Johnson, N., Schmidt, M. K., Broeks, A., Verhoef, S., Rutgers, E. J., Swerdlow, A., Ashworth, A., Orr, N., Schoemaker, M. J., Figueroa, J., Chanock, S. J., Brinton, L., Lissowska, J., Couch, F. J., Olson, J. E., Vachon, C., Pankratz, V. S., Lambrechts, D., Wildiers, H., van Ongeval, C., Van Limbergen, E., Kristensen, V., Alnaes, G. G., Nord, S., Borresen-Dale, A., Nevanlinna, H., Muranen, T. A., Aittomaeki, K., Blomqvist, C., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Fasching, P. A., Haeberle, L., Ekici, A. B., Beckmann, M. W., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Trentham-Dietz, A., Newcomb, P., Titus, L., Egan, K. M., Hunter, D. J., Lindstrom, S., Tamimi, R. M., Kraft, P., Rahman, N., Turnbull, C., Renwick, A., Seal, S., Li, J., Liu, J., Humphreys, K., Benitez, J., Zamora, M. P., Perez, J. I., Menendez, P., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Bogdanova, N. V., Antonenkova, N. N., Doerk, T., Anton-Culver, H., Neuhausen, S. L., Ziogas, A., Bernstein, L., Devilee, P., Tollenaar, R. A., Seynaeve, C., van Asperen, C. J., Cox, A., Cross, S. S., Reed, M. W., Khusnutdinova, E., Bermisheva, M., Prokofyeva, D., Takhirova, Z., Meindl, A., Schmutzler, R. K., Sutter, C., Yang, R., Schuermann, P., Bremer, M., Christiansen, H., Park-Simon, T., Hillemanns, P., Guenel, P., Truong, T., Menegaux, F., Sanchez, M., Radice, P., Peterlongo, P., Manoukian, S., Pensotti, V., Hopper, J. L., Tsimiklis, H., Apicella, C., Southey, M. C., Brauch, H., Bruening, T., Ko, Y., Sigurdson, A. J., Doody, M. M., Hamann, U., Torres, D., Ulmer, H., Foersti, A., Sawyer, E. J., Tomlinson, I., Kerin, M. J., Miller, N., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Chenevix-Trench, G., Balleine, R., Giles, G. G., Milne, R. L., McLean, C., Lindblom, A., Margolin, S., Haiman, C. A., Henderson, B. E., Schumacher, F., Le Marchand, L., Eilber, U., Wang-Gohrke, S., Hooning, M. J., Hollestelle, A., van den Ouweland, A. M., Koppert, L. B., Carpenter, J., Clarke, C., Scott, R., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Brenner, H., Arndt, V., Stegmaier, C., Dieffenbach, A. K., Winqvist, R., Pylkaes, K., Jukkola-Vuorinen, A., Grip, M., Offit, K., Vijai, J., Robson, M., Rau-Murthy, R., Dwek, M., Swann, R., Perkins, K. A., Goldberg, M. S., Labreche, F., Dumont, M., Eccles, D. M., Tapper, W. J., Rafiq, S., John, E. M., Whittemore, A. S., Slager, S., Yannoukakos, D., Toland, A. E., Yao, S., Zheng, W., Halverson, S. L., Gonzalez-Neira, A., Pita, G., Alonso, M. R., Alvarez, N., Herrero, D., Tessier, D. C., Vincent, D., Bacot, F., Luccarini, C., Baynes, C., Ahmed, S., Maranian, M., Healey, C. S., Simard, J., Hall, P., Easton, D. F., Garcia-Closas, M. 2015; 107 (5)
  • Two susceptibility loci identified for prostate cancer aggressiveness NATURE COMMUNICATIONS Berndt, S. I., Wang, Z., Yeager, M., Alavanja, M. C., Albanes, D., Amundadottir, L., Andriole, G., Freeman, L. B., Campa, D., Cancel-Tassin, G., Canzian, F., Cornu, J., Cussenot, O., Diver, W. R., Gapstur, S. M., Gronberg, H., Haiman, C. A., Henderson, B., Hutchinson, A., Hunter, D. J., Key, T. J., Kolb, S., Koutros, S., Kraft, P., Le Marchand, L., Lindstroem, S., Machiela, M. J., Ostrander, E. A., Riboli, E., Schumacher, F., Siddiq, A., Stanford, J. L., Stevens, V. L., Travis, R. C., Tsilidis, K. K., Virtamo, J., Weinstein, S., Wilkund, F., Xu, J., Zheng, S. L., Yu, K., Wheeler, W., Zhang, H., Consortium, A. A., Sampson, J., Black, A., Jacobs, K., Hoover, R. N., Tucker, M., Chanock, S. J. 2015; 6

    Abstract

    Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 × 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 × 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 × 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.

    View details for DOI 10.1038/ncomms7889

    View details for Web of Science ID 000355526400001

    View details for PubMedID 25939597

    View details for PubMedCentralID PMC4422072

  • An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers BREAST CANCER RESEARCH Blein, S., Bardel, C., Danjean, V., McGuffog, L., Healey, S., Barrowdale, D., Lee, A., Dennis, J., Kuchenbaecker, K. B., Soucy, P., Terry, M., Chung, W. K., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., van Rensburg, E. J., Neuhausen, S. L., Ding, Y., Gerdes, A., Ejlertsen, B., Nielsen, F. C., Hansen, T. O., Osorio, A., Benitez, J., Andres Conejero, R., Segota, E., Weitzel, J. N., Thelander, M., Peterlongo, P., Radice, P., Pensotti, V., Dolcetti, R., Bonanni, B., Peissel, B., Zaffaroni, D., Scuvera, G., Manoukian, S., Varesco, L., Capone, G. L., Papi, L., Ottini, L., Yannoukakos, D., Konstantopoulou, I., Garber, J., Hamann, U., Donaldson, A., Brady, A., Brewer, C., Foo, C., Evans, D., Frost, D., Eccles, D., Douglas, F., Cook, J., Adlard, J., Barwell, J., Walker, L., Izatt, L., Side, L. E., Kennedy, M., Tischkowitz, M., Rogers, M. T., Porteous, M. E., Morrison, P. J., Platte, R., Eeles, R., Davidson, R., Hodgson, S., Cole, T., Godwin, A. K., Isaacs, C., Claes, K., De Leeneer, K., Meindl, A., Gehrig, A., Wappenschmidt, B., Sutter, C., Engel, C., Niederacher, D., Steinemann, D., Plendl, H., Kast, K., Rhiem, K., Ditsch, N., Arnold, N., Varon-Mateeva, R., Schmutzler, R. K., Preisler-Adams, S., Markov, N., Wang-Gohrke, S., de Pauw, A., Lefol, C., Lasset, C., Leroux, D., Rouleau, E., Damiola, F., Dreyfus, H., Barjhoux, L., Golmard, L., Uhrhammer, N., Bonadona, V., Sornin, V., Bignon, Y., Carter, J., Van Le, L., Piedmonte, M., DiSilvestro, P. A., de la Hoya, M., Caldes, T., Nevanlinna, H., Aittomaki, K., Jager, A., van den Ouweland, A. W., Kets, C. M., Aalfs, C. M., van Leeuwen, F. E., Hogervorst, F. L., Meijers-Heijboer, H. J., Oosterwijk, J. C., van Roozendaal, K. P., Rookus, M. A., Devilee, P., van der Luijt, R. B., Olah, E., Diez, O., Teule, A., Lazaro, C., Blanco, I., Del Valle, J., Jakubowska, A., Sukiennicki, G., Gronwald, J., Lubinski, J., Durda, K., Jaworska-Bieniek, K., Agnarsson, B. A., Maugard, C., Amadori, A., Montagna, M., Teixeira, M. R., Spurdle, A. B., Foulkes, W., Olswold, C., Lindor, N. M., Pankratz, V. S., Szabo, C. I., Lincoln, A., Jacobs, L., Corines, M., Robson, M., Vijai, J., Berger, A., Fink-Retter, A., Singer, C. F., Rappaport, C., Kaulich, D., Pfeiler, G., Tea, M., Greene, M. H., Mai, P. L., Rennert, G., Imyanitov, E. N., Mulligan, A., Glendon, G., Andrulis, I. L., Tchatchou, S., Toland, A., Pedersen, I., Thomassen, M., Kruse, T. A., Jensen, U., Caligo, M. A., Friedman, E., Zidan, J., Laitman, Y., Lindblom, A., Melin, B., Arver, B., Loman, N., Rosenquist, R., Olopade, O. I., Nussbaum, R. L., Ramus, S. J., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Arun, B. K., Mitchell, G., Karlan, B. Y., Lester, J., Orsulic, S., Stoppa-Lyonnet, D., Thomas, G., Simard, J., Couch, F. J., Offit, K., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Mazoyer, S., Phelan, C. M., Sinilnikova, O. M., Cox, D. G., Breast Canc Family Registry, EMBRACE, GEMO Study Collaborators, HEBON 2015; 17: 61

    Abstract

    Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

    View details for PubMedID 25925750

  • Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA Rebbeck, T. R., Mitra, N., Wan, F., Sinilnikova, O. M., Healey, S., McGuffog, L., Mazoyer, S., Chenevix-Trench, G., Easton, D. F., Antoniou, A. C., Nathanson, K. L., Laitman, Y., Kushnir, A., Paluch-Shimon, S., Berger, R., Zidan, J., friedman, e., Ehrencrona, H., Stenmark-Askmalm, M., Einbeigi, Z., Loman, N., Harbst, K., Rantala, J., Melin, B., Huo, D., Olopade, O. I., Seldon, J., Ganz, P. A., Nussbaum, R. L., Chan, S. B., Odunsi, K., Gayther, S. A., Domchek, S. M., Arun, B. K., Lu, K. H., Mitchell, G., Karlan, B. Y., Walsh, C., Lester, J., Godwin, A. K., Pathak, H., Ross, E., Daly, M. B., Whittemore, A. S., John, E. M., Miron, A., Terry, M. B., Chung, W. K., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., Van Rensburg, E. J., Steele, L., Neuhausen, S. L., Ding, Y. C., Ejlertsen, B., Gerdes, A., Hansen, T. v., Ramón y Cajal, T., Osorio, A., Benitez, J., Godino, J., Tejada, M., Duran, M., Weitzel, J. N., Bobolis, K. A., Sand, S. R., Fontaine, A., Savarese, A., Pasini, B., Peissel, B., Bonanni, B., Zaffaroni, D., Vignolo-Lutati, F., Scuvera, G., Giannini, G., Bernard, L., Genuardi, M., Radice, P., Dolcetti, R., Manoukian, S., Pensotti, V., Gismondi, V., Yannoukakos, D., Fostira, F., Garber, J., Torres, D., Rashid, M. U., Hamann, U., Peock, S., Frost, D., Platte, R., Evans, D. G., Eeles, R., Davidson, R., Eccles, D., Cole, T., Cook, J., Brewer, C., Hodgson, S., Morrison, P. J., Walker, L., Porteous, M. E., Kennedy, M. J., Izatt, L., Adlard, J., Donaldson, A., Ellis, S., Sharma, P., Schmutzler, R. K., Wappenschmidt, B., Becker, A., Rhiem, K., Hahnen, E., Engel, C., Meindl, A., Engert, S., Ditsch, N., Arnold, N., Plendl, H. J., Mundhenke, C., Niederacher, D., Fleisch, M., Sutter, C., Bartram, C. R., Dikow, N., Wang-Gohrke, S., Gadzicki, D., Steinemann, D., Kast, K., Beer, M., Varon-Mateeva, R., Gehrig, A., Weber, B. H., Stoppa-Lyonnet, D., Sinilnikova, O. M., Mazoyer, S., Houdayer, C., Belotti, M., Gauthier-Villars, M., Damiola, F., Boutry-Kryza, N., Lasset, C., Sobol, H., Peyrat, J., Muller, D., Fricker, J., Collonge-Rame, M., Mortemousque, I., Nogues, C., Rouleau, E., Isaacs, C., De Paepe, A., Poppe, B., Claes, K., De Leeneer, K., Piedmonte, M., Rodriguez, G., Wakely, K., Boggess, J., Blank, S. V., Basil, J., Azodi, M., Phillips, K., Caldes, T., de la Hoya, M., Romero, A., Nevanlinna, H., Aittomäki, K., van der Hout, A. H., Hogervorst, F. B., Verhoef, S., Collée, J. M., Seynaeve, C., Oosterwijk, J. C., Gille, J. J., Wijnen, J. T., Garcia, E. B., Kets, C. M., Ausems, M. G., Aalfs, C. M., Devilee, P., Mensenkamp, A. R., Kwong, A., Olah, E., Papp, J., Diez, O., Lazaro, C., Darder, E., Blanco, I., Salinas, M., Jakubowska, A., Lubinski, J., Gronwald, J., Jaworska-Bieniek, K., Durda, K., Sukiennicki, G., Huzarski, T., Byrski, T., Cybulski, C., Toloczko-Grabarek, A., Zlowocka-Perlowska, E., Menkiszak, J., Arason, A., Barkardottir, R. B., Simard, J., Laframboise, R., Montagna, M., Agata, S., Alducci, E., Peixoto, A., Teixeira, M. R., Spurdle, A. B., Lee, M. H., Park, S. K., Kim, S., Friebel, T. M., Couch, F. J., Lindor, N. M., Pankratz, V. S., Guidugli, L., Wang, X., Tischkowitz, M., Foretova, L., Vijai, J., Offit, K., Robson, M., Rau-Murthy, R., Kauff, N., Fink-Retter, A., Singer, C. F., Rappaport, C., Gschwantler-Kaulich, D., Pfeiler, G., Tea, M., Berger, A., Greene, M. H., Mai, P. L., Imyanitov, E. N., Toland, A. E., Senter, L., Bojesen, A., Pedersen, I. S., Skytte, A., Sunde, L., Thomassen, M., Moeller, S. T., Kruse, T. A., Jensen, U. B., Caligo, M. A., Aretini, P., Teo, S., Selkirk, C. G., Hulick, P. J., Andrulis, I. 2015; 313 (13): 1347-1361

    Abstract

    Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.To identify mutation-specific cancer risks for carriers of BRCA1/2.Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.Mutations of BRCA1 or BRCA2.Breast and ovarian cancer risks.Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR?=?1.46; 95% CI, 1.22-1.74; P?=?2?×?10(-6)), c.4328 to c.4945 (BCCR2; RHR?=?1.34; 95% CI, 1.01-1.78; P?=?.04), and c. 5261 to c.5563 (BCCR2', RHR?=?1.38; 95% CI, 1.22-1.55; P?=?6?×?10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR?=?0.62 (95% CI, 0.56-0.70; P?=?9?×?10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR?=?1.71; 95% CI, 1.06-2.78; P?=?.03), c.772 to c.1806 (BCCR1'; RHR?=?1.63; 95% CI, 1.10-2.40; P?=?.01), and c.7394 to c.8904 (BCCR2; RHR?=?2.31; 95% CI, 1.69-3.16; P?=?.00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR?=?0.51; 95% CI, 0.44-0.60; P?=?6?×?10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR?=?0.57; 95% CI, 0.41-0.80; P?=?.001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

    View details for DOI 10.1001/jama.2014.5985

    View details for PubMedID 25849179

  • Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer NATURE GENETICS Michailidou, K., Beesley, J., Lindstrom, S., Canisius, S., Dennis, J., Lush, M. J., Maranian, M. J., Bolla, M. K., Wang, Q., Shah, M., Perkins, B. J., Czene, K., Eriksson, M., Darabi, H., Brand, J. S., Bojesen, S. E., Nordestgaard, B. G., Flyger, H., Nielsen, S. F., Rahman, N., Turnbull, C., Fletcher, O., Peto, J., Gibson, L., Dos-Santos-Silva, I., Chang-Claude, J., Flesch-Janys, D., Rudolph, A., Eilber, U., Behrens, S., Nevanlinna, H., Muranen, T. A., Aittomaki, K., Blomqvist, C., Khan, S., Aaltonen, K., Ahsan, H., Kibriya, M. G., Whittemore, A. S., John, E. M., Malone, K. E., Gammon, M. D., Santella, R. M., Ursin, G., Makalic, E., Schmidt, D. F., Casey, G., Hunter, D. J., Gapstur, S. M., Gaudet, M. M., Diver, W. R., Haiman, C. A., Schumacher, F., Henderson, B. E., Le Marchand, L., Berg, C. D., Chanock, S. J., Figueroa, J., Hoover, R. N., Lambrechts, D., Neven, P., Wildiers, H., Van Limbergen, E., Schmidt, M. K., Broeks, A., Verhoef, S., Cornelissen, S., Couch, F. J., Olson, J. E., Hallberg, E., Vachon, C., Waisfisz, Q., Meijers-Heijboer, H., Adank, M. A., van der Luijt, R. B., Li, J., Liu, J., Humphreys, K., Kang, D., Choi, J., Park, S. K., Yoo, K., Matsuo, K., Ito, H., Iwata, H., Tajima, K., Guenel, P., Truong, T., Mulot, C., Sanchez, M., Burwinkel, B., Marme, F., Surowy, H., Sohn, C., Wu, A. H., Tseng, C., Van Den Berg, D., Stram, D. O., Gonzalez-Neira, A., Benitez, J., Zamora, M. P., Arias Perez, J. I., Shu, X., Lu, W., Gao, Y., Cai, H., Cox, A., Cross, S. S., Reed, M. W., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Sawyer, E. J., Tomlinson, I., Kerin, M. J., Miller, N., Lindblom, A., Margolin, S., Teo, S. H., Yip, C. H., Taib, N. A., Tan, G., Hooning, M. J., Hollestelle, A., Martens, J. W., Collee, J. M., Blot, W., Signorello, L. B., Cai, Q., Hopper, J. L., Southey, M. C., Tsimiklis, H., Apicella, C., Shen, C., Hsiung, C., Wu, P., Hou, M., Kristensen, V. N., Nord, S., Alnaes, G. I., Giles, G. G., Milne, R. L., McLean, C., Canzian, F., Trichopoulos, D., Peeters, P., Lund, E., Sund, M., Khaw, K., Gunter, M. J., Palli, D., Mortensen, L. M., Dossus, L., Huerta, J., Meindl, A., Schmutzler, R. K., Sutter, C., Yang, R., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Hartman, M., Miao, H., Chia, K. S., Chan, C. W., Fasching, P. A., Hein, A., Beckmann, M. W., Haeberle, L., Brenner, H., Dieffenbach, A. K., Arndt, V., Stegmaier, C., Ashworth, A., Orr, N., Schoemaker, M. J., Swerdlow, A. J., Brinton, L., Garcia-Closas, M., Zheng, W., Halverson, S. L., Shrubsole, M., Long, J., Goldberg, M. S., Labreche, F., Dumont, M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Brauch, H., Hamann, U., Bruening, T., Radice, P., Peterlongo, P., Manoukian, S., Bernard, L., Bogdanova, N. V., Doerk, T., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Devilee, P., Tollenaar, R. A., Seynaeve, C., van Asperen, C. J., Jakubowska, A., Lubinski, J., Jaworska, K., Huzarski, T., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Slager, S., Toland, A. E., Ambrosone, C. B., Yannoukakos, D., Kabisch, M., Torres, D., Neuhausen, S. L., Anton-Culver, H., Luccarini, C., Baynes, C., Ahmed, S., Healey, C. S., Tessier, D. C., Vincent, D., Bacot, F., Pita, G., Rosario Alonso, M., Alvarez, N., Herrero, D., Simard, J., Pharoah, P. P., Kraft, P., Dunning, A. M., Chenevix-Trench, G., Hall, P., Easton, D. F. 2015; 47 (4): 373-U127

    Abstract

    Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ?14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

    View details for DOI 10.1038/ng.3242

    View details for Web of Science ID 000351922900013

    View details for PubMedCentralID PMC4549775

  • Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nature genetics Michailidou, K., Beesley, J., Lindstrom, S., Canisius, S., Dennis, J., Lush, M. J., Maranian, M. J., Bolla, M. K., Wang, Q., Shah, M., Perkins, B. J., Czene, K., Eriksson, M., Darabi, H., Brand, J. S., Bojesen, S. E., Nordestgaard, B. G., Flyger, H., Nielsen, S. F., Rahman, N., Turnbull, C., Fletcher, O., Peto, J., Gibson, L., Dos-Santos-Silva, I., Chang-Claude, J., Flesch-Janys, D., Rudolph, A., Eilber, U., Behrens, S., Nevanlinna, H., Muranen, T. A., Aittomäki, K., Blomqvist, C., Khan, S., Aaltonen, K., Ahsan, H., Kibriya, M. G., Whittemore, A. S., John, E. M., Malone, K. E., Gammon, M. D., Santella, R. M., Ursin, G., Makalic, E., Schmidt, D. F., Casey, G., Hunter, D. J., Gapstur, S. M., Gaudet, M. M., Diver, W. R., Haiman, C. A., Schumacher, F., Henderson, B. E., Le Marchand, L., Berg, C. D., Chanock, S. J., Figueroa, J., Hoover, R. N., Lambrechts, D., Neven, P., Wildiers, H., Van Limbergen, E., Schmidt, M. K., Broeks, A., Verhoef, S., Cornelissen, S., Couch, F. J., Olson, J. E., Hallberg, E., Vachon, C., Waisfisz, Q., Meijers-Heijboer, H., Adank, M. A., van der Luijt, R. B., Li, J., Liu, J., Humphreys, K., Kang, D., Choi, J., Park, S. K., Yoo, K., Matsuo, K., Ito, H., Iwata, H., Tajima, K., Guénel, P., Truong, T., Mulot, C., Sanchez, M., Burwinkel, B., Marme, F., Surowy, H., Sohn, C., Wu, A. H., Tseng, C., Van Den Berg, D., Stram, D. O., González-Neira, A., Benitez, J., Zamora, M. P., Perez, J. I., Shu, X., Lu, W., Gao, Y., Cai, H., Cox, A., Cross, S. S., Reed, M. W., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Sawyer, E. J., Tomlinson, I., Kerin, M. J., Miller, N., Lindblom, A., Margolin, S., Teo, S. H., Yip, C. H., Taib, N. A., Tan, G., Hooning, M. J., Hollestelle, A., Martens, J. W., Collée, J. M., Blot, W., Signorello, L. B., Cai, Q., Hopper, J. L., Southey, M. C., Tsimiklis, H., Apicella, C., Shen, C., Hsiung, C., Wu, P., Hou, M., Kristensen, V. N., Nord, S., Alnaes, G. I., Giles, G. G., Milne, R. L., McLean, C., Canzian, F., Trichopoulos, D., Peeters, P., Lund, E., Sund, M., Khaw, K., Gunter, M. J., Palli, D., Mortensen, L. M., Dossus, L., Huerta, J., Meindl, A., Schmutzler, R. K., Sutter, C., Yang, R., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Hartman, M., Miao, H., Chia, K. S., Chan, C. W., Fasching, P. A., Hein, A., Beckmann, M. W., Haeberle, L., Brenner, H., Dieffenbach, A. K., Arndt, V., Stegmaier, C., Ashworth, A., Orr, N., Schoemaker, M. J., Swerdlow, A. J., Brinton, L., Garcia-Closas, M., Zheng, W., Halverson, S. L., Shrubsole, M., Long, J., Goldberg, M. S., Labrčche, F., Dumont, M., Winqvist, R., Pylkäs, K., Jukkola-Vuorinen, A., Grip, M., Brauch, H., Hamann, U., Brüning, T., Radice, P., Peterlongo, P., Manoukian, S., Bernard, L., Bogdanova, N. V., Dörk, T., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Devilee, P., Tollenaar, R. A., Seynaeve, C., van Asperen, C. J., Jakubowska, A., Lubinski, J., Jaworska, K., Huzarski, T., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Slager, S., Toland, A. E., Ambrosone, C. B., Yannoukakos, D., Kabisch, M., Torres, D., Neuhausen, S. L., Anton-Culver, H., Luccarini, C., Baynes, C., Ahmed, S., Healey, C. S., Tessier, D. C., Vincent, D., Bacot, F., Pita, G., Alonso, M. R., Álvarez, N., Herrero, D., Simard, J., Pharoah, P. P., Kraft, P., Dunning, A. M., Chenevix-Trench, G., Hall, P., Easton, D. F. 2015; 47 (4): 373-380

    Abstract

    Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ?14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

    View details for DOI 10.1038/ng.3242

    View details for PubMedID 25751625

  • Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers PLOS ONE Blanco, I., Kuchenbaecker, K., Cuadras, D., Wang, X., Barrowdale, D., Ruiz de Garibay, G., Librado, P., Sanchez-Gracia, A., Rozas, J., Bonifaci, N., McGuffog, L., Pankratz, V. S., Islam, A., Mateo, F., Berenguer, A., Petit, A., Catala, I., Brunet, J., Feliubadalo, L., Tornero, E., Benitez, J., Osorio, A., Cajal, T. Y., Nevanlinna, H., Aittomaki, K., Arun, B. K., Toland, A. E., Karlan, B. Y., Walsh, C., Lester, J., Greene, M. H., Mai, P. L., Nussbaum, R. L., Andrulis, I. L., Domchek, S. M., Nathanson, K. L., Rebbeck, T. R., Barkardottir, R. B., Jakubowska, A., Lubinski, J., Durda, K., Jaworska-Bieniek, K., Claes, K., Van Maerken, T., Diez, O., Hansen, T. V., Jonson, L., Gerdes, A., Ejlertsen, B., de la Hoya, M., Caldes, T., Dunning, A. M., Oliver, C., Fineberg, E., Cook, M., Peock, S., McCann, E., Murray, A., Jacobs, C., Pichert, G., Lalloo, F., Chu, C., Dorkins, H., Paterson, J., Ong, K., Teixeira, M. R., Teixeira, Hogervorst, F. L., van der Hout, A. H., Seynaeve, C., van der Luijt, R. B., Ligtenberg, M. L., Devilee, P., Wijnen, J. T., Rookus, M. A., Meijers-Heijboer, H. J., Blok, M. J., van den Ouweland, A. W., Aalfs, C. M., Rodriguez, G. C., Phillips, K. A., Piedmonte, M., Nerenstone, S. R., Bae-Jump, V. L., O'Malley, D. M., Ratner, E. S., Schmutzler, R. K., Wappenschmidt, B., Rhiem, K., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Plendl, H. J., Niederacher, D., Sutter, C., Wang-Gohrke, S., Steinemann, D., Preisler-Adams, S., Kast, K., Varon-Mateeva, R., Gehrig, A., Bojesen, A., Pedersen, I., Sunde, L., Jensen, U., Thomassen, M., Kruse, T. A., Foretova, L., Peterlongo, P., Bernard, L., Peissel, B., Scuvera, G., Manoukian, S., Radice, P., Ottini, L., Montagna, M., Agata, S., Maugard, C., Simard, J., Soucy, P., Berger, A., Fink-Retter, A., Singer, C. F., Rappaport, C., Geschwantler-Kaulich, D., Tea, M., Pfeiler, G., John, E. M., Miron, A., Neuhausen, S. L., Terry, M., Chung, W. K., Daly, M. B., Goldgar, D. E., Janavicius, R., Dorfling, C. M., van Rensburg, E. J., Fostira, F., Konstantopoulou, I., Garber, J., Godwin, A. K., Olah, E., Narod, S. A., Rennert, G., Paluch, S., Laitman, Y., Friedman, E., Liljegren, A., Rantala, J., Stenmark-Askmalm, M., Loman, N., Imyanitov, E. N., Hamann, U., Spurdle, A. B., Healey, S., Weitzel, J. N., Herzog, J., Margileth, D., Gorrini, C., Esteller, M., Gomez, A., Sayols, S., Vidal, E., Heyn, H., Stoppa-Lyonnet, D., Leone, M., Barjhoux, L., Fassy-Colcombet, M., de Pauw, A., Lasset, C., Ferrer, S., Castera, L., Berthet, P., Cornelis, F., Bignon, Y., Damiola, F., Mazoyer, S., Sinilnikova, O. M., Maxwell, C. A., Vijai, J., Robson, M., Kauff, N., Corines, M. J., Villano, D., Cunningham, J., Lee, A., Lindor, N., Lazaro, C., Easton, D. F., Offit, K., Chenevix-Trench, G., Couch, F. J., Antoniou, A. C., Angel Pujana, M., BCFR, SWE-BRCA, KConFab Investigators, GEMO 2015; 10 (4): e0120020

    Abstract

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

    View details for PubMedID 25830658

  • Generalizability of established prostate cancer risk variants in men of African ancestry INTERNATIONAL JOURNAL OF CANCER Han, Y., Signorello, L. B., Strom, S. S., Kittles, R. A., Rybicki, B. A., Stanford, J. L., Goodman, P. J., Berndt, S. I., Carpten, J., Casey, G., Chu, L., Conti, D. V., Rand, K. A., Diver, W. R., Hennis, A. J., John, E. M., Kibel, A. S., Klein, E. A., Kolb, S., Le Marchand, L., Leske, M. C., Murphy, A. B., Neslund-Dudas, C., Park, J. Y., Pettaway, C., Rebbeck, T. R., Gapstur, S. M., Zheng, S. L., Wu, S., Witte, J. S., Xu, J., Isaacs, W., Ingles, S. A., Hsing, A., Easton, D. F., Eeles, R. A., Schumacher, F. R., Chanock, S., Nemesure, B., Blot, W. J., Stram, D. O., Henderson, B. E., Haiman, C. A. 2015; 136 (5): 1210-1217

    Abstract

    Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR)?= 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

    View details for DOI 10.1002/ijc.29066

    View details for Web of Science ID 000346350500046

    View details for PubMedCentralID PMC4268262

  • MAPK Genes Interact with Diet and Lifestyle Factors to Alter Risk of Breast Cancer: The Breast Cancer Health Disparities Study NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL Slattery, M. L., Lundgreen, A., John, E. M., Torres-Mejia, G., Hines, L., Giuliano, A. R., Baumgartner, K. B., Stern, M. C., Wolff, R. K. 2015; 67 (2): 292-304

    Abstract

    Mitogen-activated protein kinases (MAPK) are integration points for multiple biochemical signals. We evaluated 13 MAPK genes with breast cancer risk and determined if diet and lifestyle factors mediated risk. Data from 3 population-based case-control studies conducted in Southwestern United States, California, and Mexico included 4183 controls and 3592 cases. Percent Indigenous American (IA) ancestry was determined from 104 ancestry informative markers. The adaptive rank truncated product (ARTP) was used to determine the significance of each gene and the pathway with breast cancer risk, by menopausal status, genetic ancestry level, and estrogen receptor (ER)/progesterone receptor (PR) strata. MAP3K9 was associated with breast cancer overall (P(ARTP) = 0.02) with strongest association among women with the highest IA ancestry (P(ARTP) = 0.04). Several SNPs in MAP3K9 were associated with ER+/PR+ tumors and interacted with dietary oxidative balance score (DOBS), dietary folate, body mass index (BMI), alcohol consumption, cigarette smoking, and a history of diabetes. DUSP4 and MAPK8 interacted with calories to alter breast cancer risk; MAPK1 interacted with DOBS, dietary fiber, folate, and BMI; MAP3K2 interacted with dietary fat; and MAPK14 interacted with dietary folate and BMI. The patterns of association across diet and lifestyle factors with similar biological properties for the same SNPs within genes provide support for associations.

    View details for DOI 10.1080/01635581.2015.990568

    View details for Web of Science ID 000350338300012

    View details for PubMedID 25629224

  • Diabetes and Other Comorbidities in Breast Cancer Survival by Race/Ethnicity: The California Breast Cancer Survivorship Consortium (CBCSC). Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Wu, A. H., Kurian, A. W., Kwan, M. L., John, E. M., Lu, Y., Keegan, T. H., Gomez, S. L., Cheng, I., Shariff-Marco, S., Caan, B. J., Lee, V. S., Sullivan-Halley, J., Tseng, C., Bernstein, L., Sposto, R., Vigen, C. 2015; 24 (2): 361-368

    Abstract

    Background:The role of comorbidities in survival of breast cancer patients has not been well studied, particularly in non-white populations. Methods:We investigated the association of specific comorbidities with mortality in a multiethnic cohort of 8,952 breast cancer cases within the California Breast Cancer Survivorship Consortium (CBCSC), which pooled questionnaire and cancer registry data from five California-based studies. In total, 2,187 deaths (1,122 from breast cancer) were observed through December 31, 2010. Using multivariable Cox proportional hazards regression, we estimated hazards ratios (HR) and 95% confidence intervals (CI) for overall and breast cancer-specific mortality associated with previous cancer, diabetes, high blood pressure (HBP), and myocardial infarction (MI). Results:Risk of breast cancer-specific mortality increased among breast cancer cases with a history of diabetes (HR=1.48, 95% CI=1.18, 1.87) or MI (HR=1.94, 95% CI=1.27-2.97). Risk patterns were similar across race/ethnicity (non-Latina White, Latina, African American and Asian American), body size, menopausal status, and stage at diagnosis. In subgroup analyses, risk of breast cancer-specific mortality was significantly elevated among cases with diabetes who received neither radiation nor chemotherapy (HR=2.11, 95% CI=1.32-3.36); no increased risk was observed among those who received both treatments (HR=1.13, 95% CI= 0.70-1.84) (P interaction= 0.03). A similar pattern was found for MI by radiation and chemotherapy (P interaction=0.09). Conclusion:These results may inform future treatment guidelines for breast cancer patients with a history of diabetes or MI. Impact:Given the growing number of breast cancer survivors worldwide, we need to better understand how comorbidities may adversely affect treatment decisions and ultimately outcome.

    View details for DOI 10.1158/1055-9965.EPI-14-1140

    View details for PubMedID 25425578

  • Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nature genetics Kuchenbaecker, K. B., Ramus, S. J., Tyrer, J., Lee, A., Shen, H. C., Beesley, J., Lawrenson, K., McGuffog, L., Healey, S., Lee, J. M., Spindler, T. J., Lin, Y. G., Pejovic, T., Bean, Y., Li, Q., Coetzee, S., Hazelett, D., Miron, A., Southey, M., Terry, M. B., Goldgar, D. E., Buys, S. S., Janavicius, R., Dorfling, C. M., Van Rensburg, E. J., Neuhausen, S. L., Ding, Y. C., Hansen, T. v., Jřnson, L., Gerdes, A., Ejlertsen, B., Barrowdale, D., Dennis, J., Benitez, J., Osorio, A., Garcia, M. J., Komenaka, I., Weitzel, J. N., Ganschow, P., Peterlongo, P., Bernard, L., Viel, A., Bonanni, B., Peissel, B., Manoukian, S., Radice, P., Papi, L., Ottini, L., Fostira, F., Konstantopoulou, I., Garber, J., Frost, D., Perkins, J., Platte, R., Ellis, S., Godwin, A. K., Schmutzler, R. K., Meindl, A., Engel, C., Sutter, C., Sinilnikova, O. M., Damiola, F., Mazoyer, S., Stoppa-Lyonnet, D., Claes, K., De Leeneer, K., Kirk, J., Rodriguez, G. C., Piedmonte, M., O'Malley, D. M., de la Hoya, M., Caldes, T., Aittomäki, K., Nevanlinna, H., Collée, J. M., Rookus, M. A., Oosterwijk, J. C., Tihomirova, L., Tung, N., Hamann, U., Isaccs, C., Tischkowitz, M., Imyanitov, E. N., Caligo, M. A., Campbell, I. G., Hogervorst, F. B., Olah, E., Diez, O., Blanco, I., Brunet, J., Lazaro, C., Pujana, M. A., Jakubowska, A., Gronwald, J., Lubinski, J., Sukiennicki, G., Barkardottir, R. B., Plante, M., Simard, J., Soucy, P., Montagna, M., Tognazzo, S., Teixeira, M. R., Pankratz, V. S., Wang, X., Lindor, N., Szabo, C. I., Kauff, N., Vijai, J., Aghajanian, C. A., Pfeiler, G., Berger, A., Singer, C. F., Tea, M., Phelan, C. M., Greene, M. H., Mai, P. L., Rennert, G., Mulligan, A. M., Tchatchou, S., Andrulis, I. L., Glendon, G., Toland, A. E., Jensen, U. B., Kruse, T. A., Thomassen, M., Bojesen, A., Zidan, J., friedman, e., Laitman, Y., Soller, M., Liljegren, A., Arver, B., Einbeigi, Z., Stenmark-Askmalm, M., Olopade, O. I., Nussbaum, R. L., Rebbeck, T. R., Nathanson, K. L., Domchek, S. M., Lu, K. H., Karlan, B. Y., Walsh, C., Lester, J., Hein, A., Ekici, A. B., Beckmann, M. W., Fasching, P. A., Lambrechts, D., van Nieuwenhuysen, E., Vergote, I., Lambrechts, S., Dicks, E., Doherty, J. A., Wicklund, K. G., Rossing, M. A., Rudolph, A., Chang-Claude, J., Wang-Gohrke, S., Eilber, U., Moysich, K. B., Odunsi, K., Sucheston, L., Lele, S., Wilkens, L. R., Goodman, M. T., Thompson, P. J., Shvetsov, Y. B., Runnebaum, I. B., Dürst, M., Hillemanns, P., Dörk, T., Antonenkova, N., Bogdanova, N., Leminen, A., Pelttari, L. M., Butzow, R., Modugno, F., Kelley, J. L., Edwards, R. P., Ness, R. B., du Bois, A., Heitz, F., Schwaab, I., Harter, P., Matsuo, K., Hosono, S., Orsulic, S., Jensen, A., Kjaer, S. K., Hogdall, E., Hasmad, H. N., Azmi, M. A., Teo, S., Woo, Y., Fridley, B. L., Goode, E. L., Cunningham, J. M., Vierkant, R. A., Bruinsma, F., Giles, G. G., Liang, D., Hildebrandt, M. A., Wu, X., Levine, D. A., Bisogna, M., Berchuck, A., Iversen, E. S., Schildkraut, J. M., Concannon, P., Weber, R. P., Cramer, D. W., Terry, K. L., Poole, E. M., Tworoger, S. S., Bandera, E. V., Orlow, I., Olson, S. H., Krakstad, C., Salvesen, H. B., Tangen, I. L., Bjorge, L., van Altena, A. M., Aben, K. K., Kiemeney, L. A., Massuger, L. F., Kellar, M., Brooks-Wilson, A., Kelemen, L. E., Cook, L. S., Le, N. D., Cybulski, C., Yang, H., Lissowska, J., Brinton, L. A., Wentzensen, N., Hogdall, C., Lundvall, L., Nedergaard, L., Baker, H., Song, H., Eccles, D., McNeish, I., Paul, J., Carty, K., Siddiqui, N., Glasspool, R., Whittemore, A. S., Rothstein, J. H., McGuire, V., Sieh, W., Ji, B., Zheng, W., Shu, X., Gao, Y., Rosen, B., Risch, H. A., McLaughlin, J. R., Narod, S. A., Monteiro, A. N., Chen, A., Lin, H., Permuth-Wey, J., Sellers, T. A., Tsai, Y., Chen, Z., Ziogas, A., Anton-Culver, H., Gentry-Maharaj, A., Menon, U., Harrington, P., Lee, A. W., Wu, A. H., Pearce, C. L., Coetzee, G., Pike, M. C., Dansonka-Mieszkowska, A., Timorek, A., Rzepecka, I. K., Kupryjanczyk, J., Freedman, M., Noushmehr, H., Easton, D. F., Offit, K., Couch, F. J., Gayther, S., Pharoah, P. P., Antoniou, A. C., Chenevix-Trench, G. 2015; 47 (2): 164-171

    Abstract

    Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

    View details for DOI 10.1038/ng.3185

    View details for PubMedID 25581431

  • Overall and abdominal adiposity and premenopausal breast cancer risk among hispanic women: the breast cancer health disparities study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology John, E. M., Sangaramoorthy, M., Hines, L. M., Stern, M. C., Baumgartner, K. B., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2015; 24 (1): 138-147

    Abstract

    Few studies in Hispanic women have examined the relation between adult body size and risk of premenopausal breast cancer defined by hormone receptor status.The Breast Cancer Health Disparities Study pooled interview and anthropometric data from two large U.S. population-based case-control studies. We examined associations of overall and abdominal adiposity with risk of estrogen receptor- and progesterone receptor-positive (ER(+)PR(+)) and -negative (ER(-)PR(-)) breast cancer in Hispanic and non-Hispanic White (NHW) women, calculating ORs and 95% confidence intervals.Among Hispanics, risk of ER(+)PR(+) breast cancer was inversely associated with measures of overall adiposity, including young-adult and current body mass index (BMI). Risk was substantially reduced among those with high (above the median) young-adult BMI and current overweight or obesity. The findings for overall adiposity were similar for Hispanics and NHWs. In the subset of Hispanics with data on genetic ancestry, inverse associations of current BMI, and weight gain with ER(+)PR(+) breast cancer were limited to those with lower Indigenous American ancestry. For ER(-)PR(-) breast cancer, height was associated with increased risk, and young-adult BMI was associated with reduced risk. For all breast cancers combined, positive associations were seen for waist circumference, waist-to-hip ratio, and waist-to-height ratio in Hispanic women only.Our findings of body size associations with specific breast cancer subtypes among premenopausal Hispanic women were similar to those reported for NHW women.Adiposity throughout the premenopausal years has a major influence on breast cancer risk in Hispanic women. Cancer Epidemiol Biomarkers Prev; 24(1); 138-47. ©2014 AACR. See related article by John et al., p. 128.

    View details for DOI 10.1158/1055-9965.EPI-13-1007-T

    View details for PubMedID 25352526

    View details for PubMedCentralID PMC4294975

  • Psychosocial Adjustment in School-age Girls With a Family History of Breast Cancer. Pediatrics Bradbury, A. R., Patrick-Miller, L., Schwartz, L., Egleston, B., Sands, C. B., Chung, W. K., Glendon, G., McDonald, J. A., Moore, C., Rauch, P., Tuchman, L., Andrulis, I. L., Buys, S. S., Frost, C. J., Keegan, T. H., Knight, J. A., Terry, M. B., John, E. M., Daly, M. B. 2015; 136 (5): 927?37

    Abstract

    Understanding how young girls respond to growing up with breast cancer family histories is critical given expansion of genetic testing and breast cancer messaging. We examined the impact of breast cancer family history on psychosocial adjustment and health behaviors among >800 girls in the multicenter LEGACY Girls Study.Girls aged 6 to 13 years with a family history of breast cancer or familial BRCA1/2 mutation (BCFH+), peers without a family history (BCFH-), and their biological mothers completed assessments of psychosocial adjustment (maternal report for 6- to 13-year-olds, self-report for 10- to 13-year-olds), breast cancer-specific distress, perceived risk of breast cancer, and health behaviors (10- to 13-year-olds).BCFH+ girls had better general psychosocial adjustment than BCFH- peers by maternal report. Psychosocial adjustment and health behaviors did not differ significantly by self-report among 10- to 13-year-old girls. BCFH+ girls reported higher breast cancer-specific distress (P = .001) and were more likely to report themselves at increased breast cancer risk than BCFH- peers (38.4% vs 13.7%, P < .001), although many girls were unsure of their risk. In multivariable analyses, higher daughter anxiety was associated with higher maternal anxiety and poorer family communication. Higher daughter breast cancer-specific distress was associated with higher maternal breast cancer-specific distress.Although growing up in a family at risk for breast cancer does not negatively affect general psychosocial adjustment among preadolescent girls, those from breast cancer risk families experience greater breast cancer-specific distress. Interventions to address daughter and mother breast cancer concerns and responses to genetic or familial risk might improve psychosocial outcomes of teen daughters.

    View details for PubMedID 26482668

    View details for PubMedCentralID PMC4972044

  • Reproductive factors, tumor estrogen receptor status and contralateral breast cancer risk: results from the WECARE study. SpringerPlus Sisti, J. S., Bernstein, J. L., Lynch, C. F., Reiner, A. S., Mellemkjaer, L., Brooks, J. D., Knight, J. A., Bernstein, L., Malone, K. E., Woods, M., Liang, X., John, E. M. 2015; 4: 825

    Abstract

    Several reproductive factors are known to be associated with risk of breast cancer; however, relationships between these factors with risk of second primary asynchronous contralateral breast cancer (CBC) have not been widely studied. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) Study is a population-based case-control study of 1521 CBC cases and 2212 individually matched controls with unilateral breast cancer. Using multivariable conditional logistic regression models, we examined associations between reproductive factors and CBC risk, and whether associations differed by estrogen receptor (ER) status and menopausal status of the first breast cancer. Older age at menarche was inversely associated with CBC risk (?14 vs. ?11 years risk ratio (RR) = 0.82, 95 % confidence interval (CI) 0.65-1.03, P trend = 0.02). Among parous women, an increasing number of full-term pregnancies (FTP) was inversely associated with risk (?4 vs. 1 FTP RR = 0.60, 95 % CI 0.41-0.88, P trend = 0.005). Ever breast-feeding was inversely associated with CBC risk only among women with ER-negative first tumors (ever vs. never breast-fed RR = 0.69, 95 % CI 0.48-1.00, P heterogeneity = 0.05). Older age at first FTP was inversely associated with CBC risk among women with ER-negative first tumors (?30 vs. <20 years old RR = 0.66, 95 % CI 0.35-1.27, P trend = 0.03), but suggestively positively associated with risk among women with ER-positive first tumors (P heterogeneity = 0.03). Young age at menarche and low parity, both risk factors for first primary breast cancer, were also associated with overall CBC risk. Reductions in risk associated with breast-feeding were limited to women with ER-negative first tumors, who are at higher CBC risk than women with ER-positive primaries.

    View details for PubMedID 26751177

  • Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults. PloS one Chen, F., He, J., Zhang, J., Chen, G. K., Thomas, V., Ambrosone, C. B., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Cai, Q., Carpten, J., Casey, G., Chanock, S. J., Cheng, I., Chu, L., Deming, S. L., Driver, W. R., Goodman, P., Hayes, R. B., Hennis, A. J., Hsing, A. W., Hu, J. J., Ingles, S. A., John, E. M., Kittles, R. A., Kolb, S., Leske, M. C., Millikan, R. C., Monroe, K. R., Murphy, A., Nemesure, B., Neslund-Dudas, C., Nyante, S., Ostrander, E. A., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schumacher, F., Stanford, J. L., Signorello, L. B., Strom, S. S., Stevens, V., Van Den Berg, D., Wang, Z., Witte, J. S., Wu, S., Yamamura, Y., Zheng, W., Ziegler, R. G., Stram, A. H., Kolonel, L. N., Le Marchand, L., Henderson, B. E., Haiman, C. A., Stram, D. O. 2015; 10 (6)

    Abstract

    Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.

    View details for DOI 10.1371/journal.pone.0131106

    View details for PubMedID 26125186

  • Body size throughout adult life influences postmenopausal breast cancer risk among hispanic women: the breast cancer health disparities study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology John, E. M., Sangaramoorthy, M., Hines, L. M., Stern, M. C., Baumgartner, K. B., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2015; 24 (1): 128-137

    Abstract

    Few studies have assessed the association of body size with postmenopausal breast cancer risk in Hispanic women. Findings are inconsistent and appear to contradict those reported for non-Hispanic white (NHW) women.We pooled interview and anthropometric data for 2,023 Hispanic and 2,384 NHW women from two U.S. population-based case-control studies. Using logistic regression analysis, we examined associations of overall and abdominal adiposity with risk of postmenopausal breast cancer defined by estrogen receptor (ER) and progesterone receptor (PR) status.Weight gain was associated with increased risk of ER(+)PR(+) breast cancer in Hispanics not currently using menopausal hormone therapy (HT), but only among those with a low young-adult body mass index (BMI). In the subset of Hispanics with data on genetic ancestry, the association with weight gain was limited to women with lower Indigenous American ancestry. Young-adult BMI was inversely associated with both ER(+)PR(+) and ER(-)PR(-) breast cancers for both ethnicities combined, with similar, although nonsignificant, inverse trends in Hispanics and NHWs. Among all Hispanics, regardless of HT use, height was associated with risk of ER(-)PR(-) breast cancer and hip circumference with risk of breast cancer overall.Body size throughout adult life is associated with breast cancer risk among postmenopausal Hispanic women, as has been reported for NHW women. Associations were specific for breast cancer subtypes defined by hormone receptor status.Avoiding weight gain and maintaining a healthy weight are important strategies to reduce the risk of postmenopausal ER(+)PR(+) breast cancer, the most common breast cancer subtype. Cancer Epidemiol Biomarkers Prev; 24(1); 128-37. ©2014 AACR. See related article by John et al., p. 138.

    View details for DOI 10.1158/1055-9965.EPI-14-0560

    View details for PubMedID 25352523

    View details for PubMedCentralID PMC4295775

  • Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers BREAST CANCER RESEARCH Kuchenbaecker, K. B., Neuhausen, S. L., Robson, M., Barrowdale, D., McGuffog, L., Mulligan, A., Andrulis, I. L., Spurdle, A. B., Schmidt, M. K., Schmutzler, R. K., Engel, C., Wappenschmidt, B., Nevanlinna, H., Thomassen, M., Southey, M., Radice, P., Ramus, S. J., Domchek, S. M., Nathanson, K. L., Lee, A., Healey, S., Nussbaum, R. L., Rebbeck, T. R., Arun, B. K., James, P., Karlan, B. Y., Lester, J., Cass, I., Terry, M., Daly, M. B., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., van Rensburg, E. J., Steele, L., Hansen, T. O., Ejlertsen, B., Gerdes, A., Nielsen, F. C., Dennis, J., Cunningham, J., Hart, S., Slager, S., Osorio, A., Benitez, J., Duran, M., Weitzel, J. N., Tafur, I., Hander, M., Peterlongo, P., Manoukian, S., Peissel, B., Roversi, G., Scuvera, G., Bonanni, B., Mariani, P., Volorio, S., Dolcetti, R., Varesco, L., Papi, L., Tibiletti, M., Giannini, G., Fostira, F., Konstantopoulou, I., Garber, J., Hamann, U., Donaldson, A., Brewer, C., Foo, C., Evans, D., Frost, D., Eccles, D., Douglas, F., Brady, A., Cook, J., Tischkowitz, M., Adlard, J., Barwell, J., Ong, K., Walker, L., Izatt, L., Side, L. E., Kennedy, M., Rogers, M. T., Porteous, M. E., Morrison, P. J., Platte, R., Eeles, R., Davidson, R., Hodgson, S., Ellis, S., Godwin, A. K., Rhiem, K., Meindl, A., Ditsch, N., Arnold, N., Plendl, H., Niederacher, D., Sutter, C., Steinemann, D., Bogdanova-Markov, N., Kast, K., Varon-Mateeva, R., Wang-Gohrke, S., Gehrig, A., Markiefka, B., Buecher, B., Lefol, C., Stoppa-Lyonnet, D., Rouleau, E., Prieur, F., Damiola, F., Barjhoux, L., Faivre, L., Longy, M., Sevenet, N., Sinilnikova, O. M., Mazoyer, S., Bonadona, V., Caux-Moncoutier, V., Isaacs, C., Van Maerken, T., Claes, K., Piedmonte, M., Andrews, L., Hays, J., Rodriguez, G. C., Caldes, T., de la Hoya, M., Khan, S., Hogervorst, F. L., Aalfs, C. M., de lange, J. L., Meijers-Heijboer, H. J., van der Hout, A. H., Wijnen, J. T., van Roozendaal, K. P., Mensenkamp, A. R., van den Ouweland, A. W., van Deurzen, C. M., van der Luijt, R. B., Olah, E., Diez, O., Lazaro, C., Blanco, I., Teule, A., Menendez, M., Jakubowska, A., Lubinski, J., Cybulski, C., Gronwald, J., Jaworska-Bieniek, K., Durda, K., Arason, A., Maugard, C., Soucy, P., Montagna, M., Agata, S., Teixeira, M. R., Olswold, C., Lindor, N., Pankratz, V. S., Hallberg, E., Wang, X., Szabo, C. I., Vijai, J., Jacobs, L., Corines, M., Lincoln, A., Berger, A., Fink-Retter, A., Singer, C. F., Rappaport, C., Kaulich, D., Pfeiler, G., Tea, M., Phelan, C. M., Mai, P. L., Greene, M. H., Rennert, G., Imyanitov, E. N., Glendon, G., Toland, A., Bojesen, A., Pedersen, I., Jensen, U., Caligo, M. A., Friedman, E., Berger, R., Laitman, Y., Rantala, J., Arver, B., Loman, N., Borg, A., Ehrencrona, H., Olopade, O. I., Simard, J., Easton, D. F., Chenevix-Trench, G., Offit, K., Couch, F. J., Antoniou, A. C., Breast Canc Family Registry, EMBRACE Study, GEMO Study Collaborators, HEBON, KConFab Investigators, CIMBA 2014; 16: 3416

    Abstract

    More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)?=?0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC?=?0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC?=?0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement.Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

    View details for DOI 10.1186/s13058-014-0492-9

    View details for Web of Science ID 000209772500001

    View details for PubMedID 25919761

    View details for PubMedCentralID PMC4406179

  • Diet and lifestyle factors modify immune/inflammation response genes to alter breast cancer risk and prognosis: The Breast Cancer Health Disparities Study MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS Slattery, M. L., Lundgreen, A., Torres-Mejia, G., Wolff, R. K., Hines, L., Baumgartner, K., John, E. M. 2014; 770: 19-28

    Abstract

    Tumor necrosis factor-? (TNF) and toll-like receptors (TLR) are important mediators of inflammation. We examined 10 of these genes with respect to breast cancer risk and mortality in a genetically admixed population of Hispanic/Native American (NA) (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1585 controls) women. Additionally, we explored if diet and lifestyle factors modified associations with these genes. Overall, these genes (collectively) were associated with breast cancer risk among women with >70% NA ancestry (P(ARTP) = 0.0008), with TLR1 rs7696175 being the primary risk contributor (OR 1.77, 95% CI 1.25, 2.51). Overall, TLR1 rs7696175 (HR 1.40, 95% CI 1.03, 1.91; P(adj) = 0.032), TLR4 rs5030728 (HR 1.96, 95% CI 1.30, 2.95; P(adj) = 0.014), and TNFRSF1A rs4149578 (HR 2.71, 95% CI 1.28, 5.76; P(adj) = 0.029) were associated with increased breast cancer mortality. We observed several statistically significant interactions after adjustment for multiple comparisons, including interactions between our dietary oxidative balance score and CD40LG and TNFSF1A; between cigarette smoking and TLR1, TLR4, and TNF; between body mass index (BMI) among pre-menopausal women and TRAF2; and between regular use of aspirin/non-steroidal anti-inflammatory drugs and TLR3 and TRA2. In conclusion, our findings support a contributing role of certain TNF-? and TLR genes in both breast cancer risk and survival, particularly among women with higher NA ancestry. Diet and lifestyle factors appear to be important mediators of the breast cancer risk associated with these genes.

    View details for DOI 10.1016/j.mrfmmm.2014.08.009

    View details for Web of Science ID 000345647400003

    View details for PubMedCentralID PMC4201121

  • Tobacco smoking, polymorphisms in carcinogen metabolism enzyme genes, and risk of localized and advanced prostate cancer: results from the California Collaborative Prostate Cancer Study CANCER MEDICINE Shahabi, A., Corral, R., Catsburg, C., Joshi, A. D., Kim, A., Lewinger, J. P., Koo, J., John, E. M., Ingles, S. A., Stern, M. C. 2014; 3 (6): 1644-1655

    Abstract

    The relationship between tobacco smoking and prostate cancer (PCa) remains inconclusive. This study examined the association between tobacco smoking and PCa risk taking into account polymorphisms in carcinogen metabolism enzyme genes as possible effect modifiers (9 polymorphisms and 1 predicted phenotype from metabolism enzyme genes). The study included cases (n = 761 localized; n = 1199 advanced) and controls (n = 1139) from the multiethnic California Collaborative Case-Control Study of Prostate Cancer. Multivariable conditional logistic regression was performed to evaluate the association between tobacco smoking variables and risk of localized and advanced PCa risk. Being a former smoker, regardless of time of quit smoking, was associated with an increased risk of localized PCa (odds ratio [OR] = 1.3; 95% confidence interval [CI] = 1.0-1.6). Among non-Hispanic Whites, ever smoking was associated with an increased risk of localized PCa (OR = 1.5; 95% CI = 1.1-2.1), whereas current smoking was associated with risk of advanced PCa (OR = 1.4; 95% CI = 1.0-1.9). However, no associations were observed between smoking intensity, duration or pack-year variables, and advanced PCa. No statistically significant trends were seen among Hispanics or African-Americans. The relationship between smoking status and PCa risk was modified by the CYP1A2 rs7662551 polymorphism (P-interaction = 0.008). In conclusion, tobacco smoking was associated with risk of PCa, primarily localized disease among non-Hispanic Whites. This association was modified by a genetic variant in CYP1A2, thus supporting a role for tobacco carcinogens in PCa risk.

    View details for DOI 10.1002/cam4.334

    View details for Web of Science ID 000348226000020

    View details for PubMedID 25355624

    View details for PubMedCentralID PMC4298391

  • Associations between CYP19A1 polymorphisms, Native American ancestry, and breast cancer risk and mortality: the Breast Cancer Health Disparities Study CANCER CAUSES & CONTROL Boone, S. D., Baumgartner, K. B., Baumgartner, R. N., Connor, A. E., Pinkston, C. M., Rai, S. N., Riley, E. C., Hines, L. M., Giuliano, A. R., John, E. M., Stern, M. C., Torres-Mejia, G., Wolff, R. K., Slattery, M. L. 2014; 25 (11): 1461-1471

    Abstract

    The cytochrome p450 family 19 gene (CYP19A1) encodes for aromatase, which catalyzes the final step in estrogen biosynthesis and conversion of androgens to estrogens. Genetic variation in CYP19A1 is linked to higher circulating estrogen levels and increased aromatase expression. Using data from the Breast Cancer Health Disparities Study, a consortium of three population-based case-control studies in the United States (n = 3,030 non-Hispanic Whites; n = 2,893 Hispanic/Native Americans (H/NA) and Mexico (n = 1,810), we examined influence of 25 CYP19A1 tagging single-nucleotide polymorphisms (SNPs) on breast cancer risk and mortality, considering NA ancestry. Odds ratios (ORs) and 95 % confidence intervals (CIs) and hazard ratios estimated breast cancer risk and mortality. After multiple comparison adjustment, none of the SNPs were significantly associated with breast cancer risk or mortality. Two SNPs remained significantly associated with increased breast cancer risk in women of moderate to high NA ancestry (?29 %): rs700518, ORGG 1.36, 95 % CI 1.11-1.67 and rs11856927, ORGG 1.35, 95 % CI 1.05-1.72. A significant interaction was observed for rs2470144 and menopausal status (p adj = 0.03); risk was increased in postmenopausal (ORAA 1.22, 95 % CI 1.05-1.14), but not premenopausal (ORAA 0.78, 95 % CI 0.64-0.95) women. The absence of an overall association with CYP19A1 and breast cancer risk is similar to previous literature. However, this analysis provides support that variation in CYP19A1 may influence breast cancer risk differently in women with moderate to high NA ancestry. Additional research is warranted to investigate the how variation in an estrogen-regulating gene contributes to racial/ethnic disparities in breast cancer.

    View details for DOI 10.1007/s10552-014-0448-5

    View details for Web of Science ID 000344532000004

    View details for PubMedCentralID PMC4435673

  • A comprehensive examination of breast cancer risk loci in African American women HUMAN MOLECULAR GENETICS Feng, Y., Stram, D. O., Rhie, S. K., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Olshan, A. F., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Palmer, J. R., Olopade, O. I., Huo, D., Adebamowo, C. A., Ogundiran, T., Chen, G. K., Stram, A., Park, K., Rand, K. A., Chanock, S. J., Le Marchand, L., Kolonel, L. N., Conti, D. V., Easton, D., Henderson, B. E., Haiman, C. A. 2014; 23 (20): 5518-5526

    Abstract

    Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American women. In this study of breast cancer in African American women (3016 cases, 2745 controls), we tested an additional 54 novel breast cancer risk variants. Thirty-eight variants (70%) were found to have an association with breast cancer in the same direction as previously reported, with eight (15%) replicating at P < 0.05. Through fine-mapping, in three regions (1q32, 3p24, 10q25), we identified variants that better captured associations with overall breast cancer or estrogen receptor positive disease. We also observed suggestive associations with variants (at P < 5 × 10(-6)) in three separate regions (6q25, 14q13, 22q12) that may represent novel risk variants. Directional consistency of association observed for ?65-70% of currently known genetic variants for breast cancer in women of African ancestry implies a shared functional common variant at most loci. To validate and enhance the spectrum of alleles that define associations at the known breast cancer risk loci, as well as genome-wide, will require even larger collaborative efforts in women of African ancestry.

    View details for DOI 10.1093/hmg/ddu252

    View details for Web of Science ID 000343202400018

    View details for PubMedCentralID PMC4168823

  • Genome-wide Scan of 29,141 African Americans Finds No Evidence of Directional Selection since Admixture AMERICAN JOURNAL OF HUMAN GENETICS Bhatia, G., Tandon, A., Patterson, N., Aldrich, M. C., Ambrosone, C. B., Amos, C., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Bock, C. H., Caporaso, N., Casey, G., Deming, S. L., Diver, W. R., Gapstur, S. M., Gillanders, E. M., Harris, C. C., Henderson, B. E., Ingles, S. A., Isaacs, W., De Jager, P. L., John, E. M., Kittles, R. A., Larkin, E., McNeill, L. H., Millikan, R. C., Murphy, A., Neslund-Dudas, C., Nyante, S., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schwartz, A. G., Signorello, L. B., Spitz, M., Strom, S. S., Tucker, M. A., Wiencke, J. K., Witte, J. S., Wu, X., Yamamura, Y., Zanetti, K. A., Zheng, W., Ziegler, R. G., Chanock, S. J., Haiman, C. A., Reich, D., Price, A. L. 2014; 95 (4): 437-444

    Abstract

    The extent of recent selection in admixed populations is currently an unresolved question. We scanned the genomes of 29,141 African Americans and failed to find any genome-wide-significant deviations in local ancestry, indicating no evidence of selection influencing ancestry after admixture. A recent analysis of data from 1,890 African Americans reported that there was evidence of selection in African Americans after their ancestors left Africa, both before and after admixture. Selection after admixture was reported on the basis of deviations in local ancestry, and selection before admixture was reported on the basis of allele-frequency differences between African Americans and African populations. The local-ancestry deviations reported by the previous study did not replicate in our very large sample, and we show that such deviations were expected purely by chance, given the number of hypotheses tested. We further show that the previous study's conclusion of selection in African Americans before admixture is also subject to doubt. This is because the FST statistics they used were inflated and because true signals of unusual allele-frequency differences between African Americans and African populations would be best explained by selection that occurred in Africa prior to migration to the Americas.

    View details for DOI 10.1016/j.ajhg.2014.08.011

    View details for Web of Science ID 000342654300008

    View details for PubMedCentralID PMC4185117

  • Neighborhood influences on recreational physical activity and survival after breast cancer CANCER CAUSES & CONTROL Keegan, T. H., Shariff-Marco, S., Sangaramoorthy, M., Koo, J., Hertz, A., Schupp, C. W., Yang, J., John, E. M., Gomez, S. L. 2014; 25 (10): 1295-1308

    Abstract

    Higher levels of physical activity have been associated with improved survival after breast cancer diagnosis. However, no previous studies have considered the influence of the social and built environment on physical activity and survival among breast cancer patients.Our study included 4,345 women diagnosed with breast cancer (1995-2008) from two population-based studies conducted in the San Francisco Bay Area. We examined questionnaire-based moderate/strenuous recreational physical activity during the 3 years before diagnosis. Neighborhood characteristics were based on data from the 2000 US Census, business listings, parks, farmers' markets, and Department of Transportation. Survival was evaluated using multivariable Cox proportional hazards models, with follow-up through 2009.Women residing in neighborhoods with no fast-food restaurants (vs. fewer fast-food restaurants) to other restaurants, high traffic density, and a high percentage of foreign-born residents were less likely to meet physical activity recommendations set by the American Cancer Society. Women who were not recreationally physically active had a 22% higher risk of death from any cause than women that were the most active. Poorer overall survival was associated with lower neighborhood socioeconomic status (SES) (p(trend) = 0.02), whereas better breast cancer-specific survival was associated with a lack of parks, especially among women in high-SES neighborhoods.Certain aspects of the neighborhood have independent associations with recreational physical activity among breast cancer patients and their survival. Considering neighborhood factors may aide in the design of more effective, tailored physical activity programs for breast cancer survivors.

    View details for DOI 10.1007/s10552-014-0431-1

    View details for Web of Science ID 000343718900006

    View details for PubMedCentralID PMC4194215

  • A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nature genetics Al Olama, A. A., Kote-Jarai, Z., Berndt, S. I., Conti, D. V., Schumacher, F., Han, Y., Benlloch, S., Hazelett, D. J., Wang, Z., Saunders, E., Leongamornlert, D., Lindstrom, S., Jugurnauth-Little, S., Dadaev, T., Tymrakiewicz, M., Stram, D. O., Rand, K., Wan, P., Stram, A., Sheng, X., Pooler, L. C., Park, K., Xia, L., Tyrer, J., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Yeager, M., Burdette, L., Chung, C. C., Hutchinson, A., Yu, K., Goh, C., Ahmed, M., Govindasami, K., Guy, M., Tammela, T. L., Auvinen, A., Wahlfors, T., Schleutker, J., Visakorpi, T., Leinonen, K. A., Xu, J., Aly, M., Donovan, J., Travis, R. C., Key, T. J., Siddiq, A., Canzian, F., Khaw, K., Takahashi, A., Kubo, M., Pharoah, P., Pashayan, N., Weischer, M., Nordestgaard, B. G., Nielsen, S. F., Klarskov, P., Rřder, M. A., Iversen, P., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Stanford, J. L., Kolb, S., Holt, S., Knudsen, B., Coll, A. H., Gapstur, S. M., Diver, W. R., Stevens, V. L., Maier, C., Luedeke, M., Herkommer, K., Rinckleb, A. E., Strom, S. S., Pettaway, C., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., Cannon-Albright, L., Cybulski, C., Wokolorczyk, D., Kluzniak, W., Park, J., Sellers, T., Lin, H., Isaacs, W. B., Partin, A. W., Brenner, H., Dieffenbach, A. K., Stegmaier, C., Chen, C., Giovannucci, E. L., Ma, J., Stampfer, M., Penney, K. L., Mucci, L., John, E. M., Ingles, S. A., Kittles, R. A., Murphy, A. B., Pandha, H., Michael, A., Kierzek, A. M., Blot, W., Signorello, L. B., Zheng, W., Albanes, D., Virtamo, J., Weinstein, S., Nemesure, B., Carpten, J., Leske, C., Wu, S., Hennis, A., Kibel, A. S., Rybicki, B. A., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Batra, J., Clements, J., Spurdle, A., Teixeira, M. R., Paulo, P., Maia, S., Slavov, C., Kaneva, R., Mitev, V., Witte, J. S., Casey, G., Gillanders, E. M., Seminara, D., Riboli, E., Hamdy, F. C., Coetzee, G. A., Li, Q., Freedman, M. L., Hunter, D. J., Muir, K., Gronberg, H., Neal, D. E., Southey, M., Giles, G. G., Severi, G., Cook, M. B., Nakagawa, H., Wiklund, F., Kraft, P., Chanock, S. J., Henderson, B. E., Easton, D. F., Eeles, R. A., Haiman, C. A. 2014; 46 (10): 1103-1109

    Abstract

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

    View details for DOI 10.1038/ng.3094

    View details for PubMedID 25217961

  • Neighborhood influences on recreational physical activity and survival after breast cancer. Cancer causes & control Keegan, T. H., Shariff-Marco, S., Sangaramoorthy, M., Koo, J., Hertz, A., Schupp, C. W., Yang, J., John, E. M., Gomez, S. L. 2014; 25 (10): 1295-1308

    Abstract

    Higher levels of physical activity have been associated with improved survival after breast cancer diagnosis. However, no previous studies have considered the influence of the social and built environment on physical activity and survival among breast cancer patients.Our study included 4,345 women diagnosed with breast cancer (1995-2008) from two population-based studies conducted in the San Francisco Bay Area. We examined questionnaire-based moderate/strenuous recreational physical activity during the 3 years before diagnosis. Neighborhood characteristics were based on data from the 2000 US Census, business listings, parks, farmers' markets, and Department of Transportation. Survival was evaluated using multivariable Cox proportional hazards models, with follow-up through 2009.Women residing in neighborhoods with no fast-food restaurants (vs. fewer fast-food restaurants) to other restaurants, high traffic density, and a high percentage of foreign-born residents were less likely to meet physical activity recommendations set by the American Cancer Society. Women who were not recreationally physically active had a 22% higher risk of death from any cause than women that were the most active. Poorer overall survival was associated with lower neighborhood socioeconomic status (SES) (p(trend) = 0.02), whereas better breast cancer-specific survival was associated with a lack of parks, especially among women in high-SES neighborhoods.Certain aspects of the neighborhood have independent associations with recreational physical activity among breast cancer patients and their survival. Considering neighborhood factors may aide in the design of more effective, tailored physical activity programs for breast cancer survivors.

    View details for DOI 10.1007/s10552-014-0431-1

    View details for PubMedID 25088804

    View details for PubMedCentralID PMC4194215

  • A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer NATURE GENETICS Al Olama, A. A., Kote-Jarai, Z., Berndt, S. I., Conti, D. V., Schumacher, F., Han, Y., Benlloch, S., Hazelett, D. J., Wang, Z., Saunders, E., Leongamornlert, D., Lindstrom, S., Jugurnauth-Little, S., Dadaev, T., Tymrakiewicz, M., Stram, D. O., Rand, K., Wan, P., Stram, A., Sheng, X., Pooler, L. C., Park, K., Xia, L., Tyrer, J., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Yeager, M., Burdette, L., Chung, C. C., Hutchinson, A., Yu, K., Goh, C., Ahmed, M., Govindasami, K., Guy, M., Tammela, T. L., Auvinen, A., Wahlfors, T., Schleutker, J., Visakorpi, T., Leinonen, K. A., Xu, J., Aly, M., Donovan, J., Travis, R. C., Key, T. J., Siddiq, A., Canzian, F., Khaw, K., Takahashi, A., Kubo, M., Pharoah, P., Pashayan, N., Weischer, M., Nordestgaard, B. G., Nielsen, S. F., Klarskov, P., Roder, M. A., Iversen, P., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Stanford, J. L., Kolb, S., Holt, S., Knudsen, B., Coll, A. H., Gapstur, S. M., Diver, W. R., Stevens, V. L., Maier, C., Luedeke, M., Herkommer, K., Rinckleb, A. E., Strom, S. S., Pettaway, C., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Choklcalingam, A. P., Cannon-Albright, L., Cybulski, C., Wokolorczyk, D., Kluzniak, W., Park, J., Sellers, T., Lin, H., Isaacs, W. B., Partin, A. W., Brenner, H., Dieffenbach, A. K., Stegmaier, C., Chen, C., Giovannucci, E. L., Ma, J., Stampfer, M., Penney, K. L., Mucci, L., John, E. M., Ingles, S. A., Kittles, R. A., Murphy, A. B., Pandha, H., Michael, A., Kierzek, A. M., Blot, W., Signorello, L. B., Zheng, W., Albanes, D., Virtamo, J., Weinstein, S., Nemesure, B., Carpten, J., Leske, C., Wu, S., Hennis, A., Kibel, A. S., Rybicki, B. A., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Batra, J., Clements, J., Spurdle, A., Teixeira, M. R., Paulo, P., Maia, S., Slavov, C., Kaneva, R., Mitev, V., Witte, J. S., Casey, G., Gillanders, E. M., Seminara, D., Riboli, E., Hamdy, F. C., Coetzee, G. A., Li, Q., Freedman, M. L., Hunter, D. J., Muir, K., Gronberg, H., Nea, D. E., Southey, M., Giles, G. G., Severi, G., Cook, M. B., Nakagawa, H., Wiklund, F., Kraft, P., Chanock, S. J., Henderson, B. E., Easton, D. F., Eeles, R. A., Haiman, C. A. 2014; 46 (10): 1103-1109

    Abstract

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

    View details for DOI 10.1038/ng.3094

    View details for Web of Science ID 000342554100013

  • Genome wide association study of breast cancer in Latinas identifies protective variants of Indigenous American origin on 6q25 Fejerman, L., Ahmadiyeh, N., Hu, D., Huntsman, S., Beckman, K., Caswell, J., John, E. M., Torres-Mejia, G., Carvajal-Carmona, L., Echeverry, M., Tuazon, A., Ramirez, C., Gignoux, C., Eng, C., Gonzalez-Burchard, E., Henderson, B., Marchand, L. L., Perez-Stable, E. J., Haiman, C. A., Ziv, E., COLUMBUS Consortium AMER ASSOC CANCER RESEARCH. 2014
  • Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25 NATURE COMMUNICATIONS Fejerman, L., Ahmadiyeh, N., Hu, D., Huntsman, S., Beckman, K. B., Caswell, J. L., Tsung, K., John, E. M., Torres-Mejia, G., Carvajal-Carmona, L., Echeverry, M. M., Tuazon, A. M., Ramirez, C., Gignoux, C. R., Eng, C., Gonzalez-Burchard, E., Henderson, B., Le Marchand, L., Kooperberg, C., Hou, L., Agalliu, I., Kraft, P., Lindstroem, S., Perez-Stable, E. J., Haiman, C. A., Ziv, E. 2014; 5

    Abstract

    The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5' of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53-0.67, P=9 × 10(-18)), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49-0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.

    View details for DOI 10.1038/ncomms6260

    View details for Web of Science ID 000343985400009

    View details for PubMedCentralID PMC4204111

  • Diet and lifestyle factors interact with MAPK genes to influence survival: the Breast Cancer Health Disparities Study CANCER CAUSES & CONTROL Slattery, M. L., Hines, L. H., Lundgreen, A., Baumgartner, K. B., Wolff, R. K., Stern, M. C., John, E. M. 2014; 25 (9): 1211-1225

    Abstract

    MAPK genes are activated by a variety of factors related to growth factors, hormones, and environmental stress.We evaluated associations between 13 MAPK genes and survival among 1,187 nonHispanic White and 1,155 Hispanic/Native American (NA) women diagnosed with breast cancer. We assessed the influence of diet, lifestyle, and genetic ancestry on these associations. Percent NA ancestry was determined from 104 Ancestry Informative Markers. Adaptive rank truncation product (ARTP) was used to determine gene and pathway significance.Associations were predominantly observed among women with lower NA ancestry. Specifically, the mitogen-activated protein kinases (MAPK) pathway was associated with all-cause mortality (P ARTP = 0.02), but not with breast cancer-specific mortality (P ARTP = 0.10). However, MAP2K1 and MAP3K9 were associated with both breast cancer-specific and all-cause mortality. MAPK12 (P ARTP = 0.05) was only associated with breast cancer-specific mortality, and MAP3K1 (P ARTP = 0.02) and MAPK1 (P ARTP = 0.05) were only associated with all-cause mortality. Among women with higher NA ancestry, MAP3K2 was significantly associated with all-cause mortality (P ARTP = 0.04). Several diet and lifestyle factors, including alcohol consumption, caloric intake, dietary folate, and cigarette smoking, significantly modified the associations with MAPK genes and all-cause mortality.Our study supports an association between MAPK genes and survival after diagnosis with breast cancer, especially among women with low NA ancestry. The interaction between genetic variation in the MAPK pathway with diet and lifestyle factors for all women supports the important role of these factors for breast cancer survivorship.

    View details for DOI 10.1007/s10552-014-0426-y

    View details for Web of Science ID 000341784400013

    View details for PubMedID 24993294

    View details for PubMedCentralID PMC4156917

  • Human subjects protection: an event monitoring committee for research studies of girls from breast cancer families. journal of adolescent health Harris, D., Patrick-Miller, L., Schwartz, L., Lantos, J., Daugherty, C., Daly, M., Andrulis, I. L., Buys, S. S., Chung, W. K., Frost, C. J., John, E. M., Keegan, T. H., Knight, J. A., Terry, M. B., Bradbury, A. R. 2014; 55 (3): 352-357

    Abstract

    Researchers must monitor the safety of research participants, particularly in studies involving children and adolescents. Yet, there is limited guidance for the development and implementation of oversight committees for psychosocial, behavioral intervention, and observational studies.We implemented a model for an Event Monitoring Committee (EMC) in three related studies recruiting 6- to 19-year-old girls from families with and without breast cancer.The EMC model can be valuable for investigators and local institutional review boards when additional oversight is desired. Recommendations are provided and intended to be broadly applicable to a wide range of research activities designed to improve the health of children, adolescents, and families. EMC goals, membership, and procedures for monitoring and assessing risks and benefits should be defined but should also be flexible and tailored to the study design and population. The EMC model also provides an independent comprehensive, study-wide oversight mechanism for multicenter psychosocial, behavioral intervention, and observational studies.An EMC provides an alternative oversight approach where additional independent assessment and oversight of study-related risks are desired, particularly in the setting of vulnerable populations, children and adolescents, or where risks nontraditional to the medical field (i.e., social, emotional, or cultural) are possible.

    View details for DOI 10.1016/j.jadohealth.2014.03.007

    View details for PubMedID 24845866

  • Genetic variation in the JAK/STAT/SOCS signaling pathway influences breast cancer-specific mortality through interaction with cigarette smoking and use of aspirin/NSAIDs: the Breast Cancer Health Disparities Study BREAST CANCER RESEARCH AND TREATMENT Slattery, M. L., Lundgreen, A., Hines, L. M., Torres-Mejia, G., Wolff, R. K., Stern, M. C., John, E. M. 2014; 147 (1): 145-158

    Abstract

    The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth; genetic variation in this pathway could influence breast cancer risk. We examined 12 genes in the JAK/STAT/SOCS signaling pathway with breast cancer risk and mortality in an admixed population of Hispanic (2,111 cases, 2,597 controls) and non-Hispanic white (1,481 cases, 1,585 controls) women. Associations were assessed by Indigenous American (IA) ancestry. After adjustment for multiple comparisons, JAK1 (three of ten SNPs) and JAK2 (4 of 11 SNPs) interacted with body mass index (BMI) among pre-menopausal women, while STAT3 (four of five SNPs) interacted significantly with BMI among post-menopausal women to alter breast cancer risk. STAT6 rs3024979 and TYK2 rs280519 altered breast cancer-specific mortality among all women. Associations with breast cancer-specific mortality differed by IA ancestry; SOCS1 rs193779, STAT3 rs1026916, and STAT4 rs11685878 associations were limited to women with low IA ancestry, and associations with JAK1 rs2780890, rs2254002, and rs310245 and STAT1 rs11887698 were observed among women with high IA ancestry. JAK2 (5 of 11 SNPs), SOCS2 (one of three SNPs), and STAT4 (2 of 20 SNPs) interacted with cigarette smoking status to alter breast cancer-specific mortality. SOCS2 (one of three SNPs) and all STAT3, STAT5A, and STAT5B SNPs significantly interacted with use of aspirin/NSAIDs to alter breast cancer-specific mortality. Genetic variation in the JAK/STAT/SOCS pathway was associated with breast cancer-specific mortality. The proportion of SNPs within a gene that significantly interacted with lifestyle factors lends support for the observed associations.

    View details for DOI 10.1007/s10549-014-3071-y

    View details for Web of Science ID 000340547800014

    View details for PubMedID 25104439

    View details for PubMedCentralID PMC4167366

  • Genetic variants in interleukin genes are associated with breast cancer risk and survival in a genetically admixed population: the Breast Cancer Health Disparities Study. Carcinogenesis Slattery, M. L., Herrick, J. S., Torres-Mejia, G., John, E. M., Giuliano, A. R., Hines, L. M., Stern, M. C., Baumgartner, K. B., Presson, A. P., Wolff, R. K. 2014; 35 (8): 1750-1759

    Abstract

    Interleukins (ILs) are key regulators of immune response. Genetic variation in IL genes may influence breast cancer risk and mortality given their role in cell growth, angiogenesis and regulation of inflammatory process. We examined 16 IL genes with breast cancer risk and mortality in an admixed population of Hispanic/Native American (NA) (2111 cases and 2597 controls) and non-Hispanic white (NHW) (1481 cases and 1585 controls) women. Adaptive Rank Truncated Product (ARTP) analysis was conducted to determine gene significance and lasso (least absolute shrinkage and selection operator) was used to identify potential gene by gene and gene by lifestyle interactions. The pathway was statistically significant for breast cancer risk overall (P ARTP = 0.0006), for women with low NA ancestry (P ARTP = 0.01), for premenopausal women (P ARTP = 0.02), for estrogen receptor (ER)+/progesterone receptor (PR)+ tumors (P ARTP = 0.03) and ER-/PR- tumors (P ARTP = 0.02). Eight of the 16 genes evaluated were associated with breast cancer risk (IL1A, IL1B, IL1RN, IL2, IL2RA, IL4, IL6 and IL10); four genes were associated with breast cancer risk among women with low NA ancestry (IL1B, IL6, IL6R and IL10), two were associated with breast cancer risk among women with high NA ancestry (IL2 and IL2RA) and four genes were associated with premenopausal breast cancer risk (IL1A, IL1B, IL2 and IL3). IL4, IL6R, IL8 and IL17A were associated with breast cancer-specific mortality. We confirmed associations with several functional polymorphisms previously associated with breast cancer risk and provide support that their combined effect influences the carcinogenic process.

    View details for DOI 10.1093/carcin/bgu078

    View details for PubMedID 24670917

  • Rare Mutations in RINT1 Predispose Carriers to Breast and Lynch Syndrome-Spectrum Cancers CANCER DISCOVERY Park, D. J., Tao, K., Le Calvez-Kelm, F., Tu Nguyen-Dumont, N. D., Robinot, N., Hammet, F., Odefrey, F., Tsimiklis, H., Teo, Z. L., Thingholm, L. B., Young, E. L., Voegele, C., Lonie, A., Pope, B. J., Roane, T. C., Bell, R., Hu, H., Shankaracharya, Huff, C. D., Ellis, J., Li, J., Makunin, I. V., John, E. M., Andrulis, I. L., Terry, M. B., Daly, M., Buys, S. S., Snyder, C., Lynch, H. T., Devilee, P., Giles, G. G., Hopper, J. L., Feng, B., Lesueur, F., Tavtigian, S. V., Southey, M. C., Goldgar, D. E. 2014; 4 (7): 804-815

    Abstract

    Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case-control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confidence interval (CI), 1.29-8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome-spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7-6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7-21; P = 0.0003).The work described in this study adds RINT1 to the growing list of genes in which rare sequence variants are associated with intermediate levels of breast cancer risk. Given that RINT1 is also associated with a spectrum of cancers with mismatch repair defects, these findings have clinical applications and raise interesting biological questions.

    View details for DOI 10.1158/2159-8290.CD-14-0212

    View details for Web of Science ID 000338708900026

    View details for PubMedID 25050558

  • Correlation of DNA methylation levels in blood and saliva DNA in young girls of the LEGACY Girls study. Epigenetics Wu, H., Wang, Q., Chung, W. K., Andrulis, I. L., Daly, M. B., John, E. M., Keegan, T. H., Knight, J., Bradbury, A. R., Kappil, M. A., Gurvich, I., Santella, R. M., Terry, M. B. 2014; 9 (7): 929-933

    Abstract

    Many epidemiologic studies of environmental exposures and disease susceptibility measure DNA methylation in white blood cells (WBC). Some studies are also starting to use saliva DNA as it is usually more readily available in large epidemiologic studies. However, little is known about the correlation of methylation between WBC and saliva DNA. We examined DNA methylation in three repetitive elements, Sat2, Alu, and LINE-1, and in four CpG sites, including AHRR (cg23576855, cg05575921), cg05951221 at 2q37.1, and cg11924019 at CYP1A1, in 57 girls aged 6-15 years with blood and saliva collected on the same day. We measured all DNA methylation markers by bisulfite-pyrosequencing, except for Sat2 and Alu, which were measured by the MethyLight assay. Methylation levels measured in saliva DNA were lower than those in WBC DNA, with differences ranging from 2.8% for Alu to 14.1% for cg05575921. Methylation levels for the three repetitive elements measured in saliva DNA were all positively correlated with those in WBC DNA. However, there was a wide range in the Spearman correlations, with the smallest correlation found for Alu (0.24) and the strongest correlation found for LINE-1 (0.73). Spearman correlations for cg05575921, cg05951221, and cg11924019 were 0.33, 0.42, and 0.79, respectively. If these findings are replicated in larger studies, they suggest that, for selected methylation markers (e.g., LINE-1), methylation levels may be highly correlated between blood and saliva, while for others methylation markers, the levels may be more tissue specific. Thus, in studies that differ by DNA source, each interrogated site should be separately examined in order to evaluate the correlation in DNA methylation levels across DNA sources.

    View details for DOI 10.4161/epi.28902

    View details for PubMedID 24756002

  • Correlation of DNA methylation levels in blood and saliva DNA in young girls of the LEGACY Girls study EPIGENETICS Wu, H., Wang, Q., Chung, W. K., Andrulis, I. L., Daly, M. B., John, E. M., Keegan, T. H., Knight, J., Bradbury, A. R., Kappil, M. A., Gurvich, I., Santella, R. M., Terry, M. B. 2014; 9 (7): 929-933

    Abstract

    Many epidemiologic studies of environmental exposures and disease susceptibility measure DNA methylation in white blood cells (WBC). Some studies are also starting to use saliva DNA as it is usually more readily available in large epidemiologic studies. However, little is known about the correlation of methylation between WBC and saliva DNA. We examined DNA methylation in three repetitive elements, Sat2, Alu, and LINE-1, and in four CpG sites, including AHRR (cg23576855, cg05575921), cg05951221 at 2q37.1, and cg11924019 at CYP1A1, in 57 girls aged 6-15 years with blood and saliva collected on the same day. We measured all DNA methylation markers by bisulfite-pyrosequencing, except for Sat2 and Alu, which were measured by the MethyLight assay. Methylation levels measured in saliva DNA were lower than those in WBC DNA, with differences ranging from 2.8% for Alu to 14.1% for cg05575921. Methylation levels for the three repetitive elements measured in saliva DNA were all positively correlated with those in WBC DNA. However, there was a wide range in the Spearman correlations, with the smallest correlation found for Alu (0.24) and the strongest correlation found for LINE-1 (0.73). Spearman correlations for cg05575921, cg05951221, and cg11924019 were 0.33, 0.42, and 0.79, respectively. If these findings are replicated in larger studies, they suggest that, for selected methylation markers (e.g., LINE-1), methylation levels may be highly correlated between blood and saliva, while for others methylation markers, the levels may be more tissue specific. Thus, in studies that differ by DNA source, each interrogated site should be separately examined in order to evaluate the correlation in DNA methylation levels across DNA sources.

    View details for DOI 10.4161/epi.28902

    View details for Web of Science ID 000338429500001

    View details for PubMedCentralID PMC4143407

  • Meta-analysis of loci associated with age at natural menopause in African-American women HUMAN MOLECULAR GENETICS Chen, C. T., Liu, C., Chen, G. K., Andrews, J. S., Arnold, A. M., Dreyfus, J., Franceschini, N., Garcia, M. E., Kerr, K. F., Li, G., Lohman, K. K., Musani, S. K., Nalls, M. A., Raffel, L. J., Smith, J., Ambrosone, C. B., Bandera, E. V., Bernstein, L., Britton, A., Brzyski, R. G., Cappola, A., Carlson, C. S., Couper, D., Deming, S. L., Goodarzi, M. O., Heiss, G., John, E. M., Lu, X., Le Marchand, L., Marciante, K., McKnight, B., Millikan, R., Nock, N. L., Olshan, A. F., Press, M. F., Vaiyda, D., Woods, N. F., Taylor, H. A., Zhao, W., Zheng, W., Evans, M. K., Harris, T. B., Henderson, B. E., Kardia, S. L., Kooperberg, C., Liu, Y., Mosley, T. H., Psaty, B., Wellons, M., Windham, B. G., Zonderman, A. B., Cupples, L. A., Demerath, E. W., Haiman, C., Murabito, J. M., Rajkovic, A. 2014; 23 (12): 3327-3342

    Abstract

    Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.

    View details for DOI 10.1093/hmg/ddu041

    View details for PubMedID 24493794

  • Alcohol Consumption and Survival after a Breast Cancer Diagnosis: A Literature-Based Meta-analysis and Collaborative Analysis of Data for 29,239 Cases CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ali, A. G., Schmidt, M. K., Bolla, M. K., Wang, Q., Gago-Dominguez, M., Esteban Castelao, J., Carracedo, A., Munoz Garzon, V., Bojesen, S. E., Nordestgaard, B. G., Flyger, H., Chang-Claude, J., Vrieling, A., Rudolph, A., Seibold, P., Nevanlinna, H., Muranen, T. A., Aaltonen, K., Blomqvist, C., Matsuo, K., Ito, H., Iwata, H., Horio, A., John, E. M., Sherman, M., Lissowska, J., Figueroa, J., Garcia-Closas, M., Anton-Culver, H., Shah, M., Hopper, J. L., Trichopoulou, A., Bueno-de-Mesquita, B., Krogh, V., Weiderpass, E., Andersson, A., Clavel-Chapelon, F., Dossus, L., Fagherazzi, G., Peeters, P. H., Olsen, A., Wishart, G. C., Easton, D. F., Borgquist, S., Overvad, K., Barricarte, A., Gonzalez, C. A., Sanchez, M., Amiano, P., Riboli, E., Key, T., Pharoah, P. D. 2014; 23 (6): 934?45

    Abstract

    Evidence for an association of alcohol consumption with prognosis after a diagnosis of breast cancer has been inconsistent. We have reviewed and summarized the published evidence and evaluated the association using individual patient data from multiple case cohorts.A MEDLINE search to identify studies published up to January 2013 was performed. We combined published estimates of survival time for "moderate drinkers" versus nondrinkers. An analysis of individual participant data using Cox regression was carried out using data from 11 case cohorts.We identified 11 published studies suitable for inclusion in the meta-analysis. Moderate postdiagnosis alcohol consumption was not associated with overall survival [HR, 0.95; 95% confidence interval (CI), 0.85-1.05], but there was some evidence of better survival associated with prediagnosis consumption (HR, 0.80; 95% CI, 0.73-0.88). Individual data on alcohol consumption for 29,239 cases with 4,839 deaths were available from the 11 case cohorts, all of which had data on estrogen receptor (ER) status. For women with ER-positive disease, there was little evidence that pre- or postdiagnosis alcohol consumption is associated with breast cancer-specific mortality, with some evidence of a negative association with all-cause mortality. On the basis of a single study, moderate postdiagnosis alcohol intake was associated with a small reduction in breast cancer-specific mortality for women with ER-negative disease. There was no association with prediagnosis intake for women with ER-negative disease.There was little evidence that pre- or post-diagnosis alcohol consumption is associated with breast cancer-specific mortality for women with ER-positive disease. There was weak evidence that moderate post-diagnosis alcohol intake is associated with a small reduction in breast cancer-specific mortality in ER-negative disease.Considering the totality of the evidence, moderate postdiagnosis alcohol consumption is unlikely to have a major adverse effect on the survival of women with breast cancer.

    View details for DOI 10.1158/1055-9965.EPI-13-0901

    View details for Web of Science ID 000345270800005

    View details for PubMedID 24636975

    View details for PubMedCentralID PMC4542077

  • Impact of Neighborhood and Individual Socioeconomic Status on Survival after Breast Cancer Varies by Race/Ethnicity: The Neighborhood and Breast Cancer Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Shariff-Marco, S., Yang, J., John, E. M., Sangaramoorthy, M., Hertz, A., Koo, J., Nelson, D. O., Schupp, C. W., Shema, S. J., Cockburn, M., Satariano, W. A., Yen, I. H., Ponce, N. A., Winkleby, M., Keegan, T. H., Gomez, S. L. 2014; 23 (5): 793-811

    Abstract

    Research is limited on the independent and joint effects of individual- and neighborhood-level socioeconomic status (SES) on breast cancer survival across different racial/ethnic groups.We studied individual-level SES, measured by self-reported education, and a composite neighborhood SES (nSES) measure in females (1,068 non-Hispanic whites, 1,670 Hispanics, 993 African-Americans, and 674 Asian-Americans), ages 18 to 79 years and diagnosed 1995 to 2008, in the San Francisco Bay Area. We evaluated all-cause and breast cancer-specific survival using stage-stratified Cox proportional hazards models with cluster adjustment for census block groups.In models adjusting for education and nSES, lower nSES was associated with worse all-cause survival among African-Americans (P trend = 0.03), Hispanics (P trend = 0.01), and Asian-Americans (P trend = 0.01). Education was not associated with all-cause survival. For breast cancer-specific survival, lower nSES was associated with poorer survival only among Asian-Americans (P trend = 0.01). When nSES and education were jointly considered, women with low education and low nSES had 1.4 to 2.7 times worse all-cause survival than women with high education and high nSES across all races/ethnicities. Among African-Americans and Asian-Americans, women with high education and low nSES had 1.6 to 1.9 times worse survival, respectively. For breast cancer-specific survival, joint associations were found only among Asian-Americans with worse survival for those with low nSES regardless of education.Both neighborhood and individual SES are associated with survival after breast cancer diagnosis, but these relationships vary by race/ethnicity.A better understanding of the relative contributions and interactions of SES with other factors will inform targeted interventions toward reducing long-standing disparities in breast cancer survival.

    View details for DOI 10.1158/1055-9965.EPI-13-0924

    View details for PubMedID 24618999

  • DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers. PLoS genetics Osorio, A., Milne, R. L., Kuchenbaecker, K., Vaclová, T., Pita, G., Alonso, R., Peterlongo, P., Blanco, I., de la Hoya, M., Duran, M., Díez, O., Ramón y Cajal, T., Konstantopoulou, I., Martínez-Bouzas, C., Andrés Conejero, R., Soucy, P., McGuffog, L., Barrowdale, D., Lee, A., Swe-Brca, Arver, B., Rantala, J., Loman, N., Ehrencrona, H., Olopade, O. I., Beattie, M. S., Domchek, S. M., Nathanson, K., Rebbeck, T. R., Arun, B. K., Karlan, B. Y., Walsh, C., Lester, J., John, E. M., Whittemore, A. S., Daly, M. B., Southey, M., Hopper, J., Terry, M. B., Buys, S. S., Janavicius, R., Dorfling, C. M., Van Rensburg, E. J., Steele, L., Neuhausen, S. L., Ding, Y. C., Hansen, T. v., Jřnson, L., Ejlertsen, B., Gerdes, A., Infante, M., Herráez, B., Moreno, L. T., Weitzel, J. N., Herzog, J., Weeman, K., Manoukian, S., Peissel, B., Zaffaroni, D., Scuvera, G., Bonanni, B., Mariette, F., Volorio, S., Viel, A., Varesco, L., Papi, L., Ottini, L., Tibiletti, M. G., Radice, P., Yannoukakos, D., Garber, J., Ellis, S., Frost, D., Platte, R., Fineberg, E., Evans, G., Lalloo, F., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Cole, T., Eccles, D., Cook, J., Hodgson, S., Brewer, C., Tischkowitz, M., Douglas, F., Porteous, M., Side, L., Walker, L., Morrison, P., Donaldson, A., Kennedy, J., Foo, C., Godwin, A. K., Schmutzler, R. K., Wappenschmidt, B., Rhiem, K., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Plendl, H. J., Niederacher, D., Sutter, C., Wang-Gohrke, S., Steinemann, D., Preisler-Adams, S., Kast, K., Varon-Mateeva, R., Gehrig, A., Stoppa-Lyonnet, D., Sinilnikova, O. M., Mazoyer, S., Damiola, F., Poppe, B., Claes, K., Piedmonte, M., Tucker, K., Backes, F., Rodríguez, G., Brewster, W., Wakeley, K., Rutherford, T., Caldés, T., Nevanlinna, H., Aittomäki, K., Rookus, M. A., van Os, T. A., van der Kolk, L., de Lange, J. L., Meijers-Heijboer, H. E., van der Hout, A. H., van Asperen, C. J., Gómez Garcia, E. B., Hoogerbrugge, N., Collée, J. M., van Deurzen, C. H., van der Luijt, R. B., Devilee, P., Hebon, Olah, E., Lázaro, C., Teulé, A., Menéndez, M., Jakubowska, A., Cybulski, C., Gronwald, J., Lubinski, J., Durda, K., Jaworska-Bieniek, K., Johannsson, O. T., Maugard, C., Montagna, M., Tognazzo, S., Teixeira, M. R., Healey, S., Investigators, K., Olswold, C., Guidugli, L., Lindor, N., Slager, S., Szabo, C. I., Vijai, J., Robson, M., Kauff, N., Zhang, L., Rau-Murthy, R., Fink-Retter, A., Singer, C. F., Rappaport, C., Geschwantler Kaulich, D., Pfeiler, G., Tea, M., Berger, A., Phelan, C. M., Greene, M. H., Mai, P. L., Lejbkowicz, F., Andrulis, I., Mulligan, A. M., Glendon, G., Toland, A. E., Bojesen, A., Pedersen, I. S., Sunde, L., Thomassen, M., Kruse, T. A., Jensen, U. B., friedman, e., Laitman, Y., Shimon, S. P., Simard, J., Easton, D. F., Offit, K., Couch, F. J., Chenevix-Trench, G., Antoniou, A. C., Benitez, J. 2014; 10 (4)

    Abstract

    Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

    View details for DOI 10.1371/journal.pgen.1004256

    View details for PubMedID 24698998

  • A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Ahsan, H., Halpern, J., Kibriya, M. G., Pierce, B. L., Tong, L., Gamazon, E., McGuire, V., Felberg, A., Shi, J., Jasmine, F., Roy, S., Brutus, R., Argos, M., Melkonian, S., Chang-Claude, J., Andrulis, I., Hopper, J. L., John, E. M., Malone, K., Ursin, G., Gammon, M. D., Thomas, D. C., Seminara, D., Casey, G., Knight, J. A., Southey, M. C., Giles, G. G., Santella, R. M., Lee, E., Conti, D., Duggan, D., Gallinger, S., Haile, R., Jenkins, M., Lindor, N. M., Newcomb, P., Michailidou, K., Apicella, C., Park, D. J., Peto, J., Fletcher, O., dos Santos Silva, I., Lathrop, M., Hunter, D. J., Chanock, S. J., Meindl, A., Schmutzler, R. K., Müller-Myhsok, B., Lochmann, M., Beckmann, L., Hein, R., Makalic, E., Schmidt, D. F., Bui, Q. M., Stone, J., Flesch-Janys, D., Dahmen, N., Nevanlinna, H., Aittomäki, K., Blomqvist, C., Hall, P., Czene, K., Irwanto, A., Liu, J., Rahman, N., Turnbull, C., Dunning, A. M., Pharoah, P., Waisfisz, Q., Meijers-Heijboer, H., Uitterlinden, A. G., Rivadeneira, F., Nicolae, D., Easton, D. F., Cox, N. J., Whittemore, A. S. 2014; 23 (4): 658-669

    Abstract

    Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ? 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658-69. ©2014 AACR.

    View details for DOI 10.1158/1055-9965.EPI-13-0340

    View details for PubMedID 24493630

  • Heterogeneity of breast cancer subtypes and survival among Hispanic women with invasive breast cancer in California BREAST CANCER RESEARCH AND TREATMENT Banegas, M. P., Tao, L., Altekruse, S., Anderson, W. F., John, E. M., Clarke, C. A., Gomez, S. L. 2014; 144 (3): 625-634

    Abstract

    There are limited data regarding breast cancer subtypes among Hispanic women. The current study assessed the distribution and prognosis of molecular subtypes defined by joint expression of the hormone receptors (HR; estrogen and progesterone) and human epidermal growth factor receptor 2 (HER2). Using California Cancer Registry data, we identified Hispanic women diagnosed with invasive breast cancer from 2005 to 2010. Breast cancer subtypes were defined as HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2- (triple negative). We estimated breast cancer subtype frequencies and used polytomous logistic regression, Kaplan-Meier survival plots and Cox regression to examine differences in relation to demographic and clinical characteristics. Among 16,380 Hispanic women with breast cancer, HR+/HER- subtype was the most common (63 %), followed by triple negative (16 %), HR+/HER2+ (14 %), and HR-/HER2+ (8 %). Women in lower SES neighborhoods had greater risk of triple negative and HR-/HER2+ subtypes relative to HR+/HER2- (p < 0.05). Hispanic women with triple negative and HR-/HER2+ tumors experienced poorer survival than those with HR+/HER- tumors. Breast cancer-specific mortality increased with decreasing SES, relative to the highest SES quintile, from HR = 1.38 for quintile 4 to HR = 1.76 for quintile 1 (lowest SES level). Our findings indicate that Hispanic women residing in low SES neighborhoods had significantly increased risk of developing and dying from HR- than HR+ breast cancers. Similar patterns of subtype frequency and prognosis among California Hispanic women and studies of other racial/ethnic groups underscore the need to better understand the impact of SES on risk factor exposures that increase the risk of breast cancer subtypes with poor prognosis.

    View details for DOI 10.1007/s10549-014-2882-1

    View details for Web of Science ID 000333360700018

    View details for PubMedID 24658879

  • Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry BRITISH JOURNAL OF CANCER Work, M. E., John, E. M., Andrulis, I. L., Knight, J. A., Liao, Y., Mulligan, A. M., Southey, M. C., Giles, G. G., Dite, G. S., Apicella, C., Hibshoosh, H., Hopper, J. L., Terry, M. B. 2014; 110 (5): 1367?77

    Abstract

    Oestrogen receptor (ER)- and progesterone receptor (PR)-negative (ER-PR-) breast cancer is associated with poorer prognosis compared with other breast cancer subtypes. High parity has been associated with an increased risk of ER-PR- cancer, but emerging evidence suggests that breastfeeding may reduce this risk. Whether this potential breastfeeding benefit extends to women at high risk of breast cancer remains critical to understand for prevention.Using population-based ascertained cases (n=4011) and controls (2997) from the Breast Cancer Family Registry, we examined reproductive risk factors in relation to ER and PR status.High parity (?3 live births) without breastfeeding was positively associated only with ER-PR- tumours (odds ratio (OR)=1.57, 95% confidence interval (CI), 1.10-2.24); there was no association with parity in women who breastfed (OR=0.93, 95% CI 0.71-1.22). Across all race/ethnicities, associations for ER-PR- cancer were higher among women who did not breastfeed than among women who did. Oral contraceptive (OC) use before 1975 was associated with an increased risk of ER-PR- cancer only (OR=1.32, 95% CI 1.04-1.67). For women who began OC use in 1975 or later there was no increased risk.Our findings support that there are modifiable factors for ER-PR- breast cancer and that breastfeeding in particular may mitigate the increased risk of ER-PR- cancers seen from multiparity.

    View details for PubMedID 24548865

    View details for PubMedCentralID PMC3950851

  • The influence of genetic ancestry and ethnicity on breast cancer survival associated with genetic variation in the TGF-ß-signaling pathway: The Breast Cancer Health Disparities Study. Cancer causes & control Slattery, M. L., Lundgreen, A., Stern, M. C., Hines, L., Wolff, R. K., Giuliano, A. R., Baumgartner, K. B., John, E. M. 2014; 25 (3): 293-307

    Abstract

    The TGF-? signaling pathway regulates cellular proliferation and differentiation. We evaluated genetic variation in this pathway, its association with breast cancer survival, and survival differences by genetic ancestry and self-reported ethnicity. The Breast Cancer Health Disparities Study includes participants from the 4-Corners Breast Cancer Study (n = 1,391 cases) and the San Francisco Bay Area Breast Cancer Study (n = 946 cases) who have been followed for survival. We evaluated 28 genes in the TGF-? signaling pathway using a tagSNP approach. Adaptive rank truncated product (ARTP) was used to test the gene and pathway significance by Native American (NA) ancestry and by self-reported ethnicity (non-Hispanic white (NHW) and Hispanic/NA). Genetic variation in the TGF-? signaling pathway was associated with overall breast cancer survival (P ARTP = 0.05), especially for women with low NA ancestry (P ARTP = 0.007) and NHW women (P ARTP = 0.006). BMP2, BMP4, RUNX1, and TGFBR3 were significantly associated with breast cancer survival overall (P ARTP = 0.04, 0.02, 0.002, and 0.04, respectively). Among women with low NA, ancestry associations were as follows: BMP4 (P ARTP = 0.007), BMP6 (P ARTP = 0.001), GDF10 (P ARTP = 0.05), RUNX1 (P ARTP = 0.002), SMAD1 (P ARTP = 0.05), and TGFBR2 (P ARTP = 0.02). A polygenic risk model showed that women with low NA ancestry and high numbers of at-risk alleles had twice the risk of dying from breast cancer as did women with high NA ancestry. Our data suggest that genetic variation in the TGF-? signaling pathway influences breast cancer survival. Associations were similar when the analyses were stratified by genetic ancestry or by self-reported ethnicity.

    View details for DOI 10.1007/s10552-013-0331-9

    View details for PubMedID 24337772

  • Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer. PLoS genetics Saunders, E. J., Dadaev, T., Leongamornlert, D. A., Jugurnauth-Little, S., Tymrakiewicz, M., Wiklund, F., Al Olama, A. A., Benlloch, S., Neal, D. E., Hamdy, F. C., Donovan, J. L., Giles, G. G., Severi, G., Gronberg, H., Aly, M., Haiman, C. A., Schumacher, F., Henderson, B. E., Lindstrom, S., Kraft, P., Hunter, D. J., Gapstur, S., Chanock, S., Berndt, S. I., Albanes, D., Andriole, G., Schleutker, J., Weischer, M., Nordestgaard, B. G., Canzian, F., Campa, D., Riboli, E., Key, T. J., Travis, R. C., Ingles, S. A., John, E. M., Hayes, R. B., Pharoah, P., Khaw, K., Stanford, J. L., Ostrander, E. A., Signorello, L. B., Thibodeau, S. N., Schaid, D., Maier, C., Kibel, A. S., Cybulski, C., Cannon-Albright, L., Brenner, H., Park, J. Y., Kaneva, R., Batra, J., Clements, J. A., Teixeira, M. R., Xu, J., Mikropoulos, C., Goh, C., Govindasami, K., Guy, M., Wilkinson, R. A., Sawyer, E. J., Morgan, A., Easton, D. F., Muir, K., Eeles, R. A., Kote-Jarai, Z. 2014; 10 (2)

    Abstract

    The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P?=?2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

    View details for DOI 10.1371/journal.pgen.1004129

    View details for PubMedID 24550738

  • Angiogenesis genes, dietary oxidative balance and breast cancer risk and progression: The Breast Cancer Health Disparities Study INTERNATIONAL JOURNAL OF CANCER Slattery, M. L., John, E. M., Torres-Mejia, G., Lundgreen, A., Lewinger, J. P., Stern, M. C., Hines, L., Baumgartner, K. B., Giuliano, A. R., Wolff, R. K. 2014; 134 (3): 629-644

    Abstract

    Angiogenesis is essential for tumor development and progression. Genetic variation in angiogenesis-related genes may influence breast carcinogenesis. We evaluated dietary factors associated with oxidative balance, DDIT4 (1 SNP), FLT1 (35 SNPs), HIF1A (4 SNPs), KDR (19 SNPs), MPO (1 SNP), NOS2A (15 SNPs), TEK (40 SNPs), and VEGFA (8 SNPs) and breast cancer risk among Hispanic (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Adaptive Rank Truncated Product (ARTP) analysis was used to determine gene and pathway significance with breast cancer. TEK was associated with breast cancer overall (PARTP = 0.03) and with breast cancer survival (PARTP = 0.01). KDR was of borderline significance overall (PARTP = 0.07), although significantly associated with breast cancer in both low and intermediate Native American (NA) ancestry groups (PARTP = 0.02) and ER+/PR- tumor phenotype (PARTP = 0.008). Both VEGFA and NOS2A were associated with ER-/PR- tumor phenotype (PARTP = 0.01 and PARTP = 0.04 respectively). FLT1 was associated with breast cancer survival among those with low NA ancestry (PARTP = 0.009). With respect to diet, having a higher dietary oxidative balance score (DOBS) was significantly associated with lower breast cancer risk (OR 0.74 95% CI 0.64-0.84), with the strongest associations observed for women with the highest NA ancestry (OR 0.44 95 %CI 0.30-0.65). We observed few interactions between DOBS and angiogenesis-related genes. Our data suggest that dietary factors and genetic variation in angiogenesis-related genes contribute to breast cancer carcinogenesis. © 2013 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ijc.28377

    View details for Web of Science ID 000326880600014

  • Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study BREAST CANCER RESEARCH Damiola, F., Pertesi, M., Oliver, J., Le Calvez-Kelm, F., Voegele, C., Young, E. L., Robinot, N., Forey, N., Durand, G., Vallee, M. P., Tao, K., Roane, T. C., Williams, G. J., Hopper, J. L., Southey, M. C., Andrulis, I. L., John, E. M., Goldgar, D. E., Lesueur, F., Tavtigian, S. V. 2014; 16 (3): R58

    Abstract

    The MRE11A-RAD50-Nibrin (MRN) complex plays several critical roles related to repair of DNA double-strand breaks. Inherited mutations in the three components predispose to genetic instability disorders and the MRN genes have been implicated in breast cancer susceptibility, but the underlying data are not entirely convincing. Here, we address two related questions: (1) are some rare MRN variants intermediate-risk breast cancer susceptibility alleles, and if so (2) do the MRN genes follow a BRCA1/BRCA2 pattern wherein most susceptibility alleles are protein-truncating variants, or do they follow an ATM/CHEK2 pattern wherein half or more of the susceptibility alleles are missense substitutions?Using high-resolution melt curve analysis followed by Sanger sequencing, we mutation screened the coding exons and proximal splice junction regions of the MRN genes in 1,313 early-onset breast cancer cases and 1,123 population controls. Rare variants in the three genes were pooled using bioinformatics methods similar to those previously applied to ATM, BRCA1, BRCA2, and CHEK2, and then assessed by logistic regression.Re-analysis of our ATM, BRCA1, and BRCA2 mutation screening data revealed that these genes do not harbor pathogenic alleles (other than modest-risk SNPs) with minor allele frequencies>0.1% in Caucasian Americans, African Americans, or East Asians. Limiting our MRN analyses to variants with allele frequencies of <0.1% and combining protein-truncating variants, likely spliceogenic variants, and key functional domain rare missense substitutions, we found significant evidence that the MRN genes are indeed intermediate-risk breast cancer susceptibility genes (odds ratio (OR)=2.88, P=0.0090). Key domain missense substitutions were more frequent than the truncating variants (24 versus 12 observations) and conferred a slightly higher OR (3.07 versus 2.61) with a lower P value (0.029 versus 0.14).These data establish that MRE11A, RAD50, and NBN are intermediate-risk breast cancer susceptibility genes. Like ATM and CHEK2, their spectrum of pathogenic variants includes a relatively high proportion of missense substitutions. However, the data neither establish whether variants in each of the three genes are best evaluated under the same analysis model nor achieve clinically actionable classification of individual variants observed in this study.

    View details for DOI 10.1186/bcr3669

    View details for Web of Science ID 000349083900014

    View details for PubMedID 24894818

    View details for PubMedCentralID PMC4229874

  • Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25. Nature communications Fejerman, L., Ahmadiyeh, N., Hu, D., Huntsman, S., Beckman, K. B., Caswell, J. L., Tsung, K., John, E. M., Torres-Mejia, G., Carvajal-Carmona, L., Echeverry, M. M., Tuazon, A. M., Ramirez, C., Gignoux, C. R., Eng, C., Gonzalez-Burchard, E., Henderson, B., Le Marchand, L., Kooperberg, C., Hou, L., Agalliu, I., Kraft, P., Lindström, S., Perez-Stable, E. J., Haiman, C. A., Ziv, E. 2014; 5: 5260

    Abstract

    The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5' of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53-0.67, P=9 × 10(-18)), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49-0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.

    View details for PubMedID 25327703

    View details for PubMedCentralID PMC4204111

  • A comprehensive examination of breast cancer risk loci in African American women. Human molecular genetics Feng, Y., Stram, D. O., Rhie, S. K., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Olshan, A. F., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Palmer, J. R., Olopade, O. I., Huo, D., Adebamowo, C. A., Ogundiran, T., Chen, G. K., Stram, A., Park, K., Rand, K. A., Chanock, S. J., Le Marchand, L., Kolonel, L. N., Conti, D. V., Easton, D., Henderson, B. E., Haiman, C. A. 2014; 23 (20): 5518?26

    Abstract

    Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American women. In this study of breast cancer in African American women (3016 cases, 2745 controls), we tested an additional 54 novel breast cancer risk variants. Thirty-eight variants (70%) were found to have an association with breast cancer in the same direction as previously reported, with eight (15%) replicating at P < 0.05. Through fine-mapping, in three regions (1q32, 3p24, 10q25), we identified variants that better captured associations with overall breast cancer or estrogen receptor positive disease. We also observed suggestive associations with variants (at P < 5 × 10(-6)) in three separate regions (6q25, 14q13, 22q12) that may represent novel risk variants. Directional consistency of association observed for ?65-70% of currently known genetic variants for breast cancer in women of African ancestry implies a shared functional common variant at most loci. To validate and enhance the spectrum of alleles that define associations at the known breast cancer risk loci, as well as genome-wide, will require even larger collaborative efforts in women of African ancestry.

    View details for PubMedID 24852375

  • Genome-wide scan of 29,141 African Americans finds no evidence of directional selection since admixture. American journal of human genetics Bhatia, G., Tandon, A., Patterson, N., Aldrich, M. C., Ambrosone, C. B., Amos, C., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Bock, C. H., Caporaso, N., Casey, G., Deming, S. L., Diver, W. R., Gapstur, S. M., Gillanders, E. M., Harris, C. C., Henderson, B. E., Ingles, S. A., Isaacs, W., De Jager, P. L., John, E. M., Kittles, R. A., Larkin, E., McNeill, L. H., Millikan, R. C., Murphy, A., Neslund-Dudas, C., Nyante, S., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schwartz, A. G., Signorello, L. B., Spitz, M., Strom, S. S., Tucker, M. A., Wiencke, J. K., Witte, J. S., Wu, X., Yamamura, Y., Zanetti, K. A., Zheng, W., Ziegler, R. G., Chanock, S. J., Haiman, C. A., Reich, D., Price, A. L. 2014; 95 (4): 437?44

    Abstract

    The extent of recent selection in admixed populations is currently an unresolved question. We scanned the genomes of 29,141 African Americans and failed to find any genome-wide-significant deviations in local ancestry, indicating no evidence of selection influencing ancestry after admixture. A recent analysis of data from 1,890 African Americans reported that there was evidence of selection in African Americans after their ancestors left Africa, both before and after admixture. Selection after admixture was reported on the basis of deviations in local ancestry, and selection before admixture was reported on the basis of allele-frequency differences between African Americans and African populations. The local-ancestry deviations reported by the previous study did not replicate in our very large sample, and we show that such deviations were expected purely by chance, given the number of hypotheses tested. We further show that the previous study's conclusion of selection in African Americans before admixture is also subject to doubt. This is because the FST statistics they used were inflated and because true signals of unusual allele-frequency differences between African Americans and African populations would be best explained by selection that occurred in Africa prior to migration to the Americas.

    View details for PubMedID 25242497

    View details for PubMedCentralID PMC4185117

  • Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia. Breast cancer research Spurdle, A. B., Couch, F. J., Parsons, M. T., McGuffog, L., Barrowdale, D., Bolla, M. K., Wang, Q., Healey, S., Schmutzler, R., Wappenschmidt, B., Rhiem, K., Hahnen, E., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Plendl, H., Niederacher, D., Sutter, C., Wang-Gohrke, S., Steinemann, D., Preisler-Adams, S., Kast, K., Varon-Mateeva, R., Ellis, S., Frost, D., Platte, R., Perkins, J., Evans, D. G., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Cole, T., Scuvera, G., Manoukian, S., Bonanni, B., Mariette, F., Fortuzzi, S., Viel, A., Pasini, B., Papi, L., Varesco, L., Balleine, R., Nathanson, K. L., Domchek, S. M., Offitt, K., Jakubowska, A., Lindor, N., Thomassen, M., Jensen, U. B., Rantala, J., Borg, Ĺ., Andrulis, I. L., Miron, A., Hansen, T. v., Caldes, T., Neuhausen, S. L., Toland, A. E., Nevanlinna, H., Montagna, M., Garber, J., Godwin, A. K., Osorio, A., Factor, R. E., Terry, M. B., Rebbeck, T. R., Karlan, B. Y., Southey, M., Rashid, M. U., Tung, N., Pharoah, P. D., Blows, F. M., Dunning, A. M., Provenzano, E., Hall, P., Czene, K., Schmidt, M. K., Broeks, A., Cornelissen, S., Verhoef, S., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Slamon, D. J., Bojesen, S. E., Nordestgaard, B. G., Nielsen, S. F., Flyger, H., Chang-Claude, J., Flesch-Janys, D., Rudolph, A., Seibold, P., Aittomäki, K., Muranen, T. A., Heikkilä, P., Blomqvist, C., Figueroa, J., Chanock, S. J., Brinton, L., Lissowska, J., Olson, J. E., Pankratz, V. S., John, E. M., Whittemore, A. S., West, D. W., Hamann, U., Torres, D., Ulmer, H. U., Rüdiger, T., Devilee, P., Tollenaar, R. A., Seynaeve, C., van Asperen, C. J., Eccles, D. M., Tapper, W. J., Durcan, L., Jones, L., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Dwek, M., Swann, R., Bane, A. L., Glendon, G., Mulligan, A. M., Giles, G. G., Milne, R. L., Baglietto, L., McLean, C., Carpenter, J., Clarke, C., Scott, R., Brauch, H., Brüning, T., Ko, Y., Cox, A., Cross, S. S., Reed, M. W., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Gronwald, J., Dörk, T., Bogdanova, N., Park-Simon, T., Hillemanns, P., Haiman, C. A., Henderson, B. E., Schumacher, F., Le Marchand, L., Burwinkel, B., Marme, F., Surovy, H., Yang, R., Anton-Culver, H., Ziogas, A., Hooning, M. J., Collée, J. M., Martens, J. W., Tilanus-Linthorst, M. M., Brenner, H., Dieffenbach, A. K., Arndt, V., Stegmaier, C., Winqvist, R., Pylkäs, K., Jukkola-Vuorinen, A., Grip, M., Lindblom, A., Margolin, S., Joseph, V., Robson, M., Rau-Murthy, R., González-Neira, A., Arias, J. I., Zamora, P., Benítez, J., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Peterlongo, P., Zaffaroni, D., Barile, M., Capra, F., Radice, P., Teo, S. H., Easton, D. F., Antoniou, A. C., Chenevix-Trench, G., Goldgar, D. E. 2014; 16 (6): 3419-?

    Abstract

    The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR?=?4.13 (3.70 to 4.62)) versus younger than 50 years (LR?=?3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR?=?1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR?=?1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR?=?3.73 (3.43 to 4.05)) and 50 years or older (LR?=?4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR?=?1.79 (1.42 to 2.24)).These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

    View details for DOI 10.1186/s13058-014-0474-y

    View details for PubMedID 25857409

  • Genetic variants and non-genetic factors predict circulating vitamin D levels in Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study. International journal of molecular epidemiology and genetics Wang, W., Ingles, S. A., Torres-Mejía, G., Stern, M. C., Stanczyk, F. Z., Schwartz, G. G., Nelson, D. O., Fejerman, L., Wolff, R. K., Slattery, M. L., John, E. M. 2014; 5 (1): 31-46

    Abstract

    Genome-wide association studies (GWAS) have identified common polymorphisms in or near GC, CYP2R1, CYP24A1, and NADSYN1/DHCR7 genes to be associated with circulating levels of 25-hydroxyvitamin D [25(OH)D] in European populations. To replicate these GWAS findings, we examined six selected polymorphisms from these regions and their relation with circulating 25(OH)D levels in 1,605 Hispanic women (629 U.S. Hispanics and 976 Mexicans) and 354 non-Hispanic White (NHW) women. We also assessed the potential interactions between these variants and known non-genetic predictors of 25(OH)D levels, including body mass index (BMI), sunlight exposure and vitamin D intake from diet and supplements. The minor alleles of the two GC polymorphisms (rs7041 and rs2282679) were significantly associated with lower 25(OH)D levels in both Hispanic and NHW women. The CYP2R1 polymorphism, rs2060793, also was significantly associated with 25(OH)D levels in both groups. We found no significant associations for the polymorphisms in the CYP24A1. In Hispanic controls, 25(OH)D levels were significantly associated with the rs12785878T and rs1790349G haplotype in the NADSYN1/DHCR7 region. Significant interactions between GC rs2282679 and BMI and between rs12785878 and time spent in outdoor activities were observed. These results provide further support for the contribution of common genetic variants to individual variability in circulating 25(OH)D levels. The observed interactions between SNPs and non-genetic factors warrant confirmation.

    View details for PubMedID 24596595

  • Obesity and Mortality After Breast Cancer by Race/Ethnicity: The California Breast Cancer Survivorship Consortium AMERICAN JOURNAL OF EPIDEMIOLOGY Kwan, M. L., John, E. M., Caan, B. J., Lee, V. S., Bernstein, L., Cheng, I., Gomez, S. L., Henderson, B. E., Keegan, T. H., Kurian, A. W., Lu, Y., Monroe, K. R., Roh, J. M., Shariff-Marco, S., Sposto, R., Vigen, C., Wu, A. H. 2014; 179 (1): 95-111

    Abstract

    We investigated body size and survival by race/ethnicity in 11,351 breast cancer patients diagnosed from 1993 to 2007 with follow-up through 2009 by using data from questionnaires and the California Cancer Registry. We calculated hazard ratios and 95% confidence intervals from multivariable Cox proportional hazard model-estimated associations of body size (body mass index (BMI) (weight (kg)/height (m)(2)) and waist-hip ratio (WHR)) with breast cancer-specific and all-cause mortality. Among 2,744 ascertained deaths, 1,445 were related to breast cancer. Being underweight (BMI <18.5) was associated with increased risk of breast cancer mortality compared with being normal weight in non-Latina whites (hazard ratio (HR) = 1.91, 95% confidence interval (CI): 1.14, 3.20), whereas morbid obesity (BMI ? 40) was suggestive of increased risk (HR = 1.43, 95% CI: 0.84, 2.43). In Latinas, only the morbidly obese were at high risk of death (HR = 2.26, 95% CI: 1.23, 4.15). No BMI-mortality associations were apparent in African Americans and Asian Americans. High WHR (quartile 4 vs. quartile 1) was associated with breast cancer mortality in Asian Americans (HR = 2.21, 95% CI: 1.21, 4.03; P for trend = 0.01), whereas no associations were found in African Americans, Latinas, or non-Latina whites. For all-cause mortality, even stronger BMI and WHR associations were observed. The impact of obesity and body fat distribution on breast cancer patients' risk of death may vary across racial/ethnic groups.

    View details for DOI 10.1093/aje/kwt233

    View details for Web of Science ID 000329061100013

    View details for PubMedID 24107615

    View details for PubMedCentralID PMC3864715

  • Genetic Ancestry and Risk of Mortality among US Latinas with Breast Cancer CANCER RESEARCH Fejerman, L., Hu, D., Huntsman, S., John, E. M., Stern, M. C., Haiman, C. A., Perez-Stable, E. J., Ziv, E. 2013; 73 (24): 7243-7253

    Abstract

    Multiple studies have reported that Latina women in the United States are diagnosed with breast cancer at more advanced stages and have poorer survival than non-Latina White women. However, Latinas are a heterogeneous group with individuals having different proportions of European, Indigenous American, and African genetic ancestry. In this study, we evaluated the association between genetic ancestry and survival after breast cancer diagnosis among 899 Latina women from the San Francisco Bay area. Genetic ancestry was estimated from single-nucleotide polymorphisms from an Affymetrix 6.0 array and we used Cox proportional hazards models to evaluate the association between genetic ancestry and breast cancer-specific mortality (tests were two-sided). Women were followed for an average of 9 years during which 75 died from breast cancer. Our results showed that Individuals with higher Indigenous American ancestry had increased risk of breast cancer-specific mortality [HR: 1.57 per 25% increase in Indigenous American ancestry; 95% confidence interval (CI): 1.08-2.29]. Adjustment for demographic factors, tumor characteristics, and some treatment information did not explain the observed association (HR: 1.75; 95%CI, 1.12-2.74). In an analysis in which ancestry was dichotomized, the hazard of mortality showed a two-fold increase when comparing women with less than 50% Indigenous American ancestry to women with 50% or more [HR, 1.89, 95%CI, 1.10-3.24]. This was also reflected by Kaplan-Meier survival estimates (P for log-rank test of 0.003). Overall, results suggest that genetic factors and/or unmeasured differences in treatment or access to care should be further explored to understand and reduce ethnic disparities in breast cancer outcomes.

    View details for DOI 10.1158/0008-5472.CAN-13-2014

    View details for PubMedID 24177181

  • Body size, modifying factors, and postmenopausal breast cancer risk in a multiethnic population: the San Francisco Bay Area Breast Cancer Study. SpringerPlus John, E. M., Phipps, A. I., Sangaramoorthy, M. 2013; 2 (1): 239-?

    Abstract

    Data on body size and postmenopausal breast cancer in Hispanic and African American women are inconsistent, possibly due to the influence of modifying factors. We examined associations between adiposity and risk of breast cancer defined by hormone receptor status in a population-based case-control study conducted from 1995-2004 in the San Francisco Bay Area. Multivariate adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. Associations with body size were limited to women not currently using menopausal hormone therapy (801 cases, 1336 controls). High young-adult body mass index (BMI) was inversely associated with postmenopausal breast cancer risk, regardless of hormone receptor status, whereas high current BMI and high adult weight gain were associated with two-fold increased risk of estrogen receptor and progesterone receptor positive breast cancer, but only in women with a low young-adult BMI (?22.4 kg/m(2)) or those with ?15 years since menopause. Odds ratios were stronger among non-Hispanic Whites than Hispanics and African Americans. Waist circumference and waist-to-height ratio increased breast cancer risk in Hispanics and African Americans only, independent of BMI. These findings emphasize the importance of considering tumor hormone receptor status and other modifying factors in studies of racially/ethnically diverse populations.

    View details for DOI 10.1186/2193-1801-2-239

    View details for PubMedID 23762816

  • The California Breast Cancer Survivorship Consortium (CBCSC): prognostic factors associated with racial/ethnic differences in breast cancer survival CANCER CAUSES & CONTROL Wu, A. H., Gomez, S. L., Vigen, C., Kwan, M. L., Keegan, T. H., Lu, Y., Shariff-Marco, S., Monroe, K. R., Kurian, A. W., Cheng, I., Caan, B. J., Lee, V. S., Roh, J. M., Sullivan-Halley, J., Henderson, B. E., Bernstein, L., John, E. M., Sposto, R. 2013; 24 (10): 1821-1836

    Abstract

    Racial/ethnic disparities in mortality among US breast cancer patients are well documented. Our knowledge of the contribution of lifestyle factors to disease prognosis is based primarily on non-Latina Whites and is limited for Latina, African American, and Asian American women. To address this knowledge gap, the California Breast Cancer Survivorship Consortium (CBCSC) harmonized and pooled interview information (e.g., demographics, family history of breast cancer, parity, smoking, alcohol consumption) from six California-based breast cancer studies and assembled corresponding cancer registry data (clinical characteristics, mortality), resulting in 12,210 patients (6,501 non-Latina Whites, 2,060 African Americans, 2,032 Latinas, 1,505 Asian Americans, 112 other race/ethnicity) diagnosed with primary invasive breast cancer between 1993 and 2007. In total, 3,047 deaths (1,570 breast cancer specific) were observed with a mean (SD) follow-up of 8.3 (3.5) years. Cox proportional hazards regression models were fit to data to estimate hazards ratios (HRs) and 95 % confidence intervals (CIs) for overall and breast cancer-specific mortality. Compared with non-Latina Whites, the HR of breast cancer-specific mortality was 1.13 (95 % CI 0.97-1.33) for African Americans, 0.84 (95 % CI 0.70-1.00) for Latinas, and 0.60 (95 % CI 0.37-0.97) for Asian Americans after adjustment for age, tumor characteristics, and select lifestyle factors. The CBCSC represents a large and racially/ethnically diverse cohort of breast cancer patients from California. This cohort will enable analyses to jointly consider a variety of clinical, lifestyle, and contextual factors in attempting to explain the long-standing disparities in breast cancer outcomes.

    View details for DOI 10.1007/s10552-013-0260-7

    View details for Web of Science ID 000324252500007

    View details for PubMedID 23864487

  • Diagnostic Chest X-Rays and Breast Cancer Risk before Age 50 Years for BRCA1 and BRCA2 Mutation Carriers CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION John, E. M., McGuire, V., Thomas, D., Haile, R., Ozcelik, H., Milne, R. L., Felberg, A., West, D. W., Miron, A., Knight, J. A., Terry, M. B., Daly, M., Buys, S. S., Andrulis, I. L., Hopper, J. L., Southey, M. C., Giles, G. G., Apicella, C., Thorne, H., Whittemore, A. S. 2013; 22 (9): 1547-1556

    Abstract

    Background: The effects of low-dose medical radiation on breast cancer risk are uncertain, and few studies have included genetically susceptible women, such as those who carry germline BRCA1 and BRCA2 mutations. Methods: We studied 454 BRCA1 and 273 BRCA2 mutation carriers aged <50 years from three breast cancer family registries in the USA, Canada, and Australia/New Zealand. We estimated breast cancer risk associated with diagnostic chest x-rays by comparing mutation carriers with breast cancer (cases) with those without breast cancer (controls). Exposure to chest x-rays was self-reported. Mammograms were not considered in the analysis. Results: After adjusting for known risk factors for breast cancer, the odds ratio (OR) for a history of diagnostic chest x-rays, excluding those for tuberculosis or pneumonia, was 1.16 (95% confidence interval (CI) = 0.64-2.11) for BRCA1 mutations carriers and 1.22 (95% CI=0.62-2.42) for BRCA2 mutations carriers. The OR was statistically elevated for BRCA2 mutation carriers with 3-5 diagnostic chest x-rays (p = 0.01), but not for those with 6 or more chest x-rays. Few women reported chest fluoroscopy for tuberculosis or chest x-rays for pneumonia; the OR estimates were elevated, but not statistically significant, for BRCA1 mutation carriers. Conclusions: Our findings do not support a positive association between diagnostic chest x-rays and breast cancer risk before age 50 years for BRCA1 or BRCA2 mutation carriers. Impact: Given the increasing use of diagnostic imaging involving higher ionizing radiation doses, further studies of genetically predisposed women are warranted.

    View details for DOI 10.1158/1055-9965.EPI-13-0189

    View details for Web of Science ID 000324674500008

    View details for PubMedID 23853209

  • Associations between genetic variants in the TGF-ß signaling pathway and breast cancer risk among Hispanic and non-Hispanic white women. Breast cancer research and treatment Boone, S. D., Baumgartner, K. B., Baumgartner, R. N., Connor, A. E., Pinkston, C. M., John, E. M., Hines, L. M., Stern, M. C., Giuliano, A. R., Torres-Mejia, G., Brock, G. N., Groves, F. D., Kerber, R. A., Wolff, R. K., Slattery, M. L. 2013; 141 (2): 287-297

    Abstract

    The TGF-? signaling pathway has a significant role in breast cancer initiation and promotion by regulating various cellular processes. We evaluated whether genetic variation in eight genes (TGF-?1, TGF-?2, TGF-?R1, TGF-?R2, TGF-?R3, RUNX1, RUNX2, and RUNX3) is associated with breast cancer risk in women from the Breast Cancer Health Disparities Study. A total of 3,524 cases (1,431 non-Hispanic whites (NHW); 2,093 Hispanics/Native Americans(NA)) and 4,209 population-based controls (1,599 NHWs; 2,610 Hispanics/NAs) were included in analyses. Genotypes for 47 single nucleotide polymorphisms (SNPs) were determined. Additionally, 104 ancestral informative markers estimated proportion of NA ancestry. Associations with breast cancer risk overall, by menopausal status, NA ancestry, and estrogen receptor (ER)/progesterone receptor tumor phenotype were evaluated. After adjustment for multiple comparisons, two SNPs were significantly associated with breast cancer risk: RUNX3 (rs906296 ORCG/GG = 1.15 95 % CI 1.04-1.26) and TGF-?1 (rs4803455 ORCA/AA = 0.89 95 % CI 0.81-0.98). RUNX3 (rs906296) and TGF-?R2 (rs3773644) were associated with risk in pre-menopausal women (p adj = 0.002 and 0.02, respectively) and in those with intermediate to high NA ancestry (p adj = 0.04 and 0.01, respectively). Self-reported race was strongly correlated with NA ancestry (r = 0.86). There was a significant interaction between NA ancestry and RUNX1 (rs7279383, p adj = 0.04). Four RUNX SNPs were associated with increased risk of ER- tumors. Results provide evidence that genetic variation in TGF-? and RUNX genes are associated with breast cancer risk. This is the first report of significant associations between genetic variants in TGF-? and RUNX genes and breast cancer risk among women of NA ancestry.

    View details for DOI 10.1007/s10549-013-2690-z

    View details for PubMedID 24036662

  • Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. Journal of clinical oncology Phillips, K., Milne, R. L., Rookus, M. A., Daly, M. B., Antoniou, A. C., Peock, S., Frost, D., Easton, D. F., Ellis, S., Friedlander, M. L., Buys, S. S., Andrieu, N., Nogučs, C., Stoppa-Lyonnet, D., Bonadona, V., Pujol, P., McLachlan, S. A., John, E. M., Hooning, M. J., Seynaeve, C., Tollenaar, R. A., Goldgar, D. E., Terry, M. B., Caldes, T., Weideman, P. C., Andrulis, I. L., Singer, C. F., Birch, K., Simard, J., Southey, M. C., Olsson, H. L., Jakubowska, A., Olah, E., Gerdes, A., Foretova, L., Hopper, J. L. 2013; 31 (25): 3091-3099

    Abstract

    To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up.Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases).This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses.

    View details for DOI 10.1200/JCO.2012.47.8313

    View details for PubMedID 23918944

    View details for PubMedCentralID PMC3753701

  • Genome-wide association study of age at menarche in African-American women HUMAN MOLECULAR GENETICS Demerath, E. W., Liu, C., Franceschini, N., Chen, G., Palmer, J. R., Smith, E. N., Chen, C. T., Ambrosone, C. B., Arnold, A. M., Bandera, E. V., Berenson, G. S., Bernstein, L., Britton, A., Cappola, A. R., Carlson, C. S., Chanock, S. J., Chen, W., Chen, Z., Deming, S. L., Elks, C. E., Evans, M. K., Gajdos, Z., Henderson, B. E., Hu, J. J., Ingles, S., John, E. M., Kerr, K. F., Kolonel, L. N., Le Marchand, L., Lu, X., Millikan, R. C., Musani, S. K., Nock, N. L., North, K., Nyante, S., Press, M. F., Rodriquez-Gil, J. L., Ruiz-Narvaez, E. A., Schork, N. J., Srinivasan, S. R., Woods, N. F., Zheng, W., Ziegler, R. G., Zonderman, A., Heiss, G., Windham, B. G., Wellons, M., Murray, S. S., Nalls, M., Pastinen, T., Rajkovic, A., Hirschhorn, J., Cupples, L. A., Kooperberg, C., Murabito, J. M., Haiman, C. A. 2013; 22 (16): 3329-3346

    Abstract

    African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.

    View details for DOI 10.1093/hmg/ddt181

    View details for Web of Science ID 000322341300014

  • Genetic ancestry modifies the association between genetic risk variants and breast cancer risk among Hispanic and non-Hispanic white women CARCINOGENESIS Fejerman, L., Stern, M. C., Ziv, E., John, E. M., Torres-Mejia, G., Hines, L. M., Wolff, R., Wang, W., Baumgartner, K. B., Giuliano, A. R., Slattery, M. L. 2013; 34 (8): 1787-1793

    Abstract

    Hispanic women in the USA have lower breast cancer incidence than non-Hispanic white (NHW) women. Genetic factors may contribute to this difference. Breast cancer genome-wide association studies (GWAS) conducted in women of European or Asian descent have identified multiple risk variants. We tested the association between 10 previously reported single nucleotide polymorphisms (SNPs) and risk of breast cancer in a sample of 4697 Hispanic and 3077 NHW women recruited as part of three population-based case-control studies of breast cancer. We used stratified logistic regression analyses to compare the associations with different genetic variants in NHWs and Hispanics classified by their proportion of Indigenous American (IA) ancestry. Five of 10 SNPs were statistically significantly associated with breast cancer risk. Three of the five significant variants (rs17157903-RELN, rs7696175-TLR1 and rs13387042-2q35) were associated with risk among Hispanics but not in NHWs. The odds ratio (OR) for the heterozygous at 2q35 was 0.75 [95% confidence interval (CI) = 0.50-1.15] for low IA ancestry and 1.38 (95% CI = 1.04-1.82) for high IA ancestry (P interaction 0.02). The ORs for association at RELN were 0.87 (95% CI = 0.59-1.29) and 1.69 (95% CI = 1.04-2.73), respectively (P interaction 0.03). At the TLR1 locus, the ORs for women homozygous for the rare allele were 0.74 (95% CI = 0.42-1.31) and 1.73 (95% CI = 1.19-2.52) (P interaction 0.03). Our results suggest that the proportion of IA ancestry modifies the magnitude and direction of the association of 3 of the 10 previously reported variants. Genetic ancestry should be considered when assessing risk in women of mixed descent and in studies designed to discover causal mutations.

    View details for DOI 10.1093/carcin/bgt110

    View details for Web of Science ID 000322666800011

    View details for PubMedID 23563089

  • Associations with growth factor genes (FGF1, FGF2, PDGFB, FGFR2, NRG2, EGF, ERBB2) with breast cancer risk and survival: the Breast Cancer Health Disparities Study. Breast cancer research and treatment Slattery, M. L., John, E. M., Stern, M. C., Herrick, J., Lundgreen, A., Giuliano, A. R., Hines, L., Baumgartner, K. B., Torres-Mejia, G., Wolff, R. K. 2013; 140 (3): 587-601

    Abstract

    Growth factors (GF) stimulate cell proliferation through binding to cell membrane receptors and are thought to be involved in cancer risk and survival. We examined how genetic variation in epidermal growth factor (EGF), neuregulin 2 (NRG2), ERBB2 (HER2/neu), fibroblast growth factors 1 and 2 (FGF1 and FGF2) and its receptor 2 (FGFR2), and platelet-derived growth factor B (PDGFB) independently and collectively influence breast cancer risk and survival. We analyzed data from the Breast Cancer Health Disparities Study which includes Hispanic (2,111 cases, 2,597 controls) and non-Hispanic white (1,481 cases, 1,586 controls) women. Adaptive rank-truncated product (ARTP) analysis was conducted to determine gene significance. Odds ratios (OR) and 95 % confidence intervals were obtained from conditional logistic regression models to estimate breast cancer risk and Cox proportional hazard models were used to estimate hazard ratios (HR) of dying from breast cancer. We assessed Native American (NA) ancestry using 104 ancestry informative markers. We observed few significant associations with breast cancer risk overall or by menopausal status other than for FGFR2 rs2981582. This SNP was significantly associated with ER+/PR+ (OR 1.66, 95 % CI 1.37-2.00) and ER+/PR- (OR 1.54, 95 % CI 1.03-2.31) tumors. Multiple SNPs in FGF1, FGF2, and NRG2 significantly interacted with multiple SNPs in EGFR, ERBB2, FGFR2, and PDGFB, suggesting that breast cancer risk is dependent on the collective effects of genetic variants in other GFs. Both FGF1 and ERBB2 significantly influenced overall survival, especially among women with low levels of NA ancestry (P ARTP = 0.007 and 0.003, respectively). Our findings suggest that genetic variants in growth factors signaling appear to influence breast cancer risk through their combined effects. Genetic variation in ERBB2 and FGF1 appear to be associated with survival after diagnosis with breast cancer.

    View details for DOI 10.1007/s10549-013-2644-5

    View details for PubMedID 23912956

  • Tumour morphology predicts PALB2 germline mutation status BRITISH JOURNAL OF CANCER Teo, Z. L., Provenzano, E., Dite, G. S., Park, D. J., Apicella, C., Sawyer, S. D., James, P. A., Mitchell, G., Trainer, A. H., Lindeman, G. J., SHACKLETON, K., Cicciarelli, L., Buys, S. S., Andrulis, I. L., Mulligan, A. M., Glendon, G., John, E. M., Terry, M. B., Daly, M., Odefrey, F. A., Nguyen-Dumont, T., Giles, G. G., Dowty, J. G., Winship, I., Goldgar, D. E., Hopper, J. L., Southey, M. C. 2013; 109 (1): 154-163

    Abstract

    Background:Population-based studies of breast cancer have estimated that at least some PALB2 mutations are associated with high breast cancer risk. For women carrying PALB2 mutations, knowing their carrier status could be useful in directing them towards effective cancer risk management and therapeutic strategies. We sought to determine whether morphological features of breast tumours can predict PALB2 germline mutation status.Methods:Systematic pathology review was conducted on breast tumours from 28 female carriers of PALB2 mutations (non-carriers of other known high-risk mutations, recruited through various resources with varying ascertainment) and on breast tumours from a population-based sample of 828 Australian women diagnosed before the age of 60 years (which included 40 BRCA1 and 18 BRCA2 mutation carriers). Tumour morphological features of the 28 PALB2 mutation carriers were compared with those of 770 women without high-risk mutations.Results:Tumours arising in PALB2 mutation carriers were associated with minimal sclerosis (odds ratio (OR)=19.7; 95% confidence interval (CI)=6.0-64.6; P=5 × 10(-7)). Minimal sclerosis was also a feature that distinguished PALB2 mutation carriers from BRCA1 (P=0.05) and BRCA2 (P=0.04) mutation carriers.Conclusion:This study identified minimal sclerosis to be a predictor of germline PALB2 mutation status. Morphological review can therefore facilitate the identification of women most likely to carry mutations in PALB2.

    View details for DOI 10.1038/bjc.2013.295

    View details for Web of Science ID 000321702400021

    View details for PubMedID 23787919

    View details for PubMedCentralID PMC3708559

  • Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers CARCINOGENESIS Zheng, Y., Ogundiran, T. O., Falusi, A. G., Nathanson, K. L., John, E. M., Hennis, A. J., Ambs, S., Domchek, S. M., Rebbeck, T. R., Simon, M. S., Nemesure, B., Wu, S., Leske, M. C., Odetunde, A., Niu, Q., Zhang, J., Afolabi, C., Gamazon, E. R., Cox, N. J., Olopade, C. O., Olopade, O. I., Huo, D. 2013; 34 (7): 1520-1528

    Abstract

    Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI = 1.09-1.36; P = 0.00053) and 10p15.1 (OR = 1.22, 95% CI = 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13 and 16q12.1-q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI = 1.16-1.27; P = 9.7 × 10(-16)). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora.

    View details for DOI 10.1093/carcin/bgt090

    View details for Web of Science ID 000321753000013

    View details for PubMedID 23475944

  • Telomere length, telomere-related genes, and breast cancer risk: The breast cancer health disparities study. Genes, chromosomes & cancer Pellatt, A. J., Wolff, R. K., Torres-Mejia, G., John, E. M., Herrick, J. S., Lundgreen, A., Baumgartner, K. B., Giuliano, A. R., Hines, L. M., Fejerman, L., Cawthon, R., Slattery, M. L. 2013; 52 (7): 595-609

    Abstract

    Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere-related genes with cancer. We evaluated associations between telomere-related genes, TL, and breast cancer risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL-related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER-/PR+) tumors and TERT rs2735940 (ORadj 0.73, 95% CI 0.59, 0.91) with ER-/PR- tumors. These data provide support for an association between TL and TL-related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry. © 2013 Wiley Periodicals, Inc.

    View details for DOI 10.1002/gcc.22056

    View details for PubMedID 23629941

  • Genetic variation in bone morphogenetic proteins and breast cancer risk in hispanic and non-hispanic white women: The breast cancer health disparities study INTERNATIONAL JOURNAL OF CANCER Slattery, M. L., John, E. M., Torres-Mejia, G., Herrick, J. S., Giuliano, A. R., Baumgartner, K. B., Hines, L. M., Wolff, R. K. 2013; 132 (12): 2928-2939

    Abstract

    Bone morphogenetic proteins (BMP) are thought to be important in breast cancer promotion and progression. We evaluated genetic variation in BMP-related genes and breast cancer risk among Hispanic (2,111 cases, 2,597 controls) and non-Hispanic White (NHW) (1,481 cases, 1,586 controls) women who participated in the 4-Corner's Breast Cancer Study, the Mexico Breast Cancer Study and the San Francisco Bay Area Breast Cancer Study. BMP genes and their receptors evaluated include ACVR1, AVCR2A, ACVR2B, ACVRL1, BMP1, BMP2, BMP4, BMP6, BMP7, BMPR1A, BMPR1B, BMPR2, MSTN and GDF10. Additionally, 104 ancestral informative markers were assessed to discriminate between European and native American ancestry. The importance of estrogen on BMP-related associations was suggested through unique associations by menopausal status and estrogen (ER) and progesterone (PR) receptor status of tumors. After adjustment for multiple comparisons ACVR1 (8 SNPs) was modestly associated with ER+PR+ tumors [odds ratios (ORs) between 1.18 and 1.39 padj < 0.05]. ACVR1 (3 SNPs) and BMP4 (3 SNPs) were associated with ER+PR- tumors (ORs 0.59-2.07; padj < 0.05). BMPR2 was associated with ER-PR+ tumors (OR 4.20; 95% CI 1.62, 10.91; padj < 0.05) as was GDF10 (2 SNPs; ORs 3.62 and 3.85; padj < 0.05). After adjustment for multiple comparisons several SNPs remained associated with ER-PR- tumors (padj < 0.05) including ACVR1 BMP4 and GDF10 (ORs between 0.53 and 2.12). Differences in association also were observed by percentage of native ancestry and menopausal status. Results support the hypothesis that genetic variation in BMPs is associated with breast cancer in this admixed population.

    View details for DOI 10.1002/ijc.27960

    View details for Web of Science ID 000317593100023

    View details for PubMedID 23180569

    View details for PubMedCentralID PMC3653321

  • Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression. Human molecular genetics Kote-Jarai, Z., Saunders, E. J., Leongamornlert, D. A., Tymrakiewicz, M., Dadaev, T., Jugurnauth-Little, S., Ross-Adams, H., Al Olama, A. A., Benlloch, S., Halim, S., Russel, R., Dunning, A. M., Luccarini, C., Dennis, J., Neal, D. E., Hamdy, F. C., Donovan, J. L., Muir, K., Giles, G. G., Severi, G., Wiklund, F., Gronberg, H., Haiman, C. A., Schumacher, F., Henderson, B. E., Le Marchand, L., Lindstrom, S., Kraft, P., Hunter, D. J., Gapstur, S., Chanock, S., Berndt, S. I., Albanes, D., Andriole, G., Schleutker, J., Weischer, M., Canzian, F., Riboli, E., Key, T. J., Travis, R. C., Campa, D., Ingles, S. A., John, E. M., Hayes, R. B., Pharoah, P., Khaw, K., Stanford, J. L., Ostrander, E. A., Signorello, L. B., Thibodeau, S. N., Schaid, D., Maier, C., Vogel, W., Kibel, A. S., Cybulski, C., Lubinski, J., Cannon-Albright, L., Brenner, H., Park, J. Y., Kaneva, R., Batra, J., Spurdle, A., Clements, J. A., Teixeira, M. R., Govindasami, K., Guy, M., Wilkinson, R. A., Sawyer, E. J., Morgan, A., Dicks, E., Baynes, C., Conroy, D., Bojesen, S. E., Kaaks, R., Vincent, D., Bacot, F., Tessier, D. C., Easton, D. F., Eeles, R. A. 2013; 22 (12): 2520-2528

    Abstract

    Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.

    View details for DOI 10.1093/hmg/ddt086

    View details for PubMedID 23535824

    View details for PubMedCentralID PMC3658165

  • Matrix Metalloproteinase Genes Are Associated with Breast Cancer Risk and Survival: The Breast Cancer Health Disparities Study PLOS ONE Slattery, M. L., John, E., Torres-Mejia, G., Stern, M., Lundgreen, A., Hines, L., Giuliano, A., Baumgartner, K., Herrick, J., Wolff, R. K. 2013; 8 (5)

    Abstract

    Matrix metalloproteinases (MMPs) contribute to cancer through their involvement in cancer invasion and metastasis. We evaluated genetic variation in MMP1 (9 SNPs), MMP2 (8 SNPs), MMP3 (4 SNPs), and MMP9 (3 SNPs) and breast cancer risk among Hispanic (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Ancestral informative markers (n?=?104) were assessed to determine Native American (NA) ancestry. MMP1 [4 single nucleotide polymorphisms (SNPs)] and MMP2 (2 SNPs) were associated with breast cancer overall. MMP1 rs996999 had strongest associations among women with the most NA ancestry (OR 1.61,95% CI 1.09,2.40) as did MMP3 rs650108 (OR 1.36, 95% CI 1.05,1.75) and MMP9 rs3787268 (OR 1.52, 95% CI 1.09,2.13). The adaptive rank truncated product (ARTP) showed a significant pathway p(artp)? value of 0.04, with a stronger association among women with the most NA ancestry (p(artp)?=?0.02). Significant pathway genes using the ARTP were MMP1 for all women (p(artp)?=?0.02) and MMP9 for women with the most NA ancestry (p(artp)?=?0.024); MMP2 was borderline significant overall (p(artp)?=0.06) and MMP1 and MMP3 were borderline significant for women with the most NA ancestry (p(artp)?=?0.07 and 0.06 respectively). MMP1 and MMP2 were associated with ER+/PR+ and ER+/PR-tumors; MMP3 and MMP9 were associated with ER-/PR- tumors. The pathway was highly significant with survival (p(artp)?=?0.0041) with MMP2 having the strongest gene association (p(artp)?=?0.0007). Our findings suggest that genetic variation in MMP genes influence breast cancer development and survival in this genetically admixed population.

    View details for DOI 10.1371/journal.pone.0063165

    View details for Web of Science ID 000319081900013

    View details for PubMedID 23696797

    View details for PubMedCentralID PMC3655963

  • Genetic variants associated with breast cancer risk for Ashkenazi Jewish women with strong family histories but no identifiable BRCA1/2 mutation HUMAN GENETICS Rinella, E. S., Shao, Y., Yackowski, L., Pramanik, S., Oratz, R., Schnabel, F., Guha, S., Leduc, C., Campbell, C. L., Klugman, S. D., Terry, M. B., Senie, R. T., Andrulis, I. L., Daly, M., John, E. M., Roses, D., Chung, W. K., Ostrer, H. 2013; 132 (5): 523-536

    Abstract

    The ability to establish genetic risk models is critical for early identification and optimal treatment of breast cancer. For such a model to gain clinical utility, more variants must be identified beyond those discovered in previous genome-wide association studies (GWAS). This is especially true for women at high risk because of family history, but without BRCA1/2 mutations. This study incorporates three datasets in a GWAS analysis of women with Ashkenazi Jewish (AJ) homogeneous ancestry. Two independent discovery cohorts comprised 239 and 238 AJ women with invasive breast cancer or preinvasive ductal carcinoma in situ and strong family histories of breast cancer, but lacking the three BRCA1/2 founder mutations, along with 294 and 230 AJ controls, respectively. An independent, third cohort of 203 AJ cases with familial breast cancer history and 263 healthy controls of AJ women was used for validation. A total of 19 SNPs were identified as associated with familial breast cancer risk in AJ women. Among these SNPs, 13 were identified from a panel of 109 discovery SNPs, including an FGFR2 haplotype. In addition, six previously identified breast cancer GWAS SNPs were confirmed in this population. Seven of the 19 markers were significant in a multivariate predictive model of familial breast cancer in AJ women, three novel SNPs [rs17663555(5q13.2), rs566164(6q21), and rs11075884(16q22.2)], the FGFR2 haplotype, and three previously published SNPs [rs13387042(2q35), rs2046210(ESR1), and rs3112612(TOX3)], yielding moderate predictive power with an area under the curve (AUC) of the ROC (receiver-operator characteristic curve) of 0.74. Population-specific genetic variants in addition to variants shared with populations of European ancestry may improve breast cancer risk prediction among AJ women from high-risk families without founder BRCA1/2 mutations.

    View details for DOI 10.1007/s00439-013-1269-4

    View details for Web of Science ID 000317691100004

    View details for PubMedID 23354978

  • Risk of pancreatic cancer in breast cancer families from the breast cancer family registry. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Mocci, E., Milne, R. L., Méndez-Villamil, E. Y., Hopper, J. L., John, E. M., Andrulis, I. L., Chung, W. K., Daly, M., Buys, S. S., Malats, N., Goldgar, D. E. 2013; 22 (5): 803-811

    Abstract

    Increased risk of pancreatic cancer has been reported in breast cancer families carrying BRCA1and BRCA2 mutations; however, pancreatic cancer risk in mutation-negative (BRCAX) families has not been explored to date. The aim of this study was to estimate pancreatic cancer risk in high-risk breast cancer families according to the BRCA mutation status.A retrospective cohort analysis was applied to estimate standardized incidence ratios (SIR) for pancreatic cancer. A total of 5,799 families with ?1 breast cancer case tested for mutations in BRCA1 and/or BRCA2 were eligible. Families were divided into four classes: BRCA1, BRCA2, BRCAX with ?2 breast cancer diagnosed before age 50 (class 3), and the remaining BRCAX families (class 4).BRCA1 mutation carriers were at increased risk of pancreatic cancer [SIR = 4.11; 95% confidence interval (CI), 2.94-5.76] as were BRCA2 mutation carriers (SIR = 5.79; 95% CI, 4.28-7.84). BRCAX family members were also at increased pancreatic cancer risk, which did not appear to vary by number of members with early-onset breast cancer (SIR = 1.31; 95% CI, 1.06-1.63 for class 3 and SIR = 1.30; 95% CI, 1.13-1.49 for class 4).Germline mutations in BRCA1 and BRCA2 are associated with an increased risk of pancreatic cancer. Members of BRCAX families are also at increased risk of pancreatic cancer, pointing to the existence of other genetic factors that increase the risk of both pancreatic cancer and breast cancer. Impact: This study clarifies the relationship between familial breast cancer and pancreatic cancer. Given its high mortality, pancreatic cancer should be included in risk assessment in familial breast cancer counseling. Cancer Epidemiol Biomarkers Prev; 22(5); 803-11. ©2013 AACR.

    View details for DOI 10.1158/1055-9965.EPI-12-0195

    View details for PubMedID 23456555

  • A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. Nature genetics Monda, K. L., Chen, G. K., Taylor, K. C., Palmer, C., Edwards, T. L., Lange, L. A., Ng, M. C., Adeyemo, A. A., Allison, M. A., Bielak, L. F., Chen, G., Graff, M., Irvin, M. R., Rhie, S. K., Li, G., Liu, Y., Liu, Y., Lu, Y., Nalls, M. A., Sun, Y. V., Wojczynski, M. K., Yanek, L. R., Aldrich, M. C., Ademola, A., Amos, C. I., Bandera, E. V., Bock, C. H., Britton, A., Broeckel, U., Cai, Q., Caporaso, N. E., Carlson, C. S., Carpten, J., Casey, G., Chen, W., Chen, F., Chen, Y. I., Chiang, C. W., Coetzee, G. A., Demerath, E., Deming-Halverson, S. L., Driver, R. W., Dubbert, P., Feitosa, M. F., Feng, Y., Freedman, B. I., Gillanders, E. M., Gottesman, O., Guo, X., Haritunians, T., Harris, T., Harris, C. C., Hennis, A. J., Hernandez, D. G., McNeill, L. H., Howard, T. D., Howard, B. V., Howard, V. J., Johnson, K. C., Kang, S. J., Keating, B. J., Kolb, S., Kuller, L. H., Kutlar, A., Langefeld, C. D., Lettre, G., Lohman, K., Lotay, V., Lyon, H., Manson, J. E., Maixner, W., Meng, Y. A., Monroe, K. R., Morhason-Bello, I., Murphy, A. B., Mychaleckyj, J. C., Nadukuru, R., Nathanson, K. L., Nayak, U., N'Diaye, A., Nemesure, B., Wu, S., Leske, M. C., Neslund-Dudas, C., Neuhouser, M., Nyante, S., Ochs-Balcom, H., Ogunniyi, A., Ogundiran, T. O., Ojengbede, O., Olopade, O. I., Palmer, J. R., Ruiz-Narvaez, E. A., Palmer, N. D., Press, M. F., Rampersaud, E., Rasmussen-Torvik, L. J., Rodriguez-Gil, J. L., Salako, B., Schadt, E. E., Schwartz, A. G., Shriner, D. A., Siscovick, D., Smith, S. B., Wassertheil-Smoller, S., Speliotes, E. K., Spitz, M. R., Sucheston, L., Taylor, H., Tayo, B. O., Tucker, M. A., Van den Berg, D. J., Edwards, D. R., Wang, Z., Wiencke, J. K., Winkler, T. W., Witte, J. S., Wrensch, M., Wu, X., Yang, J. J., Levin, A. M., Young, T. R., Zakai, N. A., Cushman, M., Zanetti, K. A., Zhao, J. H., Zhao, W., Zheng, Y., Zhou, J., Ziegler, R. G., Zmuda, J. M., Fernandes, J. K., Gilkeson, G. S., Kamen, D. L., Hunt, K. J., Spruill, I. J., Ambrosone, C. B., Ambs, S., Arnett, D. K., Atwood, L., Becker, D. M., Berndt, S. I., Bernstein, L., Blot, W. J., Borecki, I. B., Bottinger, E. P., Bowden, D. W., Burke, G., Chanock, S. J., Cooper, R. S., Ding, J., Duggan, D., Evans, M. K., Fox, C., Garvey, W. T., Bradfield, J. P., Hakonarson, H., Grant, S. F., Hsing, A., Chu, L., Hu, J. J., Huo, D., Ingles, S. A., John, E. M., Jordan, J. M., Kabagambe, E. K., Kardia, S. L., Kittles, R. A., Goodman, P. J., Klein, E. A., Kolonel, L. N., Le Marchand, L., Liu, S., McKnight, B., Millikan, R. C., Mosley, T. H., Padhukasahasram, B., Williams, L. K., Patel, S. R., Peters, U., Pettaway, C. A., Peyser, P. A., Psaty, B. M., Redline, S., Rotimi, C. N., Rybicki, B. A., Sale, M. M., Schreiner, P. J., Signorello, L. B., Singleton, A. B., Stanford, J. L., Strom, S. S., Thun, M. J., Vitolins, M., Zheng, W., Moore, J. H., Williams, S. M., Ketkar, S., Zhu, X., Zonderman, A. B., Kooperberg, C., Papanicolaou, G. J., Henderson, B. E., Reiner, A. P., Hirschhorn, J. N., Loos, R. J., North, K. E., Haiman, C. A. 2013; 45 (6): 690-696

    Abstract

    Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

    View details for DOI 10.1038/ng.2608

    View details for PubMedID 23583978

  • Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array NATURE GENETICS Eeles, R. A., Al Olama, A. A., Benlloch, S., Saunders, E. J., Leongamornlert, D. A., Tymrakiewicz, M., Ghoussaini, M., Luccarini, C., Dennis, J., Jugurnauth-Little, S., Dadaev, T., Neal, D. E., Hamdy, F. C., Donovan, J. L., Muir, K., Giles, G. G., Severi, G., Wiklund, F., Gronberg, H., Haiman, C. A., Schumacher, F., Henderson, B. E., Le Marchand, L., Lindstrom, S., Kraft, P., Hunter, D. J., Gapstur, S., Chanock, S. J., Berndt, S. I., Albanes, D., Andriole, G., Schleutker, J., Weischer, M., Canzian, F., Riboli, E., Key, T. J., Travis, R. C., Campa, D., Ingles, S. A., John, E. M., Hayes, R. B., Pharoah, P. D., Pashayan, N., Khaw, K., Stanford, J. L., Ostrander, E. A., Signorello, L. B., Thibodeau, S. N., Schaid, D., Maier, C., Vogel, W., Kibel, A. S., Cybulski, C., Lubhiski, J., Cannon-Albright, L., Brenner, H., Park, J. Y., Kaneva, R., Batra, J., Spurdle, A. B., Clements, J. A., Teixeira, M. R., Dicks, E., Lee, A., Dunning, A. M., Baynes, C., Conroy, D., Maranian, M. J., Ahmed, S., Govindasami, K., Guy, M., Wilkinson, R. A., Sawyer, E. J., Morgan, A., Dearnaley, D. P., Horwich, A., Huddart, R. A., Khoo, V. S., Parker, C. C., van As, N. J., Woodhouse, C. J., Thompson, A., Dudderidge, T., Ogden, C., Cooper, C. S., Lophatananon, A., Cox, A., Southey, M. C., Hopper, J. L., English, D. R., Aly, M., Adolfsson, J., Xu, J., Zheng, S. L., Yeager, M., Kaaks, R., Diver, W. R., Gaudet, M. M., Stern, M. C., Corral, R., Joshi, A. D., Shahabi, A., Wahlfors, T., Tammela, T. L., Auvinen, A., Virtamo, J., Klarskov, P., Nordestgaard, B. G., Roder, M. A., Nielsen, S. F., Bojesen, S. E., Siddiq, A., FitzGerald, L. M., Kolb, S., Kwon, E. M., Karyadi, D. M., Blot, W. J., Zheng, W., Cai, Q., McDonnell, S. K., Rinckleb, A. E., Drake, B., Colditz, G., Wokolorczyk, D., Stephenson, R. A., Teerlink, C., Muller, H., Rothenbacher, D., Sellers, T. A., Lin, H., Slavov, C., Mitev, V., Lose, F., Srinivasan, S., Maia, S., Paulo, P., Lange, E., Cooney, K. A., Antoniou, A. C., Vincent, D., Bacot, F., Tessier, D. C., Kote-Jarai, Z., Easton, D. F. 2013; 45 (4): 385-391

    Abstract

    Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ?30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

    View details for DOI 10.1038/ng.2560

    View details for Web of Science ID 000316840600008

    View details for PubMedID 23535732

  • Genome-wide association studies identify four ER negative-specific breast cancer risk loci NATURE GENETICS Garcia-Closas, M., Couch, F. J., Lindstrom, S., Michailidouo, K., Schmidt, M. K., Brook, M. N., Orr, N., Rhie, S. K., Riboli, E., Feigelson, H. S., Le Marchand, L., Buring, J. E., Eccles, D., Miron, P., Fasching, P. A., Brauch, H., Chang-Claude, J., Carpenter, J., Godwin, A. K., Nevanlinna, H., Giles, G. G., Cox, A., Hopper, J. L., Bolla, M. K., Wang, Q., Dennis, J., Dicks, E., Howat, W. J., Schoof, N., Bojesen, S. E., Lambrechts, D., Broeks, A., Andrulis, I. L., Guenel, P., Burwinkel, B., Sawyer, E. J., Hollestelle, A., Fletcher, O., Winqvist, R., Brenner, H., Mannermaa, A., Hamann, U., Meindl, A., Lindblom, A., Zheng, W., Devillee, P., Goldberg, M. S., Lubinski, J., Kristensen, V., Swerdlow, A., Anton-Culver, H., Doerk, T., Muir, K., Matsuo, K., Wu, A. H., Radice, P., Teo, S. H., Shu, X., Blot, W., Kang, D., Hartman, M., Sangrajrang, S., Shen, C., Southey, M. C., Park, D. J., Hammet, F., Stone, J., van't Veer, L. J., Rutgers, E. J., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Peto, J., Schrauder, M. G., Ekici, A. B., Beckmann, M. W., Silva, I. d., Johnson, N., Warren, H., Tomlins, I., Kerin, M. J., Miller, N., Marme, F., Schneeweiss, A., Sohn, C., Therese Truong, T., Laurent-Puig, P., Kerbrat, P., Nordestgaard, B. G., Nielsen, S. F., Flyger, H., Milne, R. L., Arias Perez, J. I., Menendez, P., Mueller, H., Arndt, V., Stegmaier, C., Lichtner, P., Lochmann, M., Justenhoven, C., Ko, Y., Muranen, T. A., Aittomaki, K., Blomqvist, C., Greco, D., Heikkinen, T., Ito, H., Iwata, H., Yatabe, Y., Antonenkova, N. N., Margolin, S., Kataja, V., Kosma, V., Hartikainen, J. M., Balleine, R., Tseng, C., Van Den Berg, D., Stram, D. O., Neven, P., Dieudonne, A., Leunen, K., Rudolph, A., Nickels, S., Flesch-Janys, D., Peterlongo, P., Peissel, B., Bernard, L., Olson, J. E., Wang, X., Stevens, K., Severi, G., Baglietto, L., McLean, C., Coetzee, G. A., Feng, Y., Henderson, B. E., Schumacher, F., Bogdanova, N. V., Labreche, F., Dumont, M., Yip, C. H., Taib, N. A., Cheng, C., Shrubsole, M., Long, J., Pylkas, K., Jukkola-Vuorinen, A., Kauppila, S., Knight, J. A., Glendon, G., Mulligan, A. M., Tollenaar, R. A., Seynaeve, C. M., Kriege, M., Hooning, M. J., van den Ouweland, A. M., van Deurzen, C. H., Lu, W., Gao, Y., Cai, H., Balasubramanian, S. P., Cross, S. S., Reed, M. W., Signorello, L., Cai, Q., Shah, M., Miao, H., Chan, C. W., Chia, K. S., Jakubowska, A., Jaworska, K., Durda, K., Hsiung, C., Wu, P., Yu, J., Ashworth, A., Jones, M., Tessier, D. C., Gonzalez-Neira, A., Pita, G., Alonso, M. R., Vincent, D., Bacot, F., Ambrosone, C. B., Bandera, E. V., John, E. M., Chen, G. K., Hu, J. J., Rodriguez-Gil, J. L., Bernstein, L., Press, M. F., Ziegler, R. G., Millikan, R. M., Deming-Halverson, S. L., Nyante, S., Ingles, S. A., Waisfisz, Q., Tsimiklis, H., Makalic, E., Schmidt, D., Bui, M., Gibson, L., Mueller-Myhsok, B., Schmutzler, R. K., Hein, R., Dahmen, N., Beckmann, L., Aaltonen, K., Czene, K., Irwanto, A., Liu, J., Turnbull, C., Rahman, N., Meijers-Heijboer, H., Uitterlinden, A. G., Rivadeneira, F., Olswold, C., Slager, S., Pilarski, R., Ademuyiwa, F., Konstantopoulou, I., Martin, N. G., Montgomery, G. W., Slamon, D. J., Rauh, C., Lux, M. P., Jud, S. M., Bruning, T., Weaver, J., Harma, P., Pathak, H., Tapper, W., Gerty, S., Durcan, L., Trichopoulos, D., Tumino, R., Peeters, P. H., Kaaks, R., Campa, D., Canzian, F., Weiderpass, E., Johansson, M., Khaw, K., Travis, R., Clavel-Chapelon, F., Kolonel, L. N., Chen, C., Beck, A., Hankinson, S. E., Berg, C. D., Hoover, R. N., Lissowska, J., Figueroa, J. D., Chasman, D. I., Gaudet, M. M., Diver, W. R., Willett, W. C., Hunter, D. J., Simard, J., Benitez, J., Dunning, A. M., Sherman, M. E., Chenevix-Trench, G., Chanock, S. J., Hall, P., Pharoah, P. D., Vachon, C., Easton, D. F., Haiman, C. A., Kraft, P. 2013; 45 (4): 392-398

    Abstract

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

    View details for DOI 10.1038/ng.2561

    View details for Web of Science ID 000316840600009

    View details for PubMedID 23535733

    View details for PubMedCentralID PMC3771695

  • Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors PLOS GENETICS Nickels, S., Truong, T., Hein, R., Stevens, K., Buck, K., Behrens, S., Eilber, U., Schmidt, M., Haeberle, L., Vrieling, A., Gaudet, M., Figueroa, J., Schoof, N., Spurdle, A. B., Rudolph, A., Fasching, P. A., Hopper, J. L., Makalic, E., Schmidt, D. F., Southey, M. C., Beckmann, M. W., Ekici, A. B., Fletcher, O., Gibson, L., Silva, I. d., Peto, J., Humphreys, M. K., Wang, J., Cordina-Duverger, E., Menegaux, F., Nordestgaard, B. G., Bojesen, S. E., Lanng, C., Anton-Culver, H., Ziogas, A., Bernstein, L., Clarke, C. A., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Brauch, H., Bruening, T., Harth, V., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Lambrechts, D., Smeets, D., Neven, P., Paridaens, R., Flesch-Janys, D., Obi, N., Wang-Gohrke, S., Couch, F. J., Olson, J. E., Vachon, C. M., Giles, G. G., Severi, G., Baglietto, L., Offit, K., John, E. M., Miron, A., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Chanock, S. J., Lissowska, J., Liu, J., Cox, A., Cramp, H., Connley, D., Balasubramanian, S., Dunning, A. M., Shah, M., Trentham-Dietz, A., Newcomb, P., Titus, L., Egan, K., Cahoon, E. K., Rajaraman, P., Sigurdson, A. J., Doody, M. M., Guenel, P., Pharoah, P. D., Schmidt, M. K., Hall, P., Easton, D. F., Garcia-Closas, M., Milne, R. L., Chang-Claude, J. 2013; 9 (3)

    Abstract

    Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 × 10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 × 10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ? 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 × 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

    View details for DOI 10.1371/journal.pgen.1003284

    View details for Web of Science ID 000316866700004

    View details for PubMedID 23544014

    View details for PubMedCentralID PMC3609648

  • Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk PLOS GENETICS Couch, F. J., Wang, X., McGuffog, L., Lee, A., Olswold, C., Kuchenbaecker, K. B., Soucy, P., Fredericksen, Z., Barrowdale, D., Dennis, J., Gaudet, M. M., Dicks, E., Kosel, M., Healey, S., Sinilnikova, O. M., Lee, A., Bacot, F., Vincent, D., Hogervorst, F. B., Peock, S., Stoppa-Lyonnet, D., Jakubowska, A., Radice, P., Schmutzler, R. K., Domchek, S. M., Piedmonte, M., Singer, C. F., friedman, e., Thomassen, M., Hansen, T. v., Neuhausen, S. L., Szabo, C. I., Blanco, I., Greene, M. H., Karlan, B. Y., Garber, J., Phelan, C. M., Weitzel, J. N., Montagna, M., Olah, E., Andrulis, I. L., Godwin, A. K., Yannoukakos, D., Goldgar, D. E., Caldes, T., Nevanlinna, H., Osorio, A., Terry, M. B., Daly, M. B., Van Rensburg, E. J., Hamann, U., Ramus, S. J., Toland, A. E., Caligo, M. A., Olopade, O. I., Tung, N., Claes, K., Beattie, M. S., Southey, M. C., Imyanitov, E. N., Tischkowitz, M., Janavicius, R., John, E. M., Kwong, A., Diez, O., Balmana, J., Barkardottir, R. B., Arun, B. K., Rennert, G., Teo, S., Ganz, P. A., Campbell, I., van der Hout, A. H., van Deurzen, C. H., Seynaeve, C., Garcia, E. B., van Leeuwen, F. E., Meijers-Heijboer, H. E., Gille, J. J., Ausems, M. G., Blok, M. J., Ligtenberg, M. J., Rookus, M. A., Devilee, P., Verhoef, S., van Os, T. A., Wijnen, J. T., Frost, D., Ellis, S., Fineberg, E., Platte, R., Evans, D. G., Izatt, L., Eeles, R. A., Adlard, J., Eccles, D. M., Cook, J., Brewer, C., Douglas, F., Hodgson, S., Morrison, P. J., Side, L. E., Donaldson, A., Houghton, C., Rogers, M. T., Dorkins, H., Eason, J., Gregory, H., McCann, E., Murray, A., Calender, A., Hardouin, A., Berthet, P., Delnatte, C., Nogues, C., Lasset, C., Houdayer, C., Leroux, D., Rouleau, E., Prieur, F., Damiola, F., Sobol, H., Coupier, I., Venat-Bouvet, L., Castera, L., Gauthier-Villars, M., Leone, M., Pujol, P., Mazoyer, S., Bignon, Y., Zlowocka-Perlowska, E., Gronwald, J., Lubinski, J., Durda, K., Jaworska, K., Huzarski, T., Spurdle, A. B., Viel, A., Peissel, B., Bonanni, B., Melloni, G., Ottini, L., Papi, L., Varesco, L., Tibiletti, M. G., Peterlongo, P., Volorio, S., Manoukian, S., Pensotti, V., Arnold, N., Engel, C., Deissler, H., Gadzicki, D., Gehrig, A., Kast, K., Rhiem, K., Meindl, A., Niederacher, D., Ditsch, N., Plendl, H., Preisler-Adams, S., Engert, S., Sutter, C., Varon-Mateeva, R., Wappenschmidt, B., Weber, B. H., Arver, B., Stenmark-Askmalm, M., Loman, N., Rosenquist, R., Einbeigi, Z., Nathanson, K. L., Rebbeck, T. R., Blank, S. V., Cohn, D. E., Rodriguez, G. C., Small, L., Friedlander, M., Bae-Jump, V. L., Fink-Retter, A., Rappaport, C., Gschwantler-Kaulich, D., Pfeiler, G., Tea, M., Lindor, N. M., Kaufman, B., Paluch, S. S., Laitman, Y., Skytte, A., Gerdes, A., Pedersen, I. S., Moeller, S. T., Kruse, T. A., Jensen, U. B., Vijai, J., Sarrel, K., Robson, M., Kauff, N., Mulligan, A. M., Glendon, G., Ozcelik, H., Ejlertsen, B., Nielsen, F. C., Jonson, L., Andersen, M. K., Ding, Y. C., Steele, L., Foretova, L., Teule, A., Lazaro, C., Brunet, J., Angel Pujana, M., Mai, P. L., Loud, J. T., Walsh, C., Lester, J., Orsulic, S., Narod, S. A., Herzog, J., Sand, S. R., Tognazzo, S., Agata, S., Vaszko, T., Weaver, J., Stavropoulou, A. V., Buys, S. S., Romero, A., de la Hoya, M., Aittomaki, K., Muranen, T. A., Duran, M., Chung, W. K., Lasa, A., Dorfling, C. M., Miron, A., Benitez, J., Senter, L., Huo, D., Chan, S. B., Sokolenko, A. P., Chiquette, J., Tihomirova, L., Friebel, T. M., Agnarsson, B. A., Lu, K. H., Lejbkowicz, F., James, P. A., Hall, P., Dunning, A. M., Tessier, D., Cunningham, J., Slager, S. L., Wang, C., Hart, S., Stevens, K., Simard, J., Pastinen, T., Pankratz, V. S., Offit, K., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C. 2013; 9 (3)

    Abstract

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

    View details for DOI 10.1371/journal.pgen.1003212

    View details for Web of Science ID 000316866700002

    View details for PubMedID 23544013

  • A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women PLOS ONE Song, C., Chen, G. K., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Chanock, S. J., Wan, P., Sheng, X., Pooler, L. C., Van den Berg, D. J., Le Marchand, L., Kolonel, L. N., Henderson, B. E., Haiman, C. A., Stram, D. O. 2013; 8 (2)

    Abstract

    Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.

    View details for DOI 10.1371/journal.pone.0057298

    View details for Web of Science ID 000315524900070

    View details for PubMedID 23468962

    View details for PubMedCentralID PMC3585353

  • Risk of Asynchronous Contralateral Breast Cancer in Noncarriers of BRCA1 and BRCA2 Mutations With a Family History of Breast Cancer: A Report From the Women's Environmental Cancer and Radiation Epidemiology Study JOURNAL OF CLINICAL ONCOLOGY Reiner, A. S., John, E. M., Brooks, J. D., Lynch, C. F., Bernstein, L., Mellemkjaer, L., Malone, K. E., Knight, J. A., Capanu, M., Teraoka, S. N., Concannon, P., Liang, X., Figueiredo, J. C., Smith, S. A., Stovall, M., Pike, M. C., Haile, R. W., Thomas, D. C., Begg, C. B., Bernstein, J. L. 2013; 31 (4): 433-439

    Abstract

    To fully characterize the risk of contralateral breast cancer (CBC) in patients with breast cancer with a family history who test negative for BRCA1 and BRCA2 mutations.From our population-based case-control study comparing women with CBC to women with unilateral breast cancer (UBC), we selected women who tested negative for BRCA1 and BRCA2 mutations (594 patients with CBC/1,119 control patients with UBC). Rate ratios (RRs) and 95% CIs were estimated to examine the association between family history of breast cancer and risk of asynchronous CBC. Age- and family history-specific 10-year cumulative absolute risks of CBC were estimated.Family history of breast cancer was associated with increased CBC risk; risk was highest among young women (< 45 years) with first-degree relatives affected at young ages (< 45 years; RR, 2.5; 95% CI, 1.1 to 5.3) or women with first-degree relatives with bilateral disease (RR, 3.6; 95% CI, 2.0 to 6.4). Women diagnosed with UBC before age 55 years with a first-degree family history of CBC had a 10-year risk of CBC of 15.6%.Young women with breast cancer who have a family history of breast cancer and who test negative for deleterious mutations in BRCA1 and BRCA2 are at significantly greater risk of CBC than other breast cancer survivors. This risk varies with diagnosis age, family history of CBC, and degree of relationship to an affected relative. Women with a first-degree family history of bilateral disease have risks of CBC similar to mutation carriers. This has important implications for the clinical management of patients with breast cancer with family history of the disease.

    View details for DOI 10.1200/JCO.2012.43.2013

    View details for Web of Science ID 000314099800010

    View details for PubMedID 23269995

  • A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease HUMAN MOLECULAR GENETICS Al Olama, A. A., Kote-Jarai, Z., Schumacher, F. R., Wiklund, F., Berndt, S. I., Benlloch, S., Giles, G. G., Severi, G., Neal, D. E., Hamdy, F. C., Donovan, J. L., Hunter, D. J., Henderson, B. E., Thun, M. J., Gaziano, M., Giovannucci, E. L., Siddiq, A., Travis, R. C., Cox, D. G., Canzian, F., Riboli, E., Key, T. J., Andriole, G., Albanes, D., Hayes, R. B., Schleutker, J., Auvinen, A., Tammela, T. L., Weischer, M., Stanford, J. L., Ostrander, E. A., Cybulski, C., Lubinski, J., Thibodeau, S. N., Schaid, D. J., Sorensen, K. D., Batra, J., Clements, J. A., Chambers, S., Aitken, J., Gardiner, R. A., Maier, C., Vogel, W., Doerk, T., Brenner, H., Habuchi, T., Ingles, S., John, E. M., Dickinson, J. L., Cannon-Albright, L., Teixeira, M. R., Kaneva, R., Zhang, H., Lu, Y., Park, J. Y., Cooney, K. A., Muir, K. R., Leongamornlert, D. A., Saunders, E., Tymrakiewicz, M., Mahmud, N., Guy, M., Govindasami, K., O'Brien, L. T., Wilkinson, R. A., Hall, A. L., Sawyer, E. J., Dadaev, T., Morrison, J., Dearnaley, D. P., Horwich, A., Huddart, R. A., Khoo, V. S., Parker, C. C., Van As, N., Woodhouse, C. J., Thompson, A., Dudderidge, T., Ogden, C., Cooper, C. S., Lophatonanon, A., Southey, M. C., Hopper, J. L., English, D., Virtamo, J., Le Marchand, L., Campa, D., Kaaks, R., Lindstrom, S., Diver, W. R., Gapstur, S., Yeager, M., Cox, A., Stern, M. C., Corral, R., Aly, M., Isaacs, W., Adolfsson, J., Xu, J., Zheng, S. L., Wahlfors, T., Taari, K., Kujala, P., Klarskov, P., Nordestgaard, B. G., Roder, M. A., Frikke-Schmidt, R., Bojesen, S. E., FitzGerald, L. M., Kolb, S., Kwon, E. M., Karyadi, D. M., Orntoft, T. F., Borre, M., Rinckleb, A., Luedeke, M., Herkommer, K., Meyer, A., Serth, J., Marthick, J. R., Patterson, B., Wokolorczyk, D., Spurdle, A., Lose, F., McDonnell, S. K., Joshi, A. D., Shahabi, A., Pinto, P., Santos, J., Ray, A., Sellers, T. A., Lin, H., Stephenson, R. A., Teerlink, C., Muller, H., Rothenbacher, D., Tsuchiya, N., Narita, S., Cao, G., Slavov, C., Mitev, V., Chanock, S., Gronberg, H., Haiman, C. A., Kraft, P., Easton, D. F., Eeles, R. A. 2013; 22 (2): 408-415

    Abstract

    Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

    View details for DOI 10.1093/hmg/dds425

    View details for Web of Science ID 000312651800018

    View details for PubMedCentralID PMC3526158

  • Prevalence and Type of BRCA Mutations in Hispanics Undergoing Genetic Cancer Risk Assessment in the Southwestern United States: A Report From the Clinical Cancer Genetics Community Research Network JOURNAL OF CLINICAL ONCOLOGY Weitzel, J. N., Clague, J., Martir-Negron, A., Ogaz, R., Herzog, J., Ricker, C., Jungbluth, C., Cina, C., Duncan, P., Unzeitig, G., Saldivar, J. S., Beattie, M., Feldman, N., Sand, S., Port, D., Barragan, D. I., John, E. M., Neuhausen, S. L., Larson, G. P. 2013; 31 (2): 210-216

    Abstract

    To determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA).Hispanics (n = 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board-approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n = 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement.Deleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic- and population-based cohorts in the United States.BRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA.

    View details for DOI 10.1200/JCO.2011.41.0027

    View details for Web of Science ID 000313345100014

    View details for PubMedID 23233716

    View details for PubMedCentralID PMC3532393

  • A genome-wide association study of breast cancer in women of African ancestry HUMAN GENETICS Chen, F., Chen, G. K., Stram, D. O., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Palmer, J. R., Hu, J. J., Rebbeck, T. R., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Ruiz-Narvaez, E. A., Deming, S. L., Rodriguez-Gil, J. L., DeMichele, A., Chanock, S. J., Blot, W., Signorello, L., Cai, Q., Li, G., Long, J., Huo, D., Zheng, Y., Cox, N. J., Olopade, O. I., Ogundiran, T. O., Adebamowo, C., Nathanson, K. L., Domchek, S. M., Simon, M. S., Hennis, A., Nemesure, B., Wu, S., Leske, M. C., Ambs, S., Hutter, C. M., Young, A., Kooperberg, C., Peters, U., Rhie, S. K., Wan, P., Sheng, X., Pooler, L. C., Van den Berg, D. J., Le Marchand, L., Kolonel, L. N., Henderson, B. E., Haiman, C. A. 2013; 132 (1): 39-48

    Abstract

    Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of >1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, which reached statistical significance levels of 10(-6) and 10(-5) in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p = 4.3 × 10(-6); rs10510333 at chromosome 3p26: OR = 1.15, p = 1.5 × 10(-5)). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample.

    View details for DOI 10.1007/s00439-012-1214-y

    View details for Web of Science ID 000313005800005

    View details for PubMedID 22923054

  • Obesity and Mortality After Breast Cancer by Race/Ethnicity: The California Breast Cancer Survivorship Consortium AMERICAN JOURNAL OF EPIDEMIOLOGY Kwan, M. L., John, E. M., Caan, B. J., Lee, V. S., Bernstein, L., Cheng, I., Gomez, S. L., Henderson, B. E., Keegan, T. H., Kurian, A. W., Lu, Y., Monroe, K. R., Roh, J. M., Shariff-Marco, S., Sposto, R., Vigen, C., Wu, A. H. 2013; electronic publication ahead of print
  • Protective Effects of Low Calcium Intake and Low Calcium Absorption Vitamin D Receptor Genotype in the California Collaborative Prostate Cancer Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Rowland, G. W., Schwartz, G. G., John, E. M., Ingles, S. A. 2013; 22 (1): 16-24

    Abstract

    High calcium intake is consistently associated with increased prostate cancer risk in epidemiologic studies. We previously reported that the positive association between calcium intake and risk of aggressive prostate cancer was modified by the single-nucleotide polymorphism (SNP) in the CDX-2 binding site of the vitamin D receptor (VDR) gene, among African American men.We expanded our previous study to include White men, a population with a higher calcium intake and a higher prevalence of the low absorption allele. We also examined VDR polymorphisms at other loci unrelated to calcium absorption. The study included 1,857 prostate cancer cases (1,140 with advanced stage at diagnosis, 717 with localized stage) and 1,096 controls. OR were estimated using conditional logistic regression.Among both Blacks and Whites, we observed a threshold for calcium intake (604 mg/d) below which prostate cancer risk declined sharply. Low calcium intake was most strongly associated with decreased risk among men with the VDR Cdx2 low calcium absorption genotype (P for interaction = 0.001 and P = 0.06 for Whites and African Americans, respectively). Among all men with this genotype, those in the lowest quartile of calcium intake (?604 mg/d) had a 50% reduction in risk as compared with those in the upper three quartiles [OR = 0.49; 95% confidence interval (CI), 0.36-0.67]. The association between calcium intake and prostate cancer risk was not modified by genotype at other VDR loci.Our findings support the hypothesis that genetic determinants of calcium absorption influence prostate cancer risk.The differences between African Americans and Whites in calcium absorption and dietary calcium intake may contribute to racial disparities in prostate cancer incidence and mortality rates.

    View details for DOI 10.1158/1055-9965.EPI-12-0922-T

    View details for Web of Science ID 000313531900003

    View details for PubMedID 23129590

  • Mammographic density and breast cancer: a comparison of related and unrelated controls in the Breast Cancer Family Registry BREAST CANCER RESEARCH Linton, L., Martin, L. J., Li, Q., Huszti, E., Minkin, S., John, E. M., Rommens, J., Paterson, A. D., Boyd, N. F. 2013; 15 (3)

    Abstract

    INTRODUCTION: Percent mammographic density (PMD) is a strong and highly heritable risk factor for breast cancer. Studies of the role of PMD in familial breast cancer may require controls, such as the sisters of cases, selected from the same "risk set" as the cases. The use of sister controls would allow control for factors that have been shown to influence risk of breast cancer such as race/ethnicity, socio-economic status and a family history of breast cancer, but may introduce "overmatching" and attenuate case-control differences in PMD. METHODS: To examine the potential effects of using sister controls rather than unrelated controls in a case-control study we examined PMD in triplets, each comprised of a case with invasive breast cancer, an unaffected full sister control, and an unaffected unrelated control. Both controls were matched to cases on age at mammogram. Total breast area and dense area in the mammogram were measured in the unaffected breast of cases and a randomly selected breast in controls, and the non-dense area and PMD calculated from these measurements. RESULTS: The mean difference in PMD between cases and controls, and the standard deviation (SD) of the difference, were slightly less for sister controls (4.2% (SD=20.0)) than for unrelated controls (4.9% (SD=25.7)). We found statistically significant correlations in PMD between cases (n=228) and sister controls (n=228) (r= 0.39 (95% CI: 0.28, 0.50; p<0.0001)), but not between cases and unrelated controls (n=228) (r= 0.04 (95% CI: -0.09, 0.17; p=0.51)). After adjusting for other risk factors, square root transformed PMD was associated with an increased risk of breast cancer when comparing cases to sister controls (adjusted odds ratio (inter-quintile odds ratio (IQOR) = 2.19, 95% CI= 1.20, 4.00) or to unrelated controls (adjusted IQOR= 2.62, 95% CI= 1.62, 4.25). CONCLUSIONS: The use of sister controls in case-control studies of PMD resulted in a modest attenuation of case-control differences and risk estimates, but showed a statistically significant association with risk and allowed control for race/ethnicity, socio-economic status and family history.

    View details for DOI 10.1186/bcr3430

    View details for Web of Science ID 000328937600007

  • SEPP1 Influences Breast Cancer Risk among Women with Greater Native American Ancestry: The Breast Cancer Health Disparities Study. PloS one Pellatt, A. J., Wolff, R. K., John, E. M., Torres-Mejia, G., Hines, L. M., Baumgartner, K. B., Giuliano, A. R., Lundgreen, A., Slattery, M. L. 2013; 8 (11)

    Abstract

    Selenoproteins are a class of proteins containing a selenocysteine residue, many of which have been shown to have redox functions, acting as antioxidants to decrease oxidative stress. Selenoproteins have previously been associated with risk of various cancers and redox-related diseases. In this study we evaluated possible associations between breast cancer risk and survival and single nucleotide polymorphisms (SNPs) in the selenoprotein genes GPX1, GPX2, GPX3, GPX4, SELS, SEP15, SEPN1, SEPP1, SEPW1, TXNRD1, and TXNRD2 among Hispanic/Native American (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Adaptive Rank Truncated Product (ARTP) analysis was used to determine both gene and pathway significance with these genes. The overall selenoprotein pathway PARTP was not significantly associated with breast cancer risk (PARTP = 0.69), and only one gene, GPX3, was of borderline significance for the overall population (PARTP =0.09) and marginally significant among women with 0-28% Native American (NA) ancestry (PARTP=0.06). The SEPP1 gene was statistically significantly associated with breast cancer risk among women with higher NA ancestry (PARTP=0.002) and contributed to a significant pathway among those women (PARTP=0.04). GPX1, GPX3, and SELS were associated with Estrogen Receptor-/Progesterone Receptor+ status (PARTP = 0.002, 0.05, and 0.01, respectively). Four SNPs (GPX3 rs2070593, rsGPX4 rs2074451, SELS rs9874, and TXNRD1 rs17202060) significantly interacted with dietary oxidative balance score after adjustment for multiple comparisons to alter breast cancer risk. GPX4 was significantly associated with breast cancer survival among those with the highest NA ancestry (PARTP = 0.05) only. Our data suggest that SEPP1 alters breast cancer risk among women with higher levels of NA ancestry.

    View details for DOI 10.1371/journal.pone.0080554

    View details for PubMedID 24278290

    View details for PubMedCentralID PMC3835321

  • Epidermal growth factor receptor (EGFR) polymorphisms and breast cancer among Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study. International journal of molecular epidemiology and genetics Connor, A. E., Baumgartner, R. N., Baumgartner, K. B., Pinkston, C. M., John, E. M., Torres-Mejía, G., Hines, L. M., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2013; 4 (4): 235-249

    Abstract

    The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, functions in cellular processes essential to the development of cancer. Overexpression of EGFR in primary breast tumors has been linked with poor prognosis. We investigated the associations between 34 EGFR tagging SNPs and breast cancer risk and breast cancer-specific mortality in 4,703 Hispanic and 3,030 non-Hispanic white women from the Breast Cancer Health Disparities Study. We evaluated associations with risk of breast cancer defined by estrogen/progesterone receptor (ER/PR) tumor phenotype. Only one association remained statistically significant after adjusting for multiple comparisons. Rs2075112GA/AA was associated with reduced risk for ER-/PR+ tumor phenotype (odds ratio (OR), 0.34; 95% confidence interval (CI) 0.18-0.63, p adj=0.01). All additional results were significant prior to adjustment for multiple comparisons. Two of the EGFR polymorphisms were associated with breast cancer risk in the overall study population (rs11770531TT: OR, 0.56, 95% CI 0.37-0.84; and rs2293348AA: OR, 1.20, 95% CI 1.04-1.38) and two polymorphisms were associated with risk among Hispanics: rs6954351AA: OR, 2.50, 95% CI 1.32-4.76; and rs845558GA/AA: OR, 1.15, 95% CI 1.01-1.30. With regard to breast cancer-specific mortality, we found positive associations with rs6978771TT hazard ratio (HR), 1.68; 95% CI 1.11-2.56; rs9642391CC HR, 1.64; 95% CI 1.04-2.58; rs4947979AG/GG HR, 1.36; 95% CI 1.03-1.79; and rs845552GG HR, 1.62; 95% CI 1.05-2.49. Our findings provide additional insight for the role of EGFR in breast cancer development and prognosis. Further research is needed to elucidate EGFR's contribution to ethnic disparities in breast cancer.

    View details for PubMedID 24319539

    View details for PubMedCentralID PMC3852643

  • Body size, modifying factors, and postmenopausal breast cancer risk in a multiethnic population: the San Francisco Bay Area Breast Cancer Study SPRINGERPLUS John, E. M., Phipps, A. I., Sangaramoorthy, M. 2013; 2

    Abstract

    Data on body size and postmenopausal breast cancer in Hispanic and African American women are inconsistent, possibly due to the influence of modifying factors. We examined associations between adiposity and risk of breast cancer defined by hormone receptor status in a population-based case-control study conducted from 1995-2004 in the San Francisco Bay Area. Multivariate adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. Associations with body size were limited to women not currently using menopausal hormone therapy (801 cases, 1336 controls). High young-adult body mass index (BMI) was inversely associated with postmenopausal breast cancer risk, regardless of hormone receptor status, whereas high current BMI and high adult weight gain were associated with two-fold increased risk of estrogen receptor and progesterone receptor positive breast cancer, but only in women with a low young-adult BMI (?22.4 kg/m(2)) or those with ?15 years since menopause. Odds ratios were stronger among non-Hispanic Whites than Hispanics and African Americans. Waist circumference and waist-to-height ratio increased breast cancer risk in Hispanics and African Americans only, independent of BMI. These findings emphasize the importance of considering tumor hormone receptor status and other modifying factors in studies of racially/ethnically diverse populations.

    View details for DOI 10.1186/2193-1801-2-239

    View details for Web of Science ID 000209465000038

    View details for PubMedCentralID PMC3676738

  • Global patterns of prostate cancer incidence, aggressiveness, and mortality in men of african descent. Prostate cancer Rebbeck, T. R., Devesa, S. S., Chang, B., Bunker, C. H., Cheng, I., Cooney, K., Eeles, R., Fernandez, P., Giri, V. N., Gueye, S. M., Haiman, C. A., Henderson, B. E., Heyns, C. F., Hu, J. J., Ingles, S. A., Isaacs, W., Jalloh, M., John, E. M., Kibel, A. S., Kidd, L. R., Layne, P., Leach, R. J., Neslund-Dudas, C., Okobia, M. N., Ostrander, E. A., Park, J. Y., Patrick, A. L., Phelan, C. M., Ragin, C., Roberts, R. A., Rybicki, B. A., Stanford, J. L., Strom, S., Thompson, I. M., Witte, J., Xu, J., Yeboah, E., Hsing, A. W., Zeigler-Johnson, C. M. 2013; 2013: 560857-?

    Abstract

    Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

    View details for DOI 10.1155/2013/560857

    View details for PubMedID 23476788

    View details for PubMedCentralID PMC3583061

  • Total energy intake and breast cancer risk in sisters: the Breast Cancer Family Registry BREAST CANCER RESEARCH AND TREATMENT Zhang, F. F., John, E. M., Knight, J. A., Kaur, M., Daly, M., Buys, S., Andrulis, I. L., Stearman, B., West, D., Terry, M. B. 2013; 137 (2): 541-551

    Abstract

    Energy restriction inhibits mammary tumor development in animal models. Epidemiologic studies in humans generally do not support an association between dietary energy intake and breast cancer risk, although some studies suggest a more complex interplay between measures of energy intake, physical activity, and body size. We examined the association between total energy intake jointly with physical activity and body mass index (BMI) and the risk of breast cancer among 1,775 women diagnosed with breast cancer between 1995 and 2006 and 2,529 of their unaffected sisters, enrolled in the Breast Cancer Family Registry. We collected dietary data using the Hawaii-Los Angeles Multiethnic Cohort food frequency questionnaire. Using conditional logistic regression to estimate the odds ratios (OR) and 95 % confidence intervals (CI) associated with total energy intake, we observed an overall 60-70 % increased risk of breast cancer among women in the highest quartile of total energy intake compared to those in the lowest quartile (Q4 vs. Q1: OR = 1.6, 95 % CI: 1.3-2.0; P (trend) < 0.0001); these associations were limited to pre-menopausal women or women with hormone receptor-positive cancers. Although the associations were slightly stronger among women with a higher BMI or lower level of average lifetime physical activity, we observed a positive association between total energy intake and breast cancer risk across different strata of physical activity and BMI. Our results suggest that within sisters, high energy intake may increase the risk of breast cancer independent of physical activity and body size. If replicated in prospective studies, then these findings suggest that reductions in total energy intake may help in modifying breast cancer risk.

    View details for DOI 10.1007/s10549-012-2342-8

    View details for Web of Science ID 000313201100021

    View details for PubMedID 23225141

  • RAD51 and Breast Cancer Susceptibility: No Evidence for Rare Variant Association in the Breast Cancer Family Registry Study PLOS ONE Le Calvez-Kelm, F., Oliver, J., Damiola, F., Forey, N., Robinot, N., Durand, G., Voegele, C., Vallee, M. P., Byrnes, G., Hopper, J. L., Southey, M. C., Andrulis, I. L., John, E. M., Tavtigian, S. V., Lesueur, F. 2012; 7 (12)

    Abstract

    Although inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based case-control mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer.We screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75%) and 9 controls (0.80%) carrying such a variant. Variants were either likely neutral missense substitutions (3), silent substitutions (4) or non-coding substitutions (5) that were predicted to have little effect on efficiency of the splicing machinery.Altogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility.

    View details for DOI 10.1371/journal.pone.0052374

    View details for Web of Science ID 000312829100045

    View details for PubMedID 23300655

    View details for PubMedCentralID PMC3531476

  • A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11 HUMAN MOLECULAR GENETICS Siddiq, A., Couch, F. J., Chen, G. K., Lindstrom, S., Eccles, D., Millikan, R. C., Michailidou, K., Stram, D. O., Beckmann, L., Rhie, S. K., Ambrosone, C. B., Aittomaki, K., Amiano, P., Apicella, C., Baglietto, L., Bandera, E. V., Beckmann, M. W., Berg, C. D., Bernstein, L., Blomqvist, C., Brauch, H., Brinton, L., Bui, Q. M., Buring, J. E., Buys, S. S., Campa, D., Carpenter, J. E., Chasman, D. I., Chang-Claude, J., Chen, C., Clavel-Chapelon, F., Cox, A., Cross, S. S., Czene, K., Deming, S. L., Diasio, R. B., Diver, W. R., Dunning, A. M., Durcan, L., Ekici, A. B., Fasching, P. A., Feigelson, H. S., Fejerman, L., Figueroa, J. D., Fletcher, O., Flesch-Janys, D., Gaudet, M. M., Gerty, S. M., Rodriguez-Gil, J. L., Giles, G. G., van Gils, C. H., Godwin, A. K., Graham, N., Greco, D., Hall, P., Hankinson, S. E., Hartmann, A., Hein, R., Heinz, J., Hoover, R. N., Hopper, J. L., Hu, J. J., Huntsman, S., Ingles, S. A., Irwanto, A., Isaacs, C., Jacobs, K. B., John, E. M., Justenhoven, C., Kaaks, R., Kolonel, L. N., Coetzee, G. A., Lathrop, M., Le Marchand, L., Lee, A. M., Lee, I., Lesnick, T., Lichtner, P., Liu, J., Lund, E., Makalic, E., Martin, N. G., McLean, C. A., Meijers-Heijboer, H., Meindl, A., Miron, P., Monroe, K. R., Montgomery, G. W., Mueller-Myhsok, B., Nickels, S., Nyante, S. J., Olswold, C., Overvad, K., Palli, D., Park, D. J., Palmer, J. R., Pathak, H., Peto, J., Pharoah, P., Rahman, N., Rivadeneira, F., Schmidt, D. F., Schmutzler, R. K., Slager, S., Southey, M. C., Stevens, K. N., Sinn, H., Press, M. F., Ross, E., Riboli, E., Ridker, P. M., Schumacher, F. R., Severi, G., Silva, I. d., Stone, J., Sund, M., Tapper, W. J., Thun, M. J., Travis, R. C., Turnbull, C., Uitterlinden, A. G., Waisfisz, Q., Wang, X., Wang, Z., Weaver, J., Schulz-Wendtland, R., Wilkens, L. R., Van Den Berg, D., Zheng, W., Ziegler, R. G., Ziv, E., Nevanlinna, H., Easton, D. F., Hunter, D. J., Henderson, B. E., Chanock, S. J., Garcia-Closas, M., Kraft, P., Haiman, C. A., Vachon, C. M. 2012; 21 (24): 5373-5384

    Abstract

    Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ? 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

    View details for DOI 10.1093/hmg/dds381

    View details for Web of Science ID 000311965600012

    View details for PubMedID 22976474

    View details for PubMedCentralID PMC3510753

  • CHEK2*1100delC Heterozygosity in Women With Breast Cancer Associated With Early Death, Breast Cancer-Specific Death, and Increased Risk of a Second Breast Cancer JOURNAL OF CLINICAL ONCOLOGY Weischer, M., Nordestgaard, B. G., Pharoah, P., Bolla, M. K., Nevanlinna, H., van't Veer, L. J., Garcia-Closas, M., Hopper, J. L., Hall, P., Andrulis, I. L., Devilee, P., Fasching, P. A., Anton-Culver, H., Lambrechts, D., Hooning, M., Cox, A., Giles, G. G., Burwinkel, B., Lindblom, A., Couch, F. J., Mannermaa, A., Alnaes, G. G., John, E. M., Doerk, T., Flyger, H., Dunning, A. M., Wang, Q., Muranen, T. A., van Hien, R., Figueroa, J., Southey, M. C., Czene, K., Knight, J. A., Tollenaar, R. A., Beckmann, M. W., Ziogas, A., Christiaens, M., Collee, J. M., Reed, M. W., Severi, G., Marme, F., Margolin, S., Olson, J. E., Kosma, V., Kristensen, V. N., Miron, A., Bogdanova, N., Shah, M., Blomqvist, C., Broeks, A., Sherman, M., Phillips, K., Li, J., Liu, J., Glendon, G., Seynaeve, C., Ekici, A. B., Leunen, K., Kriege, M., Cross, S. S., Baglietto, L., Sohn, C., Wang, X., Kataja, V., Borresen-Dale, A., Meyer, A., Easton, D. F., Schmidt, M. K., Bojesen, S. E. 2012; 30 (35): 4308-4316

    Abstract

    We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer.From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies.CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only.Among women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.

    View details for DOI 10.1200/JCO.2012.42.7336

    View details for Web of Science ID 000312195900011

    View details for PubMedID 23109706

    View details for PubMedCentralID PMC3515767

  • Identification of fifteen novel germline variants in the BRCA1 3 ' UTR reveals a variant in a breast cancer case that introduces a functional miR-103 target site HUMAN MUTATION Brewster, B. L., Rossiello, F., French, J. D., Edwards, S. L., Wong, M., Wronski, A., Whiley, P., Waddell, N., Chen, X., Bove, B., Hopper, J. L., John, E. M., Andrulis, I., Daly, M., Volorio, S., Bernard, L., Peissel, B., Manoukian, S., Barile, M., Pizzamiglio, S., Verderio, P., Spurdle, A. B., Radice, P., Godwin, A. K., Southey, M. C., Brown, M. A., Peterlongo, P. 2012; 33 (12): 1665-1675

    Abstract

    Mutations in the BRCA1 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intron-exon boundaries, precluding the identification of mutations in noncoding and untranslated regions (UTR). As 3'UTR mutations can influence cancer susceptibility by altering protein and microRNA (miRNA) binding regions, we screened the BRCA1 3'UTR for mutations in a large series of BRCA-mutation negative, population and clinic-based breast cancer cases, and controls. Fifteen novel BRCA1 3'UTR variants were identified, the majority of which were unique to either cases or controls. Using luciferase reporter assays, three variants found in cases, c.* 528G>C, c.* 718A>G, and c.* 1271T>C and four found in controls, c.* 309T>C, c.* 379G>A, c.* 823C>T, and c.* 264C>T, reduced 3'UTR activity (P < 0.02), whereas two variants found in cases, c.* 291C>T and c.* 1139G>T, increased 3'UTR activity (P < 0.01). Three case variants, c.* 718A>G, c.* 800T>C, and c.* 1340_1342delTGT, were predicted to create new miRNA binding sites and c.* 1340_1342delTGT caused a reduction (25%, P = 0.0007) in 3'UTR reporter activity when coexpressed with the predicted targeting miRNA, miR-103. This is the most comprehensive identification and analysis of BRCA1 3'UTR variants published to date.

    View details for DOI 10.1002/humu.22159

    View details for Web of Science ID 000310975900008

    View details for PubMedID 22753153

  • Variation in Genes Related to Obesity, Weight, and Weight Change and Risk of Contralateral Breast Cancer in the WECARE Study Population CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Brooks, J. D., Bernstein, L., Teraoka, S. N., Knight, J. A., Mellemkjaer, L., John, E. M., Malone, K. E., Reiner, A. S., Lynch, C. F., Concannon, P., Haile, R. W., Bernstein, J. L. 2012; 21 (12): 2261-2267

    Abstract

    Body mass index (BMI), a known breast cancer risk factor, could influence breast risk through mechanistic pathways related to sex hormones, insulin resistance, chronic inflammation, and altered levels of adipose-derived hormones. Results from studies of the relationship between BMI and second primary breast cancer have been mixed. To explore the relationship between BMI and asynchronous contralateral breast cancer (CBC), we examined whether variants in genes related to obesity, weight, and weight change are associated with CBC risk.Variants in 20 genes [182 single-nucleotide polymorphisms (SNP)] involved in adipose tissue metabolism, energy balance, insulin resistance, and inflammation, as well as those identified through genome-wide association studies (GWAS) of BMI and type II-diabetes were evaluated. We examined the association between variants in these genes and the risk of CBC among Caucasian participants [643 cases with CBC and 1,271 controls with unilateral breast cancer (UBC)] in the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study using conditional logistic regression.After adjustment for multiple comparisons, no statistically significant associations between any variant and CBC risk were seen. Stratification by menopausal or estrogen receptor (ER) status did not alter these findings.Among women with early-onset disease who survive a first breast cancer diagnosis, there was no association between variation in obesity-related genes and risk of CBC.Genetic variants in genes related to obesity are not likely to strongly influence subsequent risk of developing a second primary breast cancer.

    View details for DOI 10.1158/1055-9965.EPI-12-1036

    View details for Web of Science ID 000312280800015

    View details for PubMedID 23033454

    View details for PubMedCentralID PMC3518741

  • Reproductive Status at First Diagnosis Influences Risk of Radiation-Induced Second Primary Contralateral Breast Cancer in the WECARE Study INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Brooks, J. D., Boice, J. D., Stovall, M., Reiner, A. S., Bernstein, L., John, E. M., Lynch, C. F., Mellemkjaer, L., Knight, J. A., Thomas, D. C., Haile, R. W., Smith, S. A., Capanu, M., Bernstein, J. L., Shore, R. E. 2012; 84 (4): 917-924

    Abstract

    Our study examined whether reproductive and hormonal factors before, at the time of, or after radiation treatment for a first primary breast cancer modify the risk of radiation-induced second primary breast cancer.The Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a multicenter, population-based study of 708 women (cases) with asynchronous contralateral breast cancer (CBC) and 1399 women (controls) with unilateral breast cancer. Radiotherapy (RT) records, coupled with anthropomorphic phantom simulations, were used to estimate quadrant-specific radiation dose to the contralateral breast for each patient. Rate ratios (RR) and 95% confidence intervals (CI) were computed to assess the relationship between reproductive factors and risk of CBC.Women who were nulliparous at diagnosis and exposed to ?1 Gy to the contralateral breast had a greater risk for CBC than did matched unexposed nulliparous women (RR=2.2; 95% CI, 1.2-4.0). No increased risk was seen in RT-exposed parous women (RR=1.1; 95% CI, 0.8-1.4). Women treated with RT who later became pregnant (8 cases and 9 controls) had a greater risk for CBC (RR=6.0; 95% CI, 1.3-28.4) than unexposed women (4 cases and 7 controls) who also became pregnant. The association of radiation with risk of CBC did not vary by number of pregnancies, history of breastfeeding, or menopausal status at the time of first breast cancer diagnosis.Nulliparous women treated with RT were at an increased risk for CBC. Although based on small numbers, women who become pregnant after first diagnosis also seem to be at an increased risk for radiation-induced CBC.

    View details for DOI 10.1016/j.ijrobp.2012.01.047

    View details for Web of Science ID 000310565300027

    View details for PubMedID 22483700

    View details for PubMedCentralID PMC3394928

  • Red meat and poultry, cooking practices, genetic susceptibility and risk of prostate cancer: results from a multiethnic case-control study CARCINOGENESIS Joshi, A. D., Corral, R., Catsburg, C., Lewinger, J. P., Koo, J., John, E. M., Ingles, S. A., Stern, M. C. 2012; 33 (11): 2108-2118

    Abstract

    Red meat, processed and unprocessed, has been considered a potential prostate cancer (PCA) risk factor; epidemiological evidence, however, is inconclusive. An association between meat intake and PCA may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures. We investigated the association between red meat and poultry intake and localized and advanced PCA taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats. We analyzed data for 1096 controls, 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study, a multiethnic, population-based case-control study. We examined nutrient density-adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes: GSTP1, PTGS2, CYP1A2, CYP2E1, EPHX1, CYP1B1, UGT1A6, NAT2, GSTM1 and GSTT1. We observed a positive association between risk of advanced PCA and high intake of red meat cooked at high temperatures (trend P = 0.026), cooked by pan-frying (trend P = 0.035), and cooked until well-done (trend P = 0.013). An inverse association was observed for baked poultry and advanced PCA risk (trend P = 0.023). A gene-by-diet interaction was observed between an SNP in the PTGS2 gene and the estimated levels of meat mutagens (interaction P = 0.008). Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential PCA risk factors, and may support a role for heterocyclic amines (HCAs) in PCA etiology.

    View details for DOI 10.1093/carcin/bgs242

    View details for Web of Science ID 000310624400012

    View details for PubMedID 22822096

    View details for PubMedCentralID PMC3584966

  • Associations between TCF7L2 polymorphisms and risk of breast cancer among Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study BREAST CANCER RESEARCH AND TREATMENT Connor, A. E., Baumgartner, R. N., Baumgartner, K. B., Kerber, R. A., Pinkston, C., John, E. M., Torres-Mejia, G., Hines, L., Giuliano, A., Wolff, R. K., Slattery, M. L. 2012; 136 (2): 593-602

    Abstract

    The transcription factor 7-like 2 (TCF7L2) gene is part of the Wnt/?-catenin signaling pathway and plays a critical role in cell development and growth regulation. TCF7L2 variants rs12255372 and rs7903146 have been associated with risk of Type 2 diabetes. Few epidemiological studies have examined the association between TCF7L2 and breast cancer risk. We investigated the associations between 25 TCF7L2 single nucleotide polymorphisms (SNPs) and breast cancer in Hispanic and non-Hispanic white (NHW) women from the 4-Corner's Breast Cancer Study, the San Francisco Bay Area Breast Cancer Study, and the Mexico Breast Cancer Study. A total of 4,703 Hispanic (2,093 cases, 2,610 controls) and 3,031 NHW (1,431 cases, 1,600 controls) women were included. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated using logistic regression to estimate the association between the TCF7L2 SNPs and breast cancer risk. We also examined effect modification by self-reported ethnicity, genetic admixture, and diabetes history. After adjusting for multiple comparisons, four TCF7L2 SNPs were significantly associated with breast cancer overall: rs7903146 (OR(TT) 1.24; 95 % CI 1.03-1.49), rs3750805 (OR(AT/TT) 1.15; 95 % CI 1.03-1.28), rs7900150 (OR(AA) 1.23; 95 % 1.07-1.42), and rs1225404 (OR(CC) 0.82; 95 % 0.70-0.94). Among women with a history of diabetes, the TT genotype of rs3750804 increased breast cancer risk (OR, 2.46; 95 % CI 1.28-4.73). However, there was no association among women without a diabetes history (OR, 1.06; 95 % CI 0.85-1.32). We did not find significant interactions by ethnicity or by genetic admixture. Findings support an association between TCF7L2 and breast cancer and history of diabetes modifies this association for specific variants.

    View details for DOI 10.1007/s10549-012-2299-7

    View details for Web of Science ID 000310378700027

    View details for PubMedID 23085767

    View details for PubMedCentralID PMC3662467

  • Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies LANCET ONCOLOGY Beral, V., Bull, D., Pirie, K., Reeves, G., Peto, R., Skegg, D., LAVECCHIA, C., Magnusson, C., Pike, M. C., Thomas, D., Hamajima, N., Hirose, K., Tajima, K., Rohan, T., Friedenreich, C. M., Calle, E. E., Gapstur, S. M., Patel, A. V., Coates, R. J., Liff, J. M., Talamini, R., CHANTARAKUL, N., KOETSAWANG, S., RACHAWAT, D., Marcou, Y., Kakouri, E., Duffy, S. W., Morabia, A., Schuman, L., Stewart, W., Szklo, M., Coogan, P. F., Palmer, J. R., Rosenberg, L., Band, P., Coldman, A. J., Gallagher, R. P., Hislop, T. G., Yang, P., Cummings, S. R., Canfell, K., Sitas, F., Chao, P., Lissowska, J., Horn-Ross, P. L., John, E. M., Kolonel, L. M., Nomura, A. M., Ghiasvand, R., Hu, J., Johnson, K. C., Mao, Y., Callaghan, K., Crossley, B., Goodill, A., Green, J., Hermon, C., Key, T., Lindgard, I., Liu, B., Pirie, K., Reeves, G., Collins, R., DOLL, R., Peto, R., Bishop, T., Fentiman, I. S., De Sanjose, S., Gonzaler, C. A., Lee, N., Marchbanks, P., Ory, H. W., Peterson, H. B., Wingo, P., Ebeling, K., Kunde, D., Nishan, P., Hopper, J. L., ELIASSEN, H., Gajalakshmi, V., Martin, N., PARDTHAISONG, T., SILPISORNKOSOL, S., Theetranont, C., BOOSIRI, B., CHUTIVONGSE, S., Jimakorn, P., Virutamasen, P., Wongsrichanalai, C., Neugut, A., Santella, R., Baines, C. J., Kreiger, N., Miller, A. B., WALL, C., Tjonneland, A., Jorgensen, T., Stahlberg, C., Pedersen, A. T., Flesch-Janys, D., Hakansson, N., Cauley, J., Heuch, I., Adami, H. O., Persson, I., Weiderpass, E., Magnusson, C., Chang-Claude, J., Kaaks, R., McCredie, M., Paul, C., Skegg, D. C., Spears, G. F., Iwasaki, M., Tsugane, S., Anderson, G., Daling, J. R., Hampton, J., Hutchinson, W. B., Li, C. I., Malone, K., Mandelson, M., Newcomb, P., NOONAN, E. A., Ray, R. M., Stanford, J. L., Tang, M. T., Thomas, D. B., Weiss, N. S., White, E., Izquierdo, A., Viladiu, P., Fourkala, E. O., Jacobs, I., Menon, U., Ryan, A., Cuevas, H. R., Ontiveros, P., PALET, A., Salazar, S. B., ARISTIZABAL, N., Cuadros, A., Tryggvadottir, L., Tulinius, H., Riboli, E., Andrieu, N., Bachelot, A., Le, M. G., Bremond, A., Gairard, B., Lansac, J., Piana, L., Renaud, R., Clavel-Chapelon, F., Fournier, A., Touillaud, M., Mesrine, S., Chabbert-Buffet, N., Boutron-Ruault, M. C., Wolk, A., Torres-Mejia, G., Franceschi, S., Romieu, I., Boyle, P., Lubin, F., Modan, B., Ron, E., Wax, Y., Friedman, G. D., Hiatt, R. A., Levi, F., Kosmelj, K., Primic-Zakelj, M., Ravnihar, B., Stare, J., Ekbom, A., Erlandsson, G., Persson, I., Beeson, W. L., Fraser, G., Peto, J., Hanson, R. L., Leske, M. C., Mahoney, M. C., Nasca, P. C., Varma, A. O., Weinstein, A. L., Hartman, M. L., Olsson, H., Goldbohm, R. A., van den Brandt, P. A., Palli, D., Teitelbaum, S., APELO, R. A., BAENS, J., de la Cruz, J. R., JAVIER, B., Lacaya, L. B., Ngelangel, C. A., La Vecchia, C., Negri, E., Marubini, E., Ferraroni, M., Pike, M. C., Gerber, M., Richardson, S., Segala, C., Gatei, D., Kenya, P., Kungu, A., Mati, J. G., Brinton, L. A., Freedman, M., Hoover, R., Schairer, C., Ziegler, R., Banks, E., Spirtas, R., Lee, H. P., Rookus, M. A., van Leeuwen, F. E., Schoenberg, J. A., Graff-Iversen, S., Selmer, R., Jones, L., McPherson, K., Neil, A., Vessey, M., Yeates, D., Mabuchi, K., Preston, D., Hannaford, P., Kay, C., McCann, S. E., Rosero-Bixby, L., Gao, Y. T., Jin, F., Yuan, J., Wei, H. Y., Yun, T., Zhiheng, C., Berry, G., Booth, J. C., JELIHOVSKY, T., MACLENNAN, R., SHEARMAN, R., Hadjisavvas, A., Kyriacou, K., Loisidou, M., Zhou, X., Wang, Q., Kawai, M., Minami, Y., Tsuji, I., Lund, E., Kumle, M., Stalsberg, H., Shu, X. O., Zheng, W., Monninkhof, E. M., Onland-Moret, N. C., Peeters, P. H., Katsouyanni, K., Trichopoulou, A., Trichopoulos, D., Tzonou, A., Baltzell, K. A., DABANCENS, A., Martinez, L., Molina, R., SALAS, O., Alexander, F. E., Anderson, K., Folsom, A. R., Gammon, M. D., Hulka, B. S., Millikan, R., Chilvers, C. E., Lumachi, F., Bain, C., Schofield, F., Siskind, V., Rebbeck, T. R., Bernstein, L. R., Enger, S., Haile, R. W., Paganini-Hill, A., Ross, R. K., Ursin, G., Wu, A. H., Yu, M. C., Ewertz, D. M., Clarke, E. A., Bergkvist, L., Anderson, G. L., Gass, M., O'Sullivan, M. J., Kalache, A., Farley, T. M., Holck, S., MEIRIK, O., Fukao, A. 2012; 13 (11): 1141-1151

    Abstract

    Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women.Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression.Breast cancer risk increased by a factor of 1·050 (95% CI 1·044-1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025-1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1·43, 1·33-1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons).The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours.Cancer Research UK.

    View details for DOI 10.1016/S1470-2045(12)70425-4

    View details for Web of Science ID 000310570900045

    View details for PubMedCentralID PMC3488186

  • 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Warren, H., Dudbridge, F., Fletcher, O., Orr, N., Johnson, N., Hopper, J. L., Apicella, C., Southey, M. C., Mahmoodi, M., Schmidt, M. K., Broeks, A., Cornelissen, S., Braaf, L. M., Muir, K. R., Lophatananon, A., Chaiwerawattana, A., Wiangnon, S., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Schulz-Wendtland, R., Sawyer, E. J., Tomlinson, I., Kerin, M., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Guenel, P., Therese Truong, T., Laurent-Puig, P., Mulot, C., Bojesen, S. E., Nielsen, S. F., Flyger, H., Nordestgaard, B. G., Milne, R. L., Benitez, J., Arias-Perez, J., Pilar Zamora, M., Anton-Culver, H., Ziogas, A., Bernstein, L., Dur, C. C., Brenner, H., Mueller, H., Arndt, V., Langheinz, A., Meindl, A., Golatta, M., Bartram, C. R., Schmutzler, R. K., Brauch, H., Justenhoven, C., Bruening, T., Chang-Claude, J., Wang-Gohrke, S., Eilber, U., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Nevanlinna, H., Muranen, T. A., Aittomaki, K., Blomqvist, C., Bogdanova, N., Antonenkova, N., Rogov, Y., Bermisheva, M., Prokofyeva, D., Zinnatullina, G., Khusnutdinova, E., Lindblom, A., Margolin, S., Mannermaa, A., Kosma, V., Hartikainen, J. M., Kataja, V., Chenevix-Trench, G., Beesley, J., Chen, X., Lambrechts, D., Smeets, A., Paridaens, R., Weltens, C., Flesch-Janys, D., Buck, K., Behrens, S., Peterlongo, P., Bernard, L., Manoukian, S., Radice, P., Couch, F. J., Vachon, C., Wang, X., Olson, J., Giles, G., Baglietto, L., McLean, C. A., Severi, G., John, E. M., Miron, A., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I. L., Knight, J. A., Mulligan, A. M., Weerasooriya, N., Devilee, P., Tollenaar, R. A., Martens, J. W., Seynaeve, C. M., Hooning, M. J., Hollestelle, A., Jager, A., Tilanus-Linthorst, M. M., Hall, P., Czene, K., Liu, J., Li, J., Cox, A., Cross, S. S., Brock, I. W., Reed, M. W., Pharoah, P., Blows, F. M., Dunning, A. M., Ghous-saini, M., Ashworth, A., Swerdlow, A., Jones, M., Schoemaker, M., Easton, D. F., Humphreys, M., Wang, Q., Peto, J., dos-Santos-Silva, I. 2012; 21 (10): 1783-1791

    Abstract

    Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls).This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors.This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer.The findings further support the view that genetic susceptibility varies according to tumor subtype.

    View details for DOI 10.1158/1055-9965.EPI-12-0526

    View details for Web of Science ID 000309576100022

    View details for PubMedID 22859399

  • The role of genetic breast cancer susceptibility variants as prognostic factors HUMAN MOLECULAR GENETICS Fasching, P. A., Pharoah, P. D., Cox, A., Nevanlinna, H., Bojesen, S. E., Karn, T., Broeks, A., van Leeuwen, F. E., van 't Veer, L. J., Udo, R., Dunning, A. M., Greco, D., Aittomaki, K., Blomqvist, C., Shah, M., Nordestgaard, B. G., Flyger, H., Hopper, J. L., Southey, M. C., Apicella, C., Garcia-Closas, M., Sherman, M., Lissowska, J., Seynaeve, C., Huijts, P. E., Tollenaar, R. A., Ziogas, A., Ekici, A. B., Rauh, C., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Andrulis, I. L., Ozcelik, H., Mulligan, A., Glendon, G., Hall, P., Czene, K., Liu, J., Chang-Claude, J., Wang-Gohrke, S., Eilber, U., Nickels, S., Doerk, T., Schiekel, M., Bremer, M., Park-Simon, T., Giles, G. G., Severi, G., Baglietto, L., Hooning, M. J., Martens, J. W., Jager, A., Kriege, M., Lindblom, A., Margolin, S., Couch, F. J., Stevens, K. N., Olson, J. E., Kosei, M., Cross, S. S., Balasubramanian, S. P., Reed, M. W., Miron, A., John, E. M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Kauppila, S., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Chenevix-Trench, G., Lambrechts, D., Dieudonne, A., Hatse, S., Van Limbergen, E., Benitez, J., Milne, R. L., Pilar Zamora, M., Arias Perez, J. I., Bonanni, B., Peissel, B., Loris, B., Peterlongo, P., Rajaraman, P., Schonfeld, S. J., Anton-Culver, H., Devilee, P., Beckmann, M. W., Slamon, D. J., Phillips, K., Figueroa, J. D., Humphreys, M. K., Easton, D. F., Schmidt, M. K. 2012; 21 (17): 3926-3939

    Abstract

    Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.

    View details for DOI 10.1093/hmg/dds159

    View details for Web of Science ID 000307504100018

    View details for PubMedCentralID PMC3412377

  • Racial and Ethnic Differences in Adjuvant Hormonal Therapy Use JOURNAL OF WOMENS HEALTH Livaudais, J. C., Li, C., John, E. M., Terry, M. B., Daly, M., Buys, S. S., Habel, L., Thompson, B., Yanez, N. D., Coronado, G. D. 2012; 21 (9): 950-958

    Abstract

    In the United States, 5-year breast cancer survival is highest among Asian American women, followed by non-Hispanic white, Hispanic, and African American women. Breast cancer treatment disparities may play a role. We examined racial/ethnic differences in adjuvant hormonal therapy use among women aged 18-64 years, diagnosed with hormone receptor-positive breast cancer, using data collected by the Northern California Breast Cancer Family Registry (NC-BCFR), and explored changes in use over time.Odds ratios (OR) comparing self-reported ever-use by race/ethnicity (African American, Hispanic, non-Hispanic white vs. Asian American) were estimated using multivariable adjusted logistic regression. Analyses were stratified by recruitment phase (phase I, diagnosed January 1995-September 1998, phase II, diagnosed October 1998-April 2003) and genetic susceptibility, as cases with increased genetic susceptibility were oversampled.Among 1385 women (731 phase I, 654 phase II), no significant racial/ethnic differences in use were observed among phase I or phase II cases. However, among phase I cases with no susceptibility indicators, African American and non-Hispanic white women were less likely than Asian American women to use hormonal therapy (OR 0.20, 95% confidence interval [CI]0.06-0.60; OR 0.40, CI 0.17-0.94, respectively). No racial/ethnic differences in use were observed among women with 1+ susceptibility indicators from either recruitment phase.Racial/ethnic differences in adjuvant hormonal therapy use were limited to earlier diagnosis years (phase I) and were attenuated over time. Findings should be confirmed in other populations but indicate that in this population, treatment disparities between African American and Asian American women narrowed over time as adjuvant hormonal treatments became more commonly prescribed.

    View details for DOI 10.1089/jwh.2011.3254

    View details for Web of Science ID 000308409200011

    View details for PubMedID 22731764

    View details for PubMedCentralID PMC3430474

  • Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC) PLOS ONE Hein, R., Maranian, M., Hopper, J. L., Kapuscinski, M. K., Southey, M. C., Park, D. J., Schmidt, M. K., Broeks, A., Hogervorst, F. B., Bueno-de-Mesquit, H. B., Muir, K. R., Lophatananon, A., Rattanamongkongul, S., Puttawibul, P., Fasching, P. A., Hein, A., Ekici, A. B., Beckmann, M. W., Fletcher, O., Johnson, N., Silva, I. d., Peto, J., Sawyer, E., Tomlinson, I., Kerin, M., Miller, N., Marmee, F., Schneeweiss, A., Sohn, C., Burwinkel, B., Guenel, P., Cordina-Duverger, E., Menegaux, F., Truong, T., Bojesen, S. E., Nordestgaard, B. G., Flyger, H., Milne, R. L., Arias Perez, J. I., Pilar Zamora, M., Benitez, J., Anton-Culver, H., Ziogas, A., Bernstein, L., Clarke, C. A., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Rahman, N., Seal, S., Turnbull, C., Renwick, A., Meindl, A., Schott, S., Bartram, C. R., Schmutzler, R. K., Brauch, H., Hamann, U., Ko, Y., Wang-Gohrke, S., Doerk, T., Schuermann, P., Karstens, J. H., Hillemanns, P., Nevanlinna, H., Heikkinen, T., Aittomaki, K., Blomqvist, C., Bogdanova, N. V., Zalutsky, I. V., Antonenkova, N. N., Bermisheva, M., Prokovieva, D., Farahtdinova, A., Khusnutdinova, E., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J., Chen, X., Beesley, J., Lambrechts, D., Zhao, H., Neven, P., Wildiers, H., Nickels, S., Flesch-Janys, D., Radice, P., Peterlongo, P., Manoukian, S., Barile, M., Couch, F. J., Olson, J. E., Wang, X., Fredericksen, Z., Giles, G. G., Baglietto, L., McLean, C. A., Severi, G., Offit, K., Robson, M., Gaudet, M. M., Vijai, J., Alnaes, G. G., Kristensen, V., Borresen-Dale, A., John, E. M., Miron, A., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Figueroa, J. D., Garcia-Closas, M., Lissowska, J., Sherman, M. E., Hooning, M., Martens, J. W., Seynaeve, C., Collee, M., Hall, P., Humpreys, K., Czene, K., Liu, J., Cox, A., Brock, I. W., Cross, S. S., Reed, M. W., Ahmed, S., Ghoussaini, M., Pharoah, P. D., Kang, D., Yoo, K., Noh, D., Jakubowska, A., Jaworska, K., Durda, K., Zlowocka, E., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Shen, C., Yu, J., Hsu, H., Hou, M., Orr, N., Schoemaker, M., Ashworth, A., Swerdlow, A., Trentham-Dietz, A., Newcomb, P. A., Titus, L., Egan, K. M., Chenevix-Trench, G., Antoniou, A. C., Humphreys, M. K., Morrison, J., Chang-Claude, J., Easton, D. F., Dunning, A. M. 2012; 7 (8)

    Abstract

    The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.

    View details for DOI 10.1371/journal.pone.0042380

    View details for Web of Science ID 000307437900035

  • A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ding, Y. C., McGuffog, L., Healey, S., friedman, e., Laitman, Y., Shani-Paluch-Shimon, Kaufman, B., Liljegren, A., Lindblom, A., Olsson, H., Kristoffersson, U., Stenmark-Askmalm, M., Melin, B., Domchek, S. M., Nathanson, K. L., Rebbeck, T. R., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Gronwald, J., Huzarski, T., Cybulski, C., Byrski, T., Osorio, A., Ramony Cajal, T., Stavropoulou, A. V., Benitez, J., Hamann, U., Rookus, M., Aalfs, C. M., de Lange, J. L., Meijers-Heijboer, H. E., Oosterwijk, J. C., van Asperen, C. J., Garcia, E. B., Hoogerbrugge, N., Jager, A., van der Luijt, R. B., Easton, D. F., Peock, S., Frost, D., Ellis, S. D., Platte, R., Fineberg, E., Evans, D. G., Lalloo, F., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J., Brewer, C., Tischkowitz, M., Godwin, A. K., Pathak, H., Stoppa-Lyonnet, D., Sinilnikova, O. M., Mazoyer, S., Barjhoux, L., Leone, M., Gauthier-Villars, M., Caux-Moncoutier, V., De Pauw, A., Hardouin, A., Berthet, P., Dreyfus, H., Ferrer, S. F., Collonge-Rame, M., Sokolowska, J., Buys, S., Daly, M., Miron, A., Terry, M. B., Chung, W., John, E. M., Southey, M., Goldgar, D., Singer, C. F., Tea, M. M., Gschwantler-Kaulich, D., Fink-Retter, A., Hansen, T. v., Ejlertsen, B., Johannsson, O. T., Offit, K., Sarrel, K., Gaudet, M. M., Vijai, J., Robson, M., Piedmonte, M. R., Andrews, L., Cohn, D., DeMars, L. R., DiSilvestro, P., Rodriguez, G., Toland, A. E., Montagna, M., Agata, S., Imyanitov, E., Isaacs, C., Janavicius, R., Lazaro, C., Blanco, I., Ramus, S. J., Sucheston, L., Karlan, B. Y., Gross, J., Ganz, P. A., Beattie, M. S., Schmutzler, R. K., Wappenschmidt, B., Meindl, A., Arnold, N., Niederacher, D., Preisler-Adams, S., Gadzicki, D., Varon-Mateeva, R., Deissler, H., Gehrig, A., Sutter, C., Kast, K., Nevanlinna, H., Aittomaki, K., Simard, J., Spurdle, A. B., Beesley, J., Chen, X., Tomlinson, G. E., Weitzel, J., Garber, J. E., Olopade, O. I., Rubinstein, W. S., Tung, N., Blum, J. L., Narod, S. A., Brummel, S., Gillen, D. L., Lindor, N., Fredericksen, Z., Pankratz, V. S., Couch, F. J., Radice, P., Peterlongo, P., Greene, M. H., Loud, J. T., Mai, P. L., Andrulis, I. L., Glendon, G., Ozcelik, H., Gerdes, A., Thomassen, M., Jensen, U. B., Skytte, A., Caligo, M. A., Lee, A., Chenevix-Trench, G., Antoniou, A. C., Neuhausen, S. L. 2012; 21 (8): 1362-1370

    Abstract

    We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

    View details for DOI 10.1158/1055-9965.EPI-12-0229

    View details for Web of Science ID 000307433800016

    View details for PubMedID 22729394

    View details for PubMedCentralID PMC3415567

  • Risk factors for uncommon histologic subtypes of breast cancer using centralized pathology review in the Breast Cancer Family Registry BREAST CANCER RESEARCH AND TREATMENT Work, M. E., Andrulis, I. L., John, E. M., Hopper, J. L., Liao, Y., Zhang, F. F., Knight, J. A., West, D. W., Milne, R. L., Giles, G. G., Longacre, T. A., O'Malley, F., Mulligan, A. M., Southey, M. C., Hibshoosh, H., Terry, M. B. 2012; 134 (3): 1209-1220

    Abstract

    Epidemiologic studies of histologic types of breast cancer including mucinous, medullary, and tubular carcinomas have primarily relied on International Classification of Diseases-Oncology (ICD-O) codes assigned by local pathologists to define histology. Using data from the Breast Cancer Family Registry (BCFR), we compared histologic agreement between centralized BCFR pathology review and ICD-O codes available from local tumor registries among 3,260 breast cancer cases. Agreement was low to moderate for less common histologies; for example, only 55 and 26 % of cases classified as mucinous and medullary, respectively, by centralized review were similarly classified using ICD-O coding. We then evaluated risk factors for each histologic subtype by comparing each histologic case group defined by centralized review with a common set of 2,997 population-based controls using polytomous logistic regression. Parity [odds ratio (OR) = 0.4, 95 % confidence interval (95 % CI): 0.2-0.9, for parous vs. nulliparous], age at menarche (OR = 0.5, 95 % CI: 0.3-0.9, for age ?13 vs. ?11), and use of oral contraceptives (OCs) (OR = 0.5, 95 % CI: 0.2-0.8, OC use >5 years vs. never) were associated with mucinous carcinoma (N = 92 cases). Body mass index (BMI) (OR = 1.05, 95 % CI: 1.0-1.1, per unit of BMI) and high parity (OR = 2.6, 95 % CI: 1.1-6.0 for ?3 live births vs. nulliparous) were associated with medullary carcinoma (N = 90 cases). We did not find any associations between breast cancer risk factors and tubular carcinoma (N = 86 cases). Relative risk estimates from analyses using ICD-O classifications of histology, rather than centralized review, resulted in attenuated, and/or more imprecise, associations. These findings suggest risk factor heterogeneity across breast cancer tumor histologies, and demonstrate the value of centralized pathology review for classifying rarer tumor types.

    View details for DOI 10.1007/s10549-012-2056-y

    View details for Web of Science ID 000307273300029

    View details for PubMedID 22527103

    View details for PubMedCentralID PMC4470278

  • Genetic variation in genes involved in hormones, inflammation and energetic factors and breast cancer risk in an admixed population CARCINOGENESIS Slattery, M. L., John, E. M., Torres-Mejia, G., Lundgreen, A., Herrick, J. S., Baumgartner, K. B., Hines, L. M., Stern, M. C., Wolff, R. K. 2012; 33 (8): 1512-1521

    Abstract

    Breast cancer incidence rates are characterized by unique racial and ethnic differences. Native American ancestry has been associated with reduced breast cancer risk. We explore the biological basis of disparities in breast cancer risk in Hispanic and non-Hispanic white women by evaluating genetic variation in genes involved in inflammation, insulin and energy homeostasis in conjunction with genetic ancestry. Hispanic (2111 cases, 2597 controls) and non-Hispanic white (1481 cases, 1586 controls) women enrolled in the 4-Corner's Breast Cancer Study, the Mexico Breast Cancer Study and the San Francisco Bay Area Breast Cancer Study were included. Genetic admixture was determined from 104 ancestral informative markers that discriminate between European and Native American ancestry. Twenty-one genes in the CHIEF candidate pathway were evaluated. Higher Native American ancestry was associated with reduced risk of breast cancer (odds ratio = 0.79, 95% confidence interval 0.65, 0.95) but was limited to postmenopausal women (odds ratio = 0.66, 95% confidence interval 0.52, 0.85). After adjusting for genetic ancestry and multiple comparisons, four genes were significantly associated with breast cancer risk, NF?B1, NF?B1A, PTEN and STK11. Within admixture strata, breast cancer risk among women with low Native American ancestry was associated with IkBKB, NF?B1, PTEN and RPS6KA2, whereas among women with high Native American ancestry, breast cancer risk was associated with IkBKB, mTOR, PDK2, PRKAA1, RPS6KA2 and TSC1. Higher Native American ancestry was associated with reduced breast cancer risk. Breast cancer risk differed by genetic ancestry along with genetic variation in genes involved in inflammation, insulin, and energy homeostasis.

    View details for DOI 10.1093/carcin/bgs163

    View details for Web of Science ID 000307781000010

    View details for PubMedID 22562547

    View details for PubMedCentralID PMC3499059

  • 11q13 is a susceptibility locus for hormone receptor positive breast cancer HUMAN MUTATION Lambrechts, D., Truong, T., Justenhoven, C., Humphreys, M. K., Wang, J., Hopper, J. L., Dite, G. S., Apicella, C., Southey, M. C., Schmidt, M. K., Broeks, A., Cornelissen, S., van Hien, R., Sawyer, E., Tomlinson, I., Kerin, M., Miller, N., Milne, R. L., Pilar Zamora, M., Arias Perez, J. I., Benitez, J., Hamann, U., Ko, Y., Bruening, T., Chang-Claude, J., Eilber, U., Hein, R., Nickels, S., Flesch-Janys, D., Wang-Gohrke, S., John, E. M., Miron, A., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Chenevix-Trench, G., Beesley, J., Chen, X., Menegaux, F., Cordina-Duverger, E., Shen, C., Yu, J., Wu, P., Hou, M., Andrulis, I. L., Selander, T., Glendon, G., Mulligan, A. M., Anton-Culver, H., Ziogas, A., Muir, K. R., Lophatananon, A., Rattanamongkongul, S., Puttawibul, P., Jones, M., Orr, N., Ashworth, A., Swerdlow, A., Severi, G., Baglietto, L., Giles, G., Southey, M., Marme, F., Schneeweiss, A., Sohn, C., Burwinkel, B., Yesilyurt, B. T., Neven, P., Paridaens, R., Wildiers, H., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Meindl, A., Schott, S., Bartram, C. R., Schmutzler, R. K., Cox, A., Brock, I. W., Elliott, G., Cross, S. S., Fasching, P. A., Schulz-Wendtland, R., Ekici, A. B., Beckmann, M. W., Fletcher, O., Johnson, N., Silva, I. d., Peto, J., Nevanlinna, H., Muranen, T. A., Aittomaki, K., Blomqvist, C., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Bogdanova, N. V., Antonenkova, N. N., Rogov, Y. I., Karstens, J. H., Khusnutdinova, E., Bermisheva, M., Prokofieva, D., Gancev, S., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Nordestgaard, B. G., Bojesen, S. E., Lanng, C., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Radice, P., Peterlongo, P., Manoukian, S., Bernard, L., Couch, F. J., Olson, J. E., Wang, X., Fredericksen, Z., Alnaes, G. G., Kristensen, V., Borresen-Dale, A., Devilee, P., Tollenaar, R. A., Seynaeve, C. M., Hooning, M. J., Garcia-Closas, M., Chanock, S. J., Lissowska, J., Sherman, M. E., Hall, P., Liu, J., Czene, K., Kang, D., Yoo, K., Noh, D., Lindblom, A., Margolin, S., Dunning, A. M., Pharoah, P. D., Easton, D. F., Guenel, P., Brauch, H. 2012; 33 (7): 1123-1132

    Abstract

    A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ? 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.

    View details for DOI 10.1002/humu.22089

    View details for Web of Science ID 000304815100017

    View details for PubMedID 22461340

    View details for PubMedCentralID PMC3370081

  • Polymorphisms in carcinogen metabolism enzymes, fish intake, and risk of prostatecancer CARCINOGENESIS Catsburg, C., Joshi, A. D., Corral, R., Lewinger, J. P., Koo, J., John, E. M., Ingles, S. A., Stern, M. C. 2012; 33 (7): 1352-1359

    Abstract

    Cooking fish at high temperature can produce potent carcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons. The effects of these carcinogens may undergo modification by the enzymes responsible for their detoxification and/or activation. In this study, we investigated genetic polymorphisms in nine carcinogen metabolism enzymes and their modifying effects on the association between white or dark fish consumption and prostate cancer (PCA) risk. We genotyped 497 localized and 936 advanced PCA cases and 760 controls from the California Collaborative Case-Control Study of Prostate Cancer. Three polymorphisms, EPHX1 Tyr113His, CYP1B1 Leu432Val and GSTT1 null/present, were associated with localized PCA risk. The PTGS2 765 G/C polymorphism modified the association between white fish consumption and advanced PCA risk (interaction P 5 0.002), with high white fish consumption being positively associated with risk only among carriers of the C allele. This effect modification by PTGS2 genotype was stronger when restricted to consumption of well-done white fish (interaction P 5 0.021). These findings support the hypotheses that changes in white fish brought upon by high-temperature cooking methods, such as carcinogen accumulation and/or fatty acid composition changes, may contribute to prostate carcinogenesis. However, the gene-diet interactions should be interpreted with caution given the limited sample size. Thus, our findings require further validation with additional studies.

    View details for DOI 10.1093/carcin/bgs175

    View details for Web of Science ID 000306925600014

    View details for PubMedID 22610071

    View details for PubMedCentralID PMC3499053

  • Genome-wide meta-analyses of smoking behaviors in African Americans TRANSLATIONAL PSYCHIATRY David, S. P., Hamidovic, A., Chen, G. K., Bergen, A. W., Wessel, J., Kasberger, J. L., BROWN, W. M., Petruzella, S., Thacker, E. L., Kim, Y., Nalls, M. A., Tranah, G. J., Sung, Y. J., Ambrosone, C. B., Arnett, D., Bandera, E. V., Becker, D. M., BECKER, L., Berndt, S. I., Bernstein, L., Blot, W. J., Broeckel, U., Buxbaum, S. G., Caporaso, N., Casey, G., Chanock, S. J., Deming, S. L., Diver, W. R., Eaton, C. B., Evans, D. S., Evans, M. K., Fornage, M., Franceschini, N., Harris, T. B., Henderson, B. E., Hernandez, D. G., Hitsman, B., Hu, J. J., Hunt, S. C., Ingles, S. A., John, E. M., Kittles, R., Kolb, S., Kolonel, L. N., Le Marchand, L., Liu, Y., Lohman, K. K., McKnight, B., Millikan, R. C., Murphy, A., Neslund-Dudas, C., Nyante, S., Press, M., Psaty, B. M., Rao, D. C., Redline, S., Rodriguez-Gil, J. L., Rybicki, B. A., Signorello, L. B., Singleton, A. B., Smoller, J., Snively, B., Spring, B., Stanford, J. L., Strom, S. S., Swan, G. E., Taylor, K. D., Thun, M. J., Wilson, A. F., Witte, J. S., Yamamura, Y., Yanek, L. R., Yu, K., Zheng, W., Ziegler, R. G., Zonderman, A. B., Jorgenson, E., Haiman, C. A., Furberg, H. 2012; 2

    Abstract

    The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (? = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

    View details for DOI 10.1038/tp.2012.41

    View details for Web of Science ID 000312895700012

    View details for PubMedID 22832964

    View details for PubMedCentralID PMC3365260

  • Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas HUMAN MOLECULAR GENETICS Fejerman, L., Chen, G. K., Eng, C., Huntsman, S., Hu, D., Williams, A., Pasaniuc, B., John, E. M., Via, M., Gignoux, C., Ingles, S., Monroe, K. R., Kolonel, L. N., Torres-Mejia, G., Perez-Stable, E. J., Burchard, E. G., Henderson, B. E., Haiman, C. A., Ziv, E. 2012; 21 (8): 1907-1917

    Abstract

    Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer. We combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer (n= 1497) and Latina controls (n= 1272) were genotyped using Affymetrix and Illumina arrays. We inferred locus-specific genetic ancestry and compared the ancestry between cases and controls. We also performed single nucleotide polymorphism (SNP) association analyses in regions of interest. Correction for multiple-hypothesis testing was conducted using permutations (P(corrected)). We identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25 [odds ratio (OR) per Indigenous American chromosome 0.75, 95% confidence interval (CI): 0.65-0.85, P= 1.1 × 10(-5), P(corrected)= 0.02]. A second region on 11p15 showed a trend towards association (OR per Indigenous American chromosome 0.77, 95% CI: 0.68-0.87, P= 4.3 × 10(-5), P(corrected)= 0.08). In both regions, breast cancer risk decreased with higher Indigenous American ancestry in concordance with observations made on global ancestry. The peak of the 6q25 signal includes the estrogen receptor 1 (ESR1) gene and 5' region, a locus previously implicated in breast cancer. Genome-wide association analysis found that a multi-SNP model explained the admixture signal in both regions. Our results confirm that the association between genetic ancestry and breast cancer risk in US Latinas is partly due to genetic differences between populations of European and Indigenous Americans origin. Fine-mapping within the 6q25 and possibly the 11p15 loci will lead to the discovery of the biologically functional variant/s behind this association.

    View details for DOI 10.1093/hmg/ddr617

    View details for Web of Science ID 000302302400019

    View details for PubMedID 22228098

    View details for PubMedCentralID PMC3313799

  • Rare Mutations in XRCC2 Increase the Risk of Breast Cancer AMERICAN JOURNAL OF HUMAN GENETICS Park, D. J., Lesueur, F., Nguyen-Dumont, T., Pertesi, M., Odefrey, F., Hammet, F., Neuhausen, S. L., John, E. M., Andrulis, I. L., Terry, M. B., Daly, M., Buys, S., Le Calvez-Kelm, F., LONIE, A., Pope, B. J., Tsimiklis, H., VOEGELE, C., Hilbers, F. M., Hoogerbrugge, N., Barroso, A., Osorio, A., Giles, G. G., Devilee, P., Benitez, J., Hopper, J. L., Tavtigian, S. V., Goldgar, D. E., Southey, M. C. 2012; 90 (4): 734-739

    Abstract

    An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.

    View details for DOI 10.1016/j.ajhg.2012.02.027

    View details for Web of Science ID 000302833400018

    View details for PubMedID 22464251

    View details for PubMedCentralID PMC3322233

  • Evaluation of 19 susceptibility loci of breast cancer in women of African ancestry CARCINOGENESIS Huo, D., Zheng, Y., Ogundiran, T. O., Adebamowo, C., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Simon, M. S., John, E. M., Hennis, A., Nemesure, B., Wu, S., Leske, M. C., Ambs, S., Niu, Q., Zhang, J., Cox, N. J., Olopade, O. I. 2012; 33 (4): 835-840

    Abstract

    Multiple breast cancer susceptibility loci have been identified in genome-wide association studies (GWAS) in populations of European and Asian ancestry using array chips optimized for populations of European ancestry. It is important to examine whether these loci are associated with breast cancer risk in women of African ancestry. We evaluated 25 single nucleotide polymorphisms (SNPs) at 19 loci in a pooled case-control study of breast cancer, which included 1509 cases and 1383 controls. Cases and controls were enrolled in Nigeria, Barbados and the USA; all women were of African ancestry. We found significant associations for three SNPs, which were in the same direction and of similar magnitude as those reported in previous fine-mapping studies in women of African ancestry. The allelic odds ratios were 1.24 [95% confidence interval (CI): 1.04-1.47; P = 0.018] for the rs2981578-G allele (10q26/FGFR2), 1.34 (95% CI: 1.10-1.63; P = 0.0035) for the rs9397435-G allele (6q25) and 1.12 (95% CI: 1.00-1.25; P = 0.04) for the rs3104793-C allele (16q12). Although a significant association was observed for an additional index SNP (rs3817198), it was in the opposite direction to prior GWAS studies. In conclusion, this study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry. Further fine-mapping studies in women of African ancestry will be needed to reveal additional and causal variants for breast cancer.

    View details for DOI 10.1093/carcin/bgs093

    View details for Web of Science ID 000302493800014

    View details for PubMedID 22357627

    View details for PubMedCentralID PMC3324445

  • Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Couch, F. J., Gaudet, M. M., Antoniou, A. C., Ramus, S. J., Kuchenbaecker, K. B., Soucy, P., Beesley, J., Chen, X., Wang, X., Kirchhoff, T., McGuffog, L., Barrowdale, D., Lee, A., Healey, S., Sinilnikova, O. M., Andrulis, I. L., Ozcelik, H., Mulligan, A. M., Thomassen, M., Gerdes, A., Jensen, U. B., Skytte, A., Kruse, T. A., Caligo, M. A., von Wachenfeldt, A., Barbany-Bustinza, G., Loman, N., Soller, M., Ehrencrona, H., Karlsson, P., Nathanson, K. L., Rebbeck, T. R., Domchek, S. M., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Zlowocka, E., Huzarski, T., Byrski, T., Gronwald, J., Cybulski, C., Gorski, B., Osorio, A., Duran, M., Isabel Tejada, M., Benitez, J., Hamann, U., Hogervorst, F. B., van Os, T. A., van Leeuwen, F. E., Meijers-Heijboer, H. E., Wijnen, J., Blok, M. J., Kets, M., Hooning, M. J., Oldenburg, R. A., Ausems, M. G., Peock, S., Frost, D., Ellis, S. D., Platte, R., Fineberg, E., Evans, D. G., Jacobs, C., Eeles, R. A., Adlard, J., Davidson, R., Eccles, D. M., Cole, T., Cook, J., Paterson, J., Brewer, C., Douglas, F., Hodgson, S. V., Morrison, P. J., Walker, L., Porteous, M. E., Kennedy, M. J., Side, L. E., Bove, B., Godwin, A. K., Stoppa-Lyonnet, D., Fassy-Colcombet, M., Castera, L., Cornelis, F., Mazoyer, S., Leone, M., Boutry-Kryza, N., Bressac-de Paillerets, B., Caron, O., Pujol, P., Coupier, I., Delnatte, C., Akloul, L., Lynch, H. T., Snyder, C. L., Buys, S. S., Daly, M. B., Terry, M., Chung, W. K., John, E. M., Miron, A., Southey, M. C., Hopper, J. L., Goldgar, D. E., Singer, C. F., Rappaport, C., Tea, M. M., Fink-Retter, A., Hansen, T. v., Nielsen, F. C., Arason, A., Vijai, J., Shah, S., Sarrel, K., Robson, M. E., Piedmonte, M., Phillips, K., Basil, J., Rubinstein, W. S., Boggess, J., Wakeley, K., Ewart-Toland, A., Montagna, M., Agata, S., Imyanitov, E. N., Isaacs, C., Janavicius, R., Lazaro, C., Blanco, I., Feliubadalo, L., Brunet, J., Gayther, S. A., Pharoah, P. P., Odunsi, K. O., Karlan, B. Y., Walsh, C. S., Olah, E., Teo, S. H., Ganz, P. A., Beattie, M. S., Van Rensburg, E. J., Dorfling, C. M., Diez, O., Kwong, A., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Heidemann, S., Niederacher, D., Preisler-Adams, S., Gadzicki, D., Varon-Mateeva, R., Deissler, H., Gehrig, A., Sutter, C., Kast, K., Fiebig, B., Heinritz, W., Caldes, T., de la Hoya, M., Muranen, T. A., Nevanlinna, H., Tischkowitz, M., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Lindor, N. M., Fredericksen, Z., Pankratz, V. S., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Barile, M., Bernard, L., Viel, A., Giannini, G., Varesco, L., Radice, P., Greene, M. H., Mai, P. L., Easton, D. F., Chenevix-Trench, G., Offit, K., Simard, J. 2012; 21 (4): 645-657

    Abstract

    Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)).19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.

    View details for DOI 10.1158/1055-9965.EPI-11-0888

    View details for Web of Science ID 000302220600010

    View details for PubMedID 22351618

    View details for PubMedCentralID PMC3319317

  • 19p13.1 Is a Triple-Negative-Specific Breast Cancer Susceptibility Locus CANCER RESEARCH Stevens, K. N., Fredericksen, Z., Vachon, C. M., Wang, X., Margolin, S., Lindblom, A., Nevanlinna, H., Greco, D., Aittomaki, K., Blomqvist, C., Chang-Claude, J., Vrieling, A., Flesch-Janys, D., Sinn, H., Wang-Gohrke, S., Nickels, S., Brauch, H., Ko, Y., Fischer, H., Schmutzler, R. K., Meindl, A., Bartram, C. R., Schott, S., Engel, C., Godwin, A. K., Weaver, J., Pathak, H. B., Sharma, P., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Miron, P., Yannoukakos, D., Stavropoulou, A., Fountzilas, G., Gogas, H. J., Swann, R., Dwek, M., Perkins, A., Milne, R. L., Benitez, J., Pilar Zamora, M., Arias Perez, J. I., Bojesen, S. E., Nielsen, S. F., Nordestgaard, B. G., Flyger, H., Guenel, P., Therese Truong, T., Menegaux, F., Cordina-Duverger, E., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Sawyer, E., Tomlinson, I., Kerin, M. J., Peto, J., Johnson, N., Fletcher, O., dos Santos Silva, I., Fasching, P. A., Beckmann, M. W., Hartmann, A., Ekici, A. B., Lophatananon, A., Muir, K., Puttawibul, P., Wiangnon, S., Schmidt, M. K., Broeks, A., Braaf, L. M., Rosenberg, E. H., Hopper, J. L., Apicella, C., Park, D. J., Southey, M. C., Swerdlow, A. J., Ashworth, A., Orr, N., Schoemaker, M. J., Anton-Culver, H., Ziogas, A., Bernstein, L., Dur, C. C., Shen, C., Yu, J., Hsu, H., Hsiung, C., Hamann, U., Duennebier, T., Ruediger, T., Ulmer, H. U., Pharoah, P. P., Dunning, A. M., Humphreys, M. K., Wang, Q., Cox, A., Cross, S. S., Reed, M. W., Hall, P., Czene, K., Ambrosone, C. B., Ademuyiwa, F., Hwang, H., Eccles, D. M., Garcia-Closas, M., Figueroa, J. D., Sherman, M. E., Lissowska, J., Devilee, P., Seynaeve, C., Tollenaar, R. A., Hooning, M. J., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., John, E. M., Miron, A., Alnaes, G. G., Kristensen, V., Borresen-Dale, A., Giles, G. G., Baglietto, L., McLean, C. A., Severi, G., Kosel, M. L., Pankratz, V. S., Slager, S., Olson, J. E., Radice, P., Peterlongo, P., Manoukian, S., Barile, M., Lambrechts, D., Hatse, S., Dieudonne, A., Christiaens, M., Chenevix-Trench, G., Beesley, J., Chen, X., Mannermaa, A., Kosma, V., Hartikainen, J. M., Soini, Y., Easton, D. F., Couch, F. J. 2012; 72 (7): 1795-1803

    Abstract

    The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways.

    View details for DOI 10.1158/0008-5472.CAN-11-3364

    View details for Web of Science ID 000302551800022

    View details for PubMedID 22331459

    View details for PubMedCentralID PMC3319792

  • Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers HUMAN MUTATION Ramus, S. J., Antoniou, A. C., Kuchenbaecker, K. B., Soucy, P., Beesley, J., Chen, X., McGuffog, L., Sinilnikova, O. M., Healey, S., Barrowdale, D., Lee, A., Thomassen, M. 2012; 33 (4): 690-702

    Abstract

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

    View details for DOI 10.1002/humu.22025

    View details for Web of Science ID 000301338900017

    View details for PubMedID 22253144

  • Genetic Susceptibility to Type 2 Diabetes and Breast Cancer Risk in Women of European and African Ancestry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hou, N., Zheng, Y., Gamazon, E. R., Ogundiran, T. O., Adebamowo, C., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Simon, M. S., John, E. M., Hennis, A., Nemesure, B., Wu, S., Leske, M. C., Ambs, S., Niu, Q., Zhang, J., Pierce, B., Cox, N. J., Olopade, O. I., Huo, D. 2012; 21 (3): 552-556

    Abstract

    Epidemiologic studies have reported a positive association between type 2 diabetes (T2D) and breast cancer risk, independent of body weight.We investigated 40 genetic variants known to be associated with T2D in relation to breast cancer risk among 2,651 breast cancer cases and 2,520 controls of African or European ancestry that were pooled from seven studies.We found that two T2D risk alleles in Caucasian women (rs5945326-G, rs12518099-C) and one in women of African ancestry (rs7578597-T) were positively associated with breast cancer risk at a nominal significance level of 0.05, whereas two T2D risk alleles were inversely associated with breast cancer risk in Caucasian women (rs1111875-C, rs10923931-T). The composite T2D susceptibility score (the number of risk allele) was not significantly associated with breast cancer risk.The association between established T2D genetic susceptibility variants and breast cancer risk in women of African or European ancestry is likely weak, if it does exist.The pleiotropic effects of known T2D risk alleles cannot explain the association between T2D and breast cancer risk.

    View details for DOI 10.1158/1055-9965.EPI-11-0979

    View details for Web of Science ID 000301284100021

    View details for PubMedID 22237986

    View details for PubMedCentralID PMC3297695

  • Genome-wide association analysis identifies three new breast cancer susceptibility loci NATURE GENETICS Ghoussaini, M., Fletcher, O., Michailidou, K., Turnbull, C., Schmidt, M. K., Dicks, E., Dennis, J., Wang, Q., Humphreys, M. K., Luccarini, C., Baynes, C., Conroy, D., Maranian, M., Ahmed, S., Driver, K., Johnson, N., Orr, N., Silva, I. d., Waisfisz, Q., Meijers-Heijboer, H., Uitterlinden, A. G., Rivadeneira, F., Hall, P., Czene, K., Irwanto, A., Liu, J., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Meindl, A., Schmutzler, R. K., Mueller-Myhsok, B., Lichtner, P., Chang-Claude, J., Hein, R., Nickels, S., Flesch-Janys, D., Tsimiklis, H., Makalic, E., Schmidt, D., Bui, M., Hopper, J. L., Apicella, C., Park, D. J., Southey, M., Hunter, D. J., Chanock, S. J., Broeks, A., Verhoef, S., Hogervorst, F. B., Fasching, P. A., Lux, M. P., Beckmann, M. W., Ekici, A. B., Sawyer, E., Tomlinson, I., Kerin, M., Marme, F., Schneeweiss, A., Sohn, C., Burwinkel, B., Guenel, P., Truong, T., Cordina-Duverger, E., Menegaux, F., Bojesen, S. E., Nordestgaard, B. G., Nielsen, S. F., Flyger, H., Milne, R. L., Rosario Alonso, M., Gonzalez-Neira, A., Benitez, J., Anton-Culver, H., Ziogas, A., Bernstein, L., Dur, C. C., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Justenhoven, C., Brauch, H., Bruening, T., Wang-Gohrke, S., Eilber, U., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Bogdanova, N. V., Antonenkova, N. N., Rogov, Y. I., Karstens, J. H., Bermisheva, M., Prokofieva, D., Khusnutdinova, E., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Lambrechts, D., Yesilyurt, B. T., Floris, G., Leunen, K., Manoukian, S., Bonanni, B., Fortuzzi, S., Peterlongo, P., Couch, F. J., Wang, X., Stevens, K., Lee, A., Giles, G. G., Baglietto, L., Severi, G., McLean, C., Alnaes, G. G., Kristensen, V., Borrensen-Dale, A., John, E. M., Miron, A., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Kauppila, S., Andrulis, I. L., Glendon, G., Mulligan, A. M., Devilee, P., Van Asperen, C. J., Tollenaar, R. A., Seynaeve, C., Figueroa, J. D., Garcia-Closas, M., Brinton, L., Lissowska, J., Hooning, M. J., Hollestelle, A., Oldenburg, R. A., van den Ouweland, A. M., Cox, A., Reed, M. W., Shah, M., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Jones, M., Schoemaker, M., Ashworth, A., Swerdlow, A., Beesley, J., Chen, X., Muir, K. R., Lophatananon, A., Rattanamongkongul, S., Chaiwerawattana, A., Kang, D., Yoo, K., Noh, D., Shen, C., Yu, J., Wu, P., Hsiung, C., Perkins, A., Swann, R., Velentzis, L., Eccles, D. M., Tapper, W. J., Gerty, S. M., Graham, N. J., Ponder, B. A., Chenevix-Trench, G., Pharoah, P. D., Lathrop, M., Dunning, A. M., Rahman, N., Peto, J., Easton, D. F. 2012; 44 (3): 312-U120

    Abstract

    Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ?8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ?70,000 cases and ?68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

    View details for DOI 10.1038/ng.1049

    View details for Web of Science ID 000300843600018

    View details for PubMedID 22267197

    View details for PubMedCentralID PMC3653403

  • Fish intake, cooking practices, and risk of prostate cancer: results from a multi-ethnic case-control study CANCER CAUSES & CONTROL Joshi, A. D., John, E. M., Koo, J., Ingles, S. A., Stern, M. C. 2012; 23 (3): 405-420

    Abstract

    Studies conducted to assess the association between fish consumption and prostate cancer (PCA) risk are inconclusive. However, few studies have distinguished between fatty and lean fish, and no studies have considered the role of different cooking practices, which may lead to differential accumulation of chemical carcinogens. In this study, we investigated the association between fish intake and localized and advanced PCA taking into account fish types (lean vs. fatty) and cooking practices.We analyzed data for 1,096 controls, 717 localized and 1,140 advanced cases from the California Collaborative Prostate Cancer Study, a multiethnic, population-based case-control study. We used multivariate conditional logistic regression to estimate odds ratios using nutrient density converted variables of fried fish, tuna, dark fish and white fish consumption. We tested for effect modification by cooking methods (high- vs. low-temperature methods) and levels of doneness.We observed that high white fish intake was associated with increased risk of advanced PCA among men who cooked with high-temperature methods (pan-frying, oven-broiling and grilling) until fish was well done (p (trend) = 0.001). No associations were found among men who cooked fish at low temperature and/or just until done (white fish x cooking method p (interaction) = 0.040).Our results indicate that consideration of fish type (oily vs. lean), specific fish cooking practices and levels of doneness of cooked fish helps elucidate the association between fish intake and PCA risk and suggest that avoiding high-temperature cooking methods for white fish may lower PCA risk.

    View details for DOI 10.1007/s10552-011-9889-2

    View details for Web of Science ID 000300891100002

    View details for PubMedID 22207320

  • Lack of association between common single nucleotide polymorphisms in the TERT-CLPTM1L locus and breast cancer in women of African ancestry BREAST CANCER RESEARCH AND TREATMENT Zheng, Y., Ogundiran, T. O., Adebamowo, C., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Simon, M. S., John, E. M., Hennis, A., Nemesure, B., Wu, S., Leske, M. C., Ambs, S., Niu, Q., Zhang, J., Cox, N. J., Olopade, O. I., Huo, D. 2012; 132 (1): 341-345

    Abstract

    As one of the most common cancers worldwide, breast cancer places an extraordinary burden on the populations of African ancestry. Common SNPs in the TERT-CLPTM1L locus have been reported to be associated with several types of cancer, including breast cancer. We sought to investigate whether the previously reported common single nucleotide polymorphisms (SNPs) in the TERT-CLPTM1L locus could also contribute to the breast cancer risk in women of African ancestry. We genotyped eleven SNPs in 2,892 women of African descent but were unable to detect any significant association between TERT-CLPTM1L SNPs and their predispositions for breast cancer risk. Given the differences in linkage disequilibrium patterns across populations, our findings suggest that larger independent studies from diverse populations are expected to evaluate the importance of the TERT-CLPTM1L locus in breast cancer.

    View details for DOI 10.1007/s10549-011-1890-7

    View details for Web of Science ID 000300278400035

    View details for PubMedID 22134622

    View details for PubMedCentralID PMC3670987

  • A Review of Cancer in US Hispanic Populations CANCER PREVENTION RESEARCH Haile, R. W., John, E. M., Levine, A. J., Cortessis, V. K., Unger, J. B., Gonzales, M., Ziv, E., Thompson, P., Spruijt-Metz, D., Tucker, K. L., Bernstein, J. L., Rohan, T. E., Ho, G. Y., Bondy, M. L., Martinez, M. E., Cook, L., Stern, M. C., Correa, M. C., Wright, J., Schwartz, S. J., Baezconde-Garbanati, L., Blinder, V., Miranda, P., Hayes, R., Friedman-Jimenez, G., Monroe, K. R., Haiman, C. A., Henderson, B. E., Thomas, D. C., Boffetta, P. 2012; 5 (2): 150-163

    Abstract

    There are compelling reasons to conduct studies of cancer in Hispanics, the fastest growing major demographic group in the United States (from 15% to 30% of the U.S. population by 2050). The genetically admixed Hispanic population coupled with secular trends in environmental exposures and lifestyle/behavioral practices that are associated with immigration and acculturation offer opportunities for elucidating the effects of genetics, environment, and lifestyle on cancer risk and identifying novel risk factors. For example, traditional breast cancer risk factors explain less of the breast cancer risk in Hispanics than in non-Hispanic whites (NHW), and there is a substantially greater proportion of never-smokers with lung cancer in Hispanics than in NHW. Hispanics have higher incidence rates for cancers of the cervix, stomach, liver, and gall bladder than NHW. With respect to these cancers, there are intriguing patterns that warrant study (e.g., depending on country of origin, the five-fold difference in gastric cancer rates for Hispanic men but not Hispanic women). Also, despite a substantially higher incidence rate and increasing secular trend for liver cancer in Hispanics, there have been no studies of Hispanics reported to date. We review the literature and discuss study design options and features that should be considered in future studies.

    View details for DOI 10.1158/1940-6207.CAPR-11-0447

    View details for Web of Science ID 000300043500002

    View details for PubMedID 22307564

  • Evaluating breast cancer risk projections for Hispanic women BREAST CANCER RESEARCH AND TREATMENT Banegas, M. P., Gail, M. H., LaCroix, A., Thompson, B., Martinez, M. E., Wactawski-Wende, J., John, E. M., Hubbell, F. A., Yasmeen, S., Katki, H. A. 2012; 132 (1): 347-353

    Abstract

    For Hispanic women, the Breast Cancer Risk Assessment Tool (BCRAT; "Gail Model") combines 1990-1996 breast cancer incidence for Hispanic women with relative risks for breast cancer risk factors from non-Hispanic white (NHW) women. BCRAT risk projections have never been comprehensively evaluated for Hispanic women. We compared the relative risks and calibration of BCRAT risk projections for 6,353 Hispanic to 128,976 NHW postmenopausal participants aged 50 and older in the Women's Health Initiative (WHI). Calibration was assessed by the ratio of the number of breast cancers observed with that expected by the BCRAT (O/E). We re-evaluated calibration for an updated BCRAT that combined BCRAT relative risks with 1993-2007 breast cancer incidence that is contemporaneous with the WHI. Cox regression was used to estimate relative risks. Discriminatory accuracy was assessed using the concordance statistic (AUC). In the WHI Main Study, the BCRAT underestimated the number of breast cancers by 18% in both Hispanics (O/E = 1.18, P = 0.06) and NHWs (O/E = 1.18, P < 0.001). Updating the BCRAT improved calibration for Hispanic women (O/E = 1.08, P = 0.4) and NHW women (O/E = 0.98, P = 0.2). For Hispanic women, relative risks for number of breast biopsies (1.71 vs. 1.27, P = 0.03) and age at first birth (0.97 vs. 1.24, P = 0.02) differed between the WHI and BCRAT. The AUC was higher for Hispanic women than NHW women (0.63 vs. 0.58, P = 0.03). Updating the BCRAT with contemporaneous breast cancer incidence rates improved calibration in the WHI. The modest discriminatory accuracy of the BCRAT for Hispanic women might improve by using risk factor relative risks specific to Hispanic women.

    View details for DOI 10.1007/s10549-011-1900-9

    View details for Web of Science ID 000300278400036

    View details for PubMedID 22147080

  • Calcium intake and prostate cancer among African Americans: Effect modification by vitamin D receptor calcium absorption genotype JOURNAL OF BONE AND MINERAL RESEARCH Rowland, G. W., Schwartz, G. G., John, E. M., Ingles, S. A. 2012; 27 (1): 187-194

    Abstract

    High dietary intake of calcium has been classified as a probable cause of prostate cancer, although the mechanism underlying the association between dietary calcium and prostate cancer risk is unclear. The vitamin D receptor (VDR) is a key regulator of calcium absorption. In the small intestine, VDR expression is regulated by the CDX-2 transcription factor, which binds a polymorphic site in the VDR gene promoter. We examined VDR Cdx2 genotype and calcium intake, assessed by a food frequency questionnaire, in 533 African-American prostate cancer cases (256 with advanced stage at diagnosis, 277 with localized stage) and 250 African-American controls who participated in the California Collaborative Prostate Cancer Study. We examined the effects of genotype, calcium intake, and diet-gene interactions by conditional logistic regression. Compared with men in the lowest quartile of calcium intake, men in the highest quartile had an approximately twofold increased risk of localized and advanced prostate cancer (odds ratio [OR]?=?2.20, 95% confidence interval [CI]?=?1.40, 3.46), with a significant dose-response. Poor absorbers of calcium (VDR Cdx2 GG genotype) had a significantly lower risk of advanced prostate cancer (OR?=?0.41, 95% CI?=?0.19, 0.90). The gene-calcium interaction was statistically significant (p?=?0.03). Among men with calcium intake below the median (680?mg/day), carriers of the G allele had an approximately 50% decreased risk compared with men with the AA genotype. These findings suggest a link between prostate cancer risk and high intestinal absorption of calcium.

    View details for DOI 10.1002/jbmr.505

    View details for Web of Science ID 000298479000021

    View details for PubMedID 21887707

    View details for PubMedCentralID PMC3234334

  • Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers BREAST CANCER RESEARCH Antoniou, A. C., Kuchenbaecker, K. B., Soucy, P., Beesley, J., Chen, X., McGuffog, L., Lee, A., Barrowdale, D., Healey, S., Sinilnikova, O. M., Caligo, M. A., Loman, N., Harbst, K., Lindblom, A., Arver, B., Rosenquist, R., Karlsson, P., Nathanson, K., Domchek, S., Rebbeck, T., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Zlowowcka-Perlowska, E., Osorio, A., Duran, M., Andres, R., Benitez, J., Hamann, U., Hogervorst, F. B., van Os, T. A., Verhoef, S., Meijers-Heijboer, H. E., Wijnen, J., Garcia, E. B., Ligtenberg, M. J., Kriege, M., Collee, M., Ausems, M. G., Oosterwijk, J. C., Peock, S., Frost, D., Ellis, S. D., Platte, R., Fineberg, E., Evans, D. G., Lalloo, F., Jacobs, C., Eeles, R., Adlard, J., Davidson, R., Cole, T., Cook, J., Paterson, J., Douglas, F., Brewer, C., Hodgson, S., Morrison, P. J., Walker, L., Rogers, M. T., Donaldson, A., Dorkins, H., Godwin, A. K., Bove, B., Stoppa-Lyonnet, D., Houdayer, C., Buecher, B., De Pauw, A., Mazoyer, S., Calender, A., Leone, M., Bressac-de Paillerets, B., Caron, O., Sobol, H., Frenay, M., Prieur, F., Ferrer, S. F., Mortemousque, I., Buys, S., Daly, M., Miron, A., Terry, M. B., Hopper, J. L., John, E. M., Southey, M., Goldgar, D., Singer, C. F., Fink-Retter, A., Tea, M., Kaulich, D. G., Hansen, T. v., Nielsen, F. C., Barkardottir, R. B., Gaudet, M., Kirchhoff, T., Joseph, V., Dutra-Clarke, A., Offit, K., Piedmonte, M., Kirk, J., Cohn, D., Hurteau, J., Byron, J., Fiorica, J., Toland, A. E., Montagna, M., Oliani, C., Imyanitov, E., Isaacs, C., Tihomirova, L., Blanco, I., Lazaro, C., Teule, A., Del Valle, J., Gayther, S. A., Odunsi, K., Gross, J., Karlan, B. Y., Olah, E., Teo, S., Ganz, P. A., Beattie, M. S., Dorfling, C. M., van Rensburg, E. J., Diez, O., Kwong, A., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Heidemann, S., Niederacher, D., Preisler-Adams, S., Gadzicki, D., Varon-Mateeva, R., Deissler, H., Gehrig, A., Sutter, C., Kast, K., Fiebig, B., Schaefer, D., Caldes, T., de la Hoya, M., Nevanlinna, H., Muranen, T. A., Lesperance, B., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Wang, X., Fredericksen, Z., Pankratz, V. S., Lindor, N. M., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Bonanni, B., Bernard, L., Dolcetti, R., Papi, L., Ottini, L., Radice, P., Greene, M. H., Loud, J. T., Andrulis, I. L., Ozcelik, H., Mulligan, A. M., Glendon, G., Thomassen, M., Gerdes, A., Jensen, U. B., Skytte, A., Kruse, T. A., Chenevix-Trench, G., Couch, F. J., Simard, J., Easton, D. F. 2012; 14 (1)

    Abstract

    Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

    View details for DOI 10.1186/bcr3121

    View details for Web of Science ID 000307444100042

    View details for PubMedID 22348646

    View details for PubMedCentralID PMC3496151

  • Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Mavaddat, N., Barrowdale, D., Andrulis, I. L., Domchek, S. M., Eccles, D., Nevanlinna, H., Ramus, S. J., Spurdle, A., Robson, M., Sherman, M., Mulligan, A. M., Couch, F. J., Engel, C., McGuffog, L., Healey, S., Sinilnikova, O. M., Southey, M. C., Terry, M. B., Goldgar, D., O'Malley, F., John, E. M., Janavicius, R., Tihomirova, L., Hansen, T. v., Nielsen, F. C., Osorio, A., Stavropoulou, A., Benitez, J., Manoukian, S., Peissel, B., Barile, M., Volorio, S., Pasini, B., Dolcetti, R., Putignano, A. L., Ottini, L., Radice, P., Hamann, U., Rashid, M. U., Hogervorst, F. B., Kriege, M., van der Luijt, R. B., Peock, S., Frost, D., Evans, D. G., Brewer, C., Walker, L., Rogers, M. T., Side, L. E., Houghton, C., Weaver, J., Godwin, A. K., Schmutzler, R. K., Wappenschmidt, B., Meindl, A., Kast, K., Arnold, N., Niederacher, D., Sutter, C., Deissler, H., Gadzicki, D., Preisler-Adams, S., Varon-Mateeva, R., Schoenbuchner, I., Gevensleben, H., Stoppa-Lyonnet, D., Belotti, M., Barjhoux, L., Isaacs, C., Peshkin, B. N., Caldes, T., de la Hoya, M., Canadas, C., Heikkinen, T., Heikkila, P., Aittomaki, K., Blanco, I., Lazaro, C., Brunet, J., Agnarsson, B. A., Arason, A., Barkardottir, R. B., Dumont, M., Simard, J., Montagna, M., Agata, S., D'Andrea, E., Yan, M., Fox, S., Rebbeck, T. R., Rubinstein, W., Tung, N., Garber, J. E., Wang, X., Fredericksen, Z., Pankratz, V. S., Lindor, N. M., Szabo, C., Offit, K., Sakr, R., Gaudet, M. M., Singer, C. F., Tea, M., Rappaport, C., Mai, P. L., Greene, M. H., Sokolenko, A., Imyanitov, E., Toland, A. E., Senter, L., Sweet, K., Thomassen, M., Gerdes, A., Kruse, T., Caligo, M., Aretini, P., Rantala, J., von Wachenfeld, A., Henriksson, K., Steele, L., Neuhausen, S. L., Nussbaum, R., Beattie, M., Odunsi, K., Sucheston, L., Gayther, S. A., Nathanson, K., Gross, J., Walsh, C., Karlan, B., Chenevix-Trench, G., Easton, D. F., Antoniou, A. C. 2012; 21 (1): 134-147

    Abstract

    Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). CONCLUSIONS/IMPACT: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.

    View details for DOI 10.1158/1055-9965.EPI-11-0775

    View details for Web of Science ID 000299051500014

    View details for PubMedID 22144499

  • Breast Cancer Prognosis in BRCA1 and BRCA2 Mutation Carriers: An International Prospective Breast Cancer Family Registry Population-Based Cohort Study JOURNAL OF CLINICAL ONCOLOGY Goodwin, P. J., Phillips, K., West, D. W., Ennis, M., Hopper, J. L., John, E. M., O'Malley, F. P., Milne, R. L., Andrulis, I. L., Friedlander, M. L., Southey, M. C., Apicella, C., Giles, G. G., Longacre, T. A. 2012; 30 (1): 19-26

    Abstract

    To compare breast cancer prognosis in BRCA1 and BRCA2 mutation carriers with that in patients with sporadic disease.An international population-based cohort study was conducted in Canada, the United States, and Australia of 3,220 women with incident breast cancer diagnosed between 1995 and 2000 and observed prospectively. Ninety-three had BRCA1 mutations; 71, BRCA2 mutations; one, both mutations; 1,550, sporadic breast cancer; and 1,505, familial breast cancer (without known BRCA1 or BRCA2 mutation). Distant recurrence and death were analyzed.Mean age at diagnosis was 45.3 years; mean follow-up was 7.9 years. Risks of distant recurrence and death did not differ significantly between BRCA1 mutation carriers and those with sporadic disease in univariable and multivariable analyses. Risk of distant recurrence was higher for BRCA2 mutation carriers compared with those with sporadic disease in univariable analysis (hazard ratio [HR], 1.63; 95% CI, 1.02 to 2.60; P = .04). Risk of death was also higher in BRCA2 carriers in univariable analysis (HR, 1.81; 95% CI, 1.15 to 2.86; P = .01). After adjustment for age, tumor stage and grade, nodal status, hormone receptors, and year of diagnosis, no differences were observed for distant recurrence (HR, 1.00; 95% CI, 0.62 to 1.61; P = 1.00) or death (HR, 1.12; 95% CI, 0.70 to 1.79; P = .64).Outcomes of BRCA1 mutation carriers were similar to those of patients with sporadic breast cancer. Worse outcomes in BRCA2 mutation carriers in univariable analysis seem to reflect the presence of more adverse tumor characteristics in these carriers. Similar outcomes were identified in BRCA2 carriers and those with sporadic disease in multivariable analyses.

    View details for DOI 10.1200/JCO.2010.33.0068

    View details for Web of Science ID 000302617900009

    View details for PubMedID 22147742

  • Body mass index and risk of second primary breast cancer: The WECARE Study BREAST CANCER RESEARCH AND TREATMENT Brooks, J. D., John, E. M., Mellemkjaer, L., Reiner, A. S., Malone, K. E., Lynch, C. F., Figueiredo, J. C., Haile, R. W., Shore, R. E., Bernstein, J. L., Bernstein, L. 2012; 131 (2): 571-580

    Abstract

    The identification of potentially modifiable risk factors, such as body size, could allow for interventions that could help reduce the burden of contralateral breast cancer (CBC) among breast cancer survivors. Studies examining the relationship between body mass index (BMI) and CBC have yielded mixed results. From the population-based, case-control, Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study, we included 511 women with CBC (cases) and 999 women with unilateral breast cancer (controls) who had never used postmenopausal hormone therapy. Rate ratios (RR) and 95% confidence intervals (CI) were used to assess the relationship between BMI and CBC risk. No associations between BMI at first diagnosis or weight-change between first diagnosis and date of CBC diagnosis (or corresponding date in matched controls) and CBC risk were seen. However, obese (BMI ? 30 kg/m(2)) postmenopausal women with estrogen receptor (ER)-negative first primary tumors (n = 12 cases and 9 controls) were at an increased risk of CBC compared with normal weight women (BMI < 25 kg/m(2)) (n = 43 cases and 98 controls) (RR = 5.64 (95% CI 1.76, 18.1)). No association between BMI and CBC risk was seen in premenopausal or postmenopausal women with ER-positive first primaries. Overall, BMI is not associated with CBC risk in this population of young breast cancer survivors. Our finding of an over five-fold higher risk of CBC in a small subgroup of obese postmenopausal women with an ER-negative first primary breast cancer is based on limited numbers and requires confirmation in a larger study.

    View details for DOI 10.1007/s10549-011-1743-4

    View details for Web of Science ID 000298752200021

    View details for PubMedID 21892703

    View details for PubMedCentralID PMC3251700

  • Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk BRITISH JOURNAL OF CANCER Stevens, K. N., Garcia-Closas, M., Fredericksen, Z., Kosel, M., Pankratz, V. S., Hopper, J. L., Dite, G. S., Apicella, C., Southey, M. C., Schmidt, M. K., Broeks, A., van 't Veer, L. J., Tollenaar, R. A., Fasching, P. A., Beckmann, M. W., Hein, A., Ekici, A. B., Johnson, N., Peto, J., Silva, I. d., Gibson, L., Sawyer, E., Tomlinson, I., Kerin, M. J., Chanock, S., Lissowska, J., Hunter, D. J., HOOVER, R. N., Thomas, G. D., Milne, R. L., Perez, J. I., Gonzalez-Neira, A., Benitez, J., Burwinkel, B., Meindl, A., Schmutzler, R. K., Bartrar, C. R., Hamann, U., Ko, Y. D., Bruening, T., Chang-Claude, J., HEIN, R., Wang-Gohrke, S., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Bogdanova, N., Zalutsky, J. V., Rogov, Y. I., Antonenkova, N., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J., Chenevix-Trench, G., Chen, X., Peterlongo, P., Bonanni, B., Bernard, L., Manoukian, S., Wang, X., Cerhan, J., Vachon, C. M., Olson, J., Giles, G. G., Baglietto, L., McLean, C. A., Severi, G., John, E. M., Miron, A., Winqvist, R., Pylkaes, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I., Knight, J. A., Glendon, G., Mulligan, A. M., Cox, A., Brock, I. W., Elliott, G., Cross, S. S., Pharoah, P. P., Dunning, A. M., Pooley, K. A., Humphreys, M. K., Wang, J., Kang, D., Yoo, K., Noh, D., Sangrajrang, S., Gabrieau, V., Brennan, P., McKay, J., Anton-Culver, H., Ziogas, A., Couch, F. J., Easton, D. F. 2011; 105 (12): 1934-1939

    Abstract

    Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer.A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30?949 cases and 29?788 controls from the Breast Cancer Association Consortium (BCAC).Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139).Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

    View details for DOI 10.1038/bjc.2011.448

    View details for Web of Science ID 000298140800018

    View details for PubMedID 22033276

    View details for PubMedCentralID PMC3251877

  • Breast Cancer Risk for Noncarriers of Family-Specific BRCA1 and BRCA2 Mutations: Findings From the Breast Cancer Family Registry JOURNAL OF CLINICAL ONCOLOGY Kurian, A. W., Gong, G. D., John, E. M., Johnston, D. A., Felberg, A., West, D. W., Miron, A., Andrulis, I. L., Hopper, J. L., Knight, J. A., Ozcelik, H., Dite, G. S., Apicella, C., Southey, M. C., Whittemore, A. S. 2011; 29 (34): 4505-4509

    Abstract

    Women with germline BRCA1 and BRCA2 mutations have five- to 20-fold increased risks of developing breast and ovarian cancer. A recent study claimed that women testing negative for their family-specific BRCA1 or BRCA2 mutation (noncarriers) have a five-fold increased risk of breast cancer. We estimated breast cancer risks for noncarriers by using a population-based sample of patients with breast cancer and their female first-degree relatives (FDRs).Patients were women with breast cancer and their FDRs enrolled in the population-based component of the Breast Cancer Family Registry; patients with breast cancer were tested for BRCA1 and BRCA2 mutations, as were FDRs of identified mutation carriers. We used segregation analysis to fit a model that accommodates familial correlation in breast cancer risk due to unobserved shared risk factors.We studied 3,047 families; 160 had BRCA1 and 132 had BRCA2 mutations. There was no evidence of increased breast cancer risk for noncarriers of identified mutations compared with FDRs from families without BRCA1 or BRCA2 mutations: relative risk was 0.39 (95% CI, 0.04 to 3.81). Residual breast cancer correlation within families was strong, suggesting substantial risk heterogeneity in women without BRCA1 or BRCA2 mutations, with some 3.4% of them accounting for roughly one third of breast cancer cases.These results support the practice of advising noncarriers that they do not have any increase in breast cancer risk attributable to the family-specific BRCA1 or BRCA2 mutation.

    View details for DOI 10.1200/JCO.2010.34.4440

    View details for PubMedID 22042950

    View details for PubMedCentralID PMC3236651

  • Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers HUMAN MOLECULAR GENETICS Cox, D. G., Simard, J., Sinnett, D., Hamdi, Y., Soucy, P., Ouimet, M., Barjhoux, L., Verny-Pierre, C., McGuffog, L., Healey, S., Szabo, C., Greene, M. H., Mai, P. L., Andrulis, I. L., Thomassen, M., Gerdes, A., Caligo, M. A., Friedman, E., Laitman, Y., Kaufman, B., Paluch, S. S., Borg, A., Karlsson, P., Askmalm, M., Bustinza, G., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Benitez, J., Hamann, U., Rookus, M. A., van den Ouweland, A. W., Ausems, M. M., Aalfs, C. M., van Asperen, C. J., Devilee, P., Gille, H. P., Peock, S., Frost, D., Evans, D., Eeles, R., Izatt, L., Adlard, J., Paterson, J., Eason, J., Godwin, A. K., Remon, M., Moncoutier, V., Gauthier-Villars, M., Lasset, C., Giraud, S., Hardouin, A., Berthet, P., Sobol, H., Eisinger, F., de Paillerets, B., Caron, O., Delnatte, C., Goldgar, D., Miron, A., Ozcelik, H., Buys, S., Southey, M. C., Terry, M., Singer, C. F., Dressler, A., Tea, M., Hansen, T. O., Johannsson, O., Piedmonte, M., Rodriguez, G. C., Basil, J. B., Blank, S., Toland, A. E., Montagna, M., Isaacs, C., Blanco, I., Gayther, S. A., Moysich, K. B., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Sutter, C., Gadzicki, D., Fiebig, B., Caldes, T., Laframboise, R., Nevanlinna, H., Chen, X., Beesley, J., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Couch, F. J., Wang, X., Peterlongo, P., Manoukian, S., Bernard, L., Radice, P., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Stoppa-Lyonnet, D., Mazoyer, S., Sinilnikova, O. M., Ontario Canc Genetics Network, SWE-BRCA Collaborators, HEBON, EMBRACE, GEMO Study Collaborators, Breast Canc Family Registry, Consortium Investigators Modifiers 2011; 20 (23): 4732?47

    Abstract

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

    View details for DOI 10.1093/hmg/ddr388

    View details for Web of Science ID 000297049600019

    View details for PubMedID 21890493

    View details for PubMedCentralID PMC3733139

  • Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium HUMAN MOLECULAR GENETICS Figueroa, J. D., Garcia-Closas, M., Humphreys, M., Platte, R., Hopper, J. L., Southey, M. C., Apicella, C., Hammet, F., Schmidt, M. K., Broeks, A., Tollenaar, R. A., van't Veer, L. J., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Strick, R., Peto, J., Silva, I. d., Fletcher, O., Johnson, N., Sawyer, E., Tomlinson, I., Kerin, M., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Bojesen, S., Flyger, H., Nordestgaard, B. G., Benitez, J., Milne, R. L., Ignacio Arias, J., Pilar Zamora, M., Brenner, H., Mueller, H., Arndt, V., Rahman, N., Turnbull, C., Seal, S., Renwick, A., Brauch, H., Justenhoven, C., Bruening, T., Chang-Claude, J., Hein, R., Wang-Gohrke, S., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Nevanlinna, H., Heikkinen, T., Aittomaki, K., Blomqvist, C., Bogdanova, N., Antonenkova, N., Rogov, Y. I., Karstens, J. H., Bermisheva, M., Prokofieva, D., Gantcev, S. H., Khusnutdinova, E., Lindblom, A., Margolin, S., Chenevix-Trench, G., Beesley, J., Chen, X., Mannermaa, A., Kosma, V., Soini, Y., Kataja, V., Lambrechts, D., Yesilyurt, B. T., Chrisiaens, M., Peeters, S., Radice, P., Peterlongo, P., Manoukian, S., Barile, M., Couch, F., Lee, A. M., Diasio, R., Wang, X., Giles, G. G., Severi, G., Baglietto, L., Maclean, C., Offit, K., Robson, M., Joseph, V., Gaudet, M., John, E. M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I., Knight, J. A., Mulligan, A. M., O'Malley, F. P., Brinton, L. A., Sherman, M. E., Lissowska, J., Chanock, S. J., Hooning, M., Martens, J. W., van den Ouweland, A. M., Collee, J. M., Hall, P., Czene, K., Cox, A., Brock, I. W., Reed, M. W., Cross, S. S., Pharoah, P., Dunning, A. M., Kang, D., Yoo, K., Noh, D., Ahn, S., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Shen, C., Ding, S., Hsu, H., Yu, J., Anton-Culver, H., Ziogas, A., Ashworth, A., Swerdlow, A., Jones, M., Orr, N., Trentham-Dietz, A., Egan, K., Newcomb, P., Titus-Ernstoff, L., Easton, D., Spurdle, A. B. 2011; 20 (23): 4693-4706

    Abstract

    A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heter