Bio

Academic Appointments


Honors & Awards


  • Developmental Cancer Research Award, Stanford Cancer Institute (2008, 2009)
  • Career Development Award, National Cancer Institute (2010-2015)

Professional Education


  • Postdoc, University of Washington, Statistical Genetics (2007)
  • PhD, University of Washington, Epidemiology (2003)
  • MS, University of Washington, Biostatistics (2002)
  • MD, McGill University, Medicine (1997)
  • BA, Harvard University, Biology (1992)

Research & Scholarship

Current Research and Scholarly Interests


Genetic epidemiology; cancer epidemiology; ovarian, breast, and prostate cancer.

Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


  • Intrauterine Factors and Risk of Nonepithelial Ovarian Cancers. Gynecologic oncology Sieh, W., Sundquist, K., Sundquist, J., Winkleby, M. A., Crump, C. 2014

    Abstract

    The majority of ovarian tumors in girls and young women are nonepithelial in origin. The etiology of nonepithelial ovarian tumors remains largely unknown, and intrauterine exposures may play an important role. We examined the association of perinatal factors with risk of nonepithelial ovarian tumors in girls and young women.National cohort study of 1,536,057 women born in Sweden during 1973-2004 and followed for diagnoses of nonepithelial ovarian tumors through 2009 (attained ages 5-37years). Perinatal and maternal characteristics, and cancer diagnoses were ascertained using nationwide health registry data.147 women were diagnosed with nonepithelial ovarian tumors in 31.6 million person-years of follow-up, including 94 with germ cell tumors and 53 with sex-cord stromal tumors. Women born preterm (<37weeks of gestation) had significantly increased risk of developing nonepithelial ovarian tumors (adjusted hazard ratio 1.86, 95% CI 1.03-3.37; p=0.04). Histological subgroup analyses showed that preterm birth was associated with increased risk of sex-cord stromal tumors (4.39, 2.12-9.10; p<0.001), but not germ cell tumors (0.68, 0.21-2.15; p=0.51). No significant associations were found with fetal growth, birth order, and maternal age at birth.This large cohort study provides the first evidence that preterm birth is a risk factor for developing sex cord-stromal tumors. Ovarian hyperstimulation in response to high gonadotropin levels in preterm girls could mediate disease risk through the proliferative and steroidogenic effects of FSH and LH on granulosa and theca cells, from which most sex-cord stromal tumors are derived.

    View details for DOI 10.1016/j.ygyno.2014.02.007

    View details for PubMedID 24530563

  • Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. lancet oncology Sieh, W., Köbel, M., Longacre, T. A., Bowtell, D. D., deFazio, A., Goodman, M. T., Høgdall, E., Deen, S., Wentzensen, N., Moysich, K. B., Brenton, J. D., Clarke, B. A., Menon, U., Gilks, C. B., Kim, A., Madore, J., Fereday, S., George, J., Galletta, L., Lurie, G., Wilkens, L. R., Carney, M. E., Thompson, P. J., Matsuno, R. K., Kjær, S. K., Jensen, A., Høgdall, C., Kalli, K. R., Fridley, B. L., Keeney, G. L., Vierkant, R. A., Cunningham, J. M., Brinton, L. A., Yang, H. P., Sherman, M. E., García-Closas, M., Lissowska, J., Odunsi, K., Morrison, C., Lele, S., Bshara, W., Sucheston, L., Jimenez-Linan, M., Driver, K., Alsop, J., Mack, M., McGuire, V., Rothstein, J. H., Rosen, B. P., Bernardini, M. Q., Mackay, H., Oza, A., Wozniak, E. L., Benjamin, E., Gentry-Maharaj, A., Gayther, S. A., Tinker, A. V., Prentice, L. M., Chow, C., Anglesio, M. S., Johnatty, S. E., Chenevix-Trench, G., Whittemore, A. S., Pharoah, P. D., Goode, E. L., Huntsman, D. G., Ramus, S. J. 2013; 14 (9): 853-862

    Abstract

    Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed.2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74).PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer.Carraresi Foundation and others.

    View details for DOI 10.1016/S1470-2045(13)70253-5

    View details for PubMedID 23845225

  • Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Sieh, W., Salvador, S., McGuire, V., Weber, R. P., Terry, K. L., Rossing, M. A., Risch, H., Wu, A. H., Webb, P. M., Moysich, K., Doherty, J. A., Felberg, A., Miller, D., Jordan, S. J., Goodman, M. T., Lurie, G., Chang-Claude, J., Rudolph, A., Kjaer, S. K., Jensen, A., Hogdall, E., Bandera, E. V., Olson, S. H., King, M. G., Rodriguez-Rodriguez, L., Kiemeney, L. A., Marees, T., Massuger, L. F., van Altena, A. M., Ness, R. B., Cramer, D. W., Pike, M. C., Pearce, C. L., Berchuck, A., Schildkraut, J. M., Whittemore, A. S. 2013; 42 (2): 579-589

    Abstract

    Tubal ligation is a protective factor for ovarian cancer, but it is unknown whether this protection extends to all invasive histological subtypes or borderline tumors. We undertook an international collaborative study to examine the association between tubal ligation and ovarian cancer subtypes.We pooled primary data from 13 population-based case-control studies, including 10,157 patients with ovarian cancer (7942 invasive; 2215 borderline) and 13,904 control women. Invasive cases were analysed by histological type, grade and stage, and borderline cases were analysed by histological type. Pooled odds ratios were estimated using conditional logistic regression to match on site, race/ethnicity and age categories, and to adjust for age, oral contraceptive use duration and number of full-term births.Tubal ligation was associated with significantly reduced risks of invasive serous (OR, 0.81; 95% CI, 0.74-0.89; P < 0.001), endometrioid (OR, 0.48; 95% CI, 0.40-0.59; P < 0.001), clear cell (OR, 0.52; 95% CI, 0.40-0.67; P < 0.001) and mucinous (OR, 0.68; 95% CI, 0.52-0.89; P = 0.005) cancers. The magnitude of risk reduction was significantly greater for invasive endometrioid (P < 0.0001) and clear cell (P = 0.0018) than for serous cancer. No significant associations were found with borderline serous or mucinous tumours.We found that the protective effects of tubal ligation on ovarian cancer risk were subtype-specific. These findings provide insights into distinct aetiologies of ovarian cancer subtypes and mechanisms underlying the protective effects of tubal ligation.

    View details for DOI 10.1093/ije/dyt042

    View details for Web of Science ID 000317627800032

    View details for PubMedID 23569193

  • Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates HUMAN MOLECULAR GENETICS Sieh, W., Choi, Y., Chapman, N. H., Craig, U., Steinbart, E. J., Rothstein, J. H., Oyanagi, K., Garruto, R. M., Bird, T. D., Galasko, D. R., Schellenberg, G. D., Wijsman, E. M. 2009; 18 (19): 3725-3738

    Abstract

    Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a fatal neurodegenerative disease found in the Chamorro people of Guam and other Pacific Island populations. The etiology is unknown, although both genetic and environmental factors appear important. To identify loci for ALS/PDC, we conducted both genome-wide linkage and association analyses, using approximately 400 microsatellite markers, in the largest sample assembled to date, comprising a nearly complete sample of all living and previously sampled deceased cases. A single, large, complex pedigree was ascertained from a village on Guam, with smaller families and a case-control sample ascertained from the rest of Guam by population-based neurological screening and archival review. We found significant evidence for two regions with novel ALS/PDC loci on chromosome 12 and supportive evidence for the involvement of the MAPT region on chromosome 17. D12S1617 on 12p gave the strongest evidence of linkage (maximum LOD score, Z(max) = 4.03) in our initial scan, with additional support in the complete case-control sample in the form of evidence of allelic association at this marker and another nearby marker. D12S79 on 12q also provided significant evidence of linkage (Z(max) = 3.14) with support from flanking markers. Our results suggest that ALS/PDC may be influenced by as many as three loci, while illustrating challenges that are intrinsic in genetic analyses of isolated populations, as well as analytical strategies that are useful in this context. Elucidation of the genetic basis of ALS/PDC should improve our understanding of related neurodegenerative disorders including Alzheimer disease, Parkinson disease, frontotemporal dementia and ALS.

    View details for DOI 10.1093/hmg/ddp300

    View details for Web of Science ID 000270707900017

    View details for PubMedID 19567404

  • Risk of Ovarian Cancer and the NF-?B Pathway: Genetic Association with IL1A and TNFSF10. Cancer research Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, S. S., Poole, E., Risch, H. A., Salvesen, H. B., Kiemeney, L. A., Baglietto, L., Giles, G. G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A. S., Sieh, W., Chang-Claude, J., Bandera, E. V., Orlow, I., Terry, K., Goodman, M. T., Thompson, P. J., Cook, L. S., Rossing, M. A., Ness, R. B., Narod, S. A., Kupryjanczyk, J., Lu, K., Butzow, R., Dörk, T., Pejovic, T., Campbell, I., Le, N. D., Bunker, C. H., Bogdanova, N., Runnebaum, I. B., Eccles, D., Paul, J., Wu, A. H., Gayther, S. A., Hogdall, E., Heitz, F., Kaye, S. B., Karlan, B. Y., Anton-Culver, H., Gronwald, J., Hogdall, C. K., Lambrechts, D., Fasching, P. A., Menon, U., Schildkraut, J., Pearce, C. L., Levine, D. A., Kjaer, S. K., Cramer, D., Flanagan, J. M., Phelan, C. M., Brown, R., Massuger, L. F., Song, H., Doherty, J. A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y. T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S. H., Harter, P., Tyrer, J., Vitonis, A. F., Brooks-Wilson, A., Aben, K. K., Pike, M. C., Ramus, S. J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, R., McGuire, V., Lester, J., du Bois, A., Lundvall, L., Wang-Gohrke, S., Szafron, L. M., Lambrechts, S., Yang, H., Beckmann, M. W., Pelttari, L. M., van Altena, A. M., Van Den Berg, D., Halle, M. K., Gentry-Maharaj, A., Schwaab, I., Chandran, U., Menkiszak, J., Ekici, A. B., Wilkens, L. R., Leminen, A., Modugno, F., Friel, G., Rothstein, J. H., Vergote, I., Garcia-Closas, M., Hildebrandt, M. A., Sobiczewski, P., Kelemen, L. E., Pharoah, P. D., Moysich, K., Knutson, K. L., Cunningham, J. M., Fridley, B. L., Goode, E. L. 2014; 74 (3): 852-861

    Abstract

    A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852-61. ©2013 AACR.

    View details for DOI 10.1158/0008-5472.CAN-13-1051

    View details for PubMedID 24272484

  • Season of birth and other perinatal risk factors for melanoma. International journal of epidemiology Crump, C., Sundquist, K., Sieh, W., Winkleby, M. A., Sundquist, J. 2014

    Abstract

    Ultraviolet radiation (UVR) exposure is the main risk factor for cutaneous malignant melanoma (CMM), but its specific effect in infancy is unknown. We examined whether season of birth, a proxy for solar UVR exposure in the first few months of life, is associated with CMM in childhood through young adulthood.National cohort study of 3 571 574 persons born in Sweden in 1973-2008, followed up for CMM incidence through 2009 (maximum age 37 years) to examine season of birth and other perinatal factors.There were 1595 CMM cases in 63.9 million person-years of follow-up. We found a sinusoidal pattern in CMM risk by season of birth (P = 0.006), with peak risk corresponding to birthdates in spring (March-May). Adjusted odds ratios for CMM by season of birth were 1.21 [95% confidence interval (CI), 1.05-1.39; P = 0.008] for spring, 1.07 (95% CI, 0.92-1.24; P = 0.40) for summer and 1.12 (95% CI, 0.96-1.29; P = 0.14) for winter, relative to fall. Spring birth was associated with superficial spreading subtype of CMM (P = 0.02), whereas there was no seasonal association with nodular subtype (P = 0.26). Other CMM risk factors included family history of CMM in a sibling (>6-fold) or parent (>3-fold), female gender, high fetal growth and high paternal education level.In this large cohort study, persons born in spring had increased risk of CMM in childhood through young adulthood, suggesting that the first few months of life may be a critical period of UVR susceptibility. Sun avoidance in early infancy may play an important role in the prevention of CMM in high-risk populations.

    View details for DOI 10.1093/ije/dyt277

    View details for PubMedID 24453238

  • Season of birth and risk of Hodgkin and non-Hodgkin lymphoma. International journal of cancer. Journal international du cancer Crump, C., Sundquist, J., Sieh, W., Winkleby, M. A., Sundquist, K. 2014

    Abstract

    Infectious etiologies have been hypothesized for Hodgkin and non-Hodgkin lymphoma (HL and NHL) in early life, but findings to date for specific lymphomas and periods of susceptibility are conflicting. We conducted the first national cohort study to examine whether season of birth, a proxy for infectious exposures in the first few months of life, is associated with HL or NHL in childhood through young adulthood. A total of 3,571,574 persons born in Sweden in 1973-2008 were followed up through 2009 to examine the association between season of birth and incidence of HL (943 cases) or NHL (936 cases). We found a sinusoidal pattern in NHL risk by season of birth (P=0.04), with peak risk occurring among birthdates in April. Relative to persons born in fall (September-November), odds ratios for NHL by season of birth were 1.25 (95% CI, 1.04-1.50; P=0.02) for spring (March-May), 1.22 (95% CI, 1.01-1.48; P=0.04) for summer (June-August), and 1.11 (95% CI, 0.91-1.35; P=0.29) for winter (December-February). These findings did not vary by sex, age at diagnosis, or major subtypes. In contrast, there was no seasonal association between birthdate and risk of HL (P=0.78). In this large cohort study, birth in spring or summer was associated with increased risk of NHL (but not HL) in childhood through young adulthood, possibly related to immunologic effects of delayed infectious exposures compared with fall or winter birth. These findings suggest that immunologic responses in early infancy may play an important role in the development of NHL. © 2014 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ijc.28909

    View details for PubMedID 24752499

  • Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Block, M. S., Charbonneau, B., Vierkant, R. A., Fogarty, Z., Bamlet, W. R., Pharoah, P. D., Chenevix-Trench, G., Rossing, M. A., Cramer, D., Pearce, C. L., Schildkraut, J., Menon, U., Kjaer, S. K., Levine, D. A., Gronwald, J., Anton-Culver, H., Whittemore, A. S., Karlan, B. Y., Lambrechts, D., Wentzensen, N., Kupryjanczyk, J., Chang-Claude, J., Bandera, E. V., Hogdall, E., Heitz, F., Kaye, S. B., Fasching, P. A., Campbell, I., Goodman, M. T., Pejovic, T., Bean, Y. T., Hays, L., Lurie, G., Eccles, D. M., Hein, A., Beckmann, M. W., Ekici, A. B., Paul, J., Brown, R., Flanagan, J. M., Harter, P., du Bois, A., Schwaab, I., Hogdall, C. K., Lundvall, L., Olson, S. H., Orlow, I., Paddock, L. E., Rudolph, A., Eilber, U., Dansonka-Mieszkowska, A., Rzepecka, I. K., Ziolkowska-Seta, I., Brinton, L. A., Yang, H., Garcia-Closas, M., Despierre, E., Lambrechts, S., Vergote, I., Walsh, C. S., Lester, J., Sieh, W., McGuire, V., Rothstein, J. H., Ziogas, A., Lubinski, J., Cybulski, C., Menkiszak, J., Jensen, A., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Berchuck, A., Wu, A. H., Pike, M. C., Van Den Berg, D. J., Terry, K. L., Vitonis, A. F., Ramirez, S. M., Rider, D. N., Knutson, K. L., Sellers, T. A., Phelan, C. M., Doherty, J. A., Johnatty, S. E., Defazio, A., Song, H., Tyrer, J., Kalli, K. R., Fridley, B. L., Cunningham, J. M., Goode, E. L. 2014

    Abstract

    Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance-p < 2.5x10-5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41-2.35, p=4.13x10-6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56-0.82, p=2.33x10-5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77-0.92, p=6.49x10-5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26-0.73, p=4.56x10-4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.

    View details for DOI 10.1158/1055-9965.EPI-13-0962

    View details for PubMedID 24740199

  • Perinatal risk factors for Wilms tumor in a Swedish national cohort. European journal of epidemiology Crump, C., Sundquist, J., Sieh, W., Winkleby, M. A., Sundquist, K. 2014

    Abstract

    Perinatal risk factors including high birth weight have been associated with Wilms tumor in case-control studies. However, these findings have seldom been examined in large cohort studies, and the specific contributions of gestational age at birth and fetal growth remain unknown. We conducted the largest population-based cohort study to date consisting of 3,571,574 persons born in Sweden in 1973-2008, followed up for Wilms tumor incidence through 2009 to examine perinatal risk factors. There were 443 Wilms tumor cases identified in 66.3 million person-years of follow-up. After adjusting for gestational age and other perinatal factors, high fetal growth was associated with increased risk of Wilms tumor among girls (hazard ratio per 1 standard deviation (SD), 1.36; 95 % CI 1.20-1.54; P < 0.001), but not boys (1.10; 95 % CI 0.97-1.25; P = 0.14) (P interaction = 0.02). Among girls, high fetal growth was associated with disease onset before age 5 years (odds ratio per 1 SD, 1.47; 95 % CI 1.28-1.69; P < 0.001), but not beyond (1.00; 95 % CI 0.76-1.31; P = 0.99). No clear associations were found for gestational age at birth or other perinatal factors. In this large cohort study, high fetal growth was associated with Wilms tumor before age 5 years among girls. These findings suggest that early-life growth factor pathways for Wilms tumor may be more common among girls than boys. Further elucidation of these mechanisms may reveal better targets for prevention or treatment of specific subtypes of Wilms tumor.

    View details for DOI 10.1007/s10654-014-9880-9

    View details for PubMedID 24510487

  • Genital Powder Use and Risk of Ovarian Cancer: A Pooled Analysis of 8,525 Cases and 9,859 Controls CANCER PREVENTION RESEARCH Terry, K. L., Karageorgi, S., Shvetsov, Y. B., Merritt, M. A., Lurie, G., Thompson, P. J., Carney, M. E., Weber, R. P., Akushevich, L., Lo-Ciganic, W., Cushing-Haugen, K., Sieh, W., Moysich, K., Doherty, J. A., Nagle, C. M., Berchuck, A., Pearce, C. L., Pike, M., Ness, R. B., Webb, P. M., Rossing, M. A., Schildkraut, J., Risch, H., Goodman, M. T. 2013; 6 (8): 811-821

    Abstract

    Genital powder use has been associated with risk of epithelial ovarian cancer in some, but not all, epidemiologic investigations, possibly reflecting the carcinogenic effects of talc particles found in most of these products. Whether risk increases with number of genital-powder applications and for all histologic types of ovarian cancer also remains uncertain. Therefore, we estimated the association between self-reported genital powder use and epithelial ovarian cancer risk in eight population-based case-control studies. Individual data from each study was collected and harmonized. Lifetime number of genital-powder applications was estimated from duration and frequency of use. Pooled odds ratios were calculated using conditional logistic regression matched on study and age and adjusted for potential confounders. Subtype-specific risks were estimated according to tumor behavior and histology. 8,525 cases and 9,859 controls were included in the analyses. Genital powder use was associated with a modest increased risk of epithelial ovarian cancer (odds ratio 1.24, 95% confidence interval 1.15-1.33) relative to women who never used powder. Risk was elevated for invasive serous (1.20, 1.09-1.32), endometrioid (1.22, 1.04-1.43), and clear cell (1.24, 1.01-1.52) tumors, and for borderline serous tumors (1.46, 1.24-1.72). Among genital powder users, we observed no significant trend (p=0.17) in risk with increasing number of lifetime applications (assessed in quartiles). We noted no increase in risk among women who only reported non-genital powder use. In summary, genital powder use is a modifiable exposure associated with small-to-moderate increases in risk of most histologic subtypes of epithelial ovarian cancer.

    View details for DOI 10.1158/1940-6207.CAPR-13-0037

    View details for Web of Science ID 000322768600008

    View details for PubMedID 23761272

  • Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology White, K. L., Vierkant, R. A., Fogarty, Z. C., Charbonneau, B., Block, M. S., Pharoah, P. D., Chenevix-Trench, G., Rossing, M. A., Cramer, D. W., Pearce, C. L., Schildkraut, J. M., Menon, U., Kjaer, S. K., Levine, D. A., Gronwald, J., Culver, H. A., Whittemore, A. S., Karlan, B. Y., Lambrechts, D., Wentzensen, N., Kupryjanczyk, J., Chang-Claude, J., Bandera, E. V., Hogdall, E., Heitz, F., Kaye, S. B., Fasching, P. A., Campbell, I., Goodman, M. T., Pejovic, T., Bean, Y., Lurie, G., Eccles, D., Hein, A., Beckmann, M. W., Ekici, A. B., Paul, J., Brown, R., Flanagan, J. M., Harter, P., du Bois, A., Schwaab, I., Hogdall, C. K., Lundvall, L., Olson, S. H., Orlow, I., Paddock, L. E., Rudolph, A., Eilber, U., Dansonka-Mieszkowska, A., Rzepecka, I. K., Ziolkowska-Seta, I., Brinton, L., Yang, H., Garcia-Closas, M., Despierre, E., Lambrechts, S., Vergote, I., Walsh, C., Lester, J., Sieh, W., McGuire, V., Rothstein, J. H., Ziogas, A., Lubinski, J., Cybulski, C., Menkiszak, J., Jensen, A., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Berchuck, A., Wu, A. H., Pike, M. C., Van Denberg, D., Terry, K. L., Vitonis, A. F., Doherty, J. A., Johnatty, S. E., deFazio, A., Song, H., Tyrer, J., Sellers, T. A., Phelan, C. M., Kalli, K. R., Cunningham, J. M., Fridley, B. L., Goode, E. L. 2013; 22 (5): 987-992

    Abstract

    Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes.Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates.We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined.These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987-. ©2013 AACR.

    View details for DOI 10.1158/1055-9965.EPI-13-0028

    View details for PubMedID 23513043

  • Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies. Cancer causes & control Faber, M. T., Kjær, S. K., Dehlendorff, C., Chang-Claude, J., Andersen, K. K., Høgdall, E., Webb, P. M., Jordan, S. J., Rossing, M. A., Doherty, J. A., Lurie, G., Thompson, P. J., Carney, M. E., Goodman, M. T., Ness, R. B., Modugno, F., Edwards, R. P., Bunker, C. H., Goode, E. L., Fridley, B. L., Vierkant, R. A., Larson, M. C., Schildkraut, J., Cramer, D. W., Terry, K. L., Vitonis, A. F., Bandera, E. V., Olson, S. H., King, M., Chandran, U., Kiemeney, L. A., Massuger, L. F., van Altena, A. M., Vermeulen, S. H., Brinton, L., Wentzensen, N., Lissowska, J., Yang, H. P., Moysich, K. B., Odunsi, K., Kasza, K., Odunsi-Akanji, O., Song, H., Pharaoh, P., Shah, M., Whittemore, A. S., McGuire, V., Sieh, W., Sutphen, R., Menon, U., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Pearce, C. L., Wu, A. H., Pike, M. C., Risch, H. A., Jensen, A. 2013; 24 (5): 989-1004

    Abstract

    The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology.We used data from 21 case-control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model.Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03-1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39-2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12-1.50). For these histological types, consistent dose-response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer.Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease.

    View details for DOI 10.1007/s10552-013-0174-4

    View details for PubMedID 23456270

  • Combined and Interactive Effects of Environmental and GWAS-Identified Risk Factors in Ovarian Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Pearce, C. L., Rossing, M. A., Lee, A. W., Ness, R. B., Webb, P. M., Chenevix-Trench, G., Jordan, S. M., Stram, D. A., Chang-Claude, J., Hein, R., Nickels, S., Lurie, G., Thompson, P. J., Carney, M. E., Goodman, M. T., Moysich, K., Hogdall, E., Jensen, A., Goode, E. L., Fridley, B. L., Cunningham, J. M., Vierkant, R. A., Weber, R. P., Ziogas, A., Anton-Culver, H., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Brinton, L., Wentzensen, N., Lissowska, J., Garcia-Closas, M., Massuger, L. F., Kiemeney, L. A., van Altena, A. M., Aben, K. K., Berchuck, A., Doherty, J. A., Iversen, E., McGuire, V., Moorman, P. G., Pharoah, P., Pike, M. C., Risch, H., Sieh, W., Stram, D. O., Terry, K. L., Whittemore, A., Wu, A. H., Schildkraut, J. M., Kjaer, S. K. 2013; 22 (5): 880-890

    Abstract

    There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied.Data from 14 ovarian cancer case-control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histologic subtypes. A genetic "risk score" was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk.Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared with women in the lowest [95% confidence interval (CI), 1.48-1.84]. Analyses by histologic subtype yielded risk differences across subtype for endometriosis (Phet < 0.001), parity (Phet < 0.01), and tubal ligation (Phet = 0.041).The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of the effect of each risk factor that sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histologic subtype is warranted. Cancer Epidemiol Biomarkers Prev; 22(5); 880-90. ©2013 AACR.

    View details for DOI 10.1158/1055-9965.EPI-12-1030-T

    View details for PubMedID 23462924

  • Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer NATURE GENETICS Bojesen, S. E., Pooley, K. A., Johnatty, S. E., Beesley, J., Michailidou, K., Tyrer, J. P., Edwards, S. L., Pickett, H. A., Shen, H. C., Smart, C. E., Hillman, K. M., Mai, P. L., Lawrenson, K., Stutz, M. D., Lu, Y., Karevan, R., Woods, N., Johnstonw, R. L., French, J. D., Chen, X., Weischer, M., Nielsen, S. F., Maranian, M. J., Ghoussaini, M., Ahmed, S., Baynes, C., Bolla, M. K., Wang, Q., Dennis, J., McGuffog, L., Barrowdale, D., Lee, A., Healey, S., Lush, M., Tessier, D. C., Vincent, D., Bacot, F., Vergote, I., Lambrechts, S., Despierre, E., Risch, H. A., Gonzalez-Neira, A., Rossing, M. A., Pita, G., Doherty, J. A., Alvarez, N., Larson, M. C., Fridley, B. L., Schoof, N., Chang-Claude, J., Cicek, M. S., Peto, J., Kalli, K. R., Broeks, A., Armasu, S. M., Schmidt, M. K., Braaf, L. M., Winterhoff, B., Nevanlinna, H., Konecny, G. E., Lambrechts, D., Rogmann, L., Guenel, P., Teoman, A., Milne, R. L., Garcia, J. J., Cox, A., Shridhar, V., Burwinkel, B., Marme, F., Hein, R., Sawyer, E. J., Haiman, C. A., Wang-Gohrke, S., Andrulis, I. L., Moysich, K. B., Hopper, J. L., Odunsi, K., Lindblom, A., Giles, G. G., Brenner, H., Simard, J., Lurie, G., Fasching, P. A., Carney, M. E., Radice, P., Wilkens, L. R., Swerdlow, A., Goodman, M. T., Brauch, H., Garcia-Closas, M., Hillemanns, P., Winqvist, R., Durst, M., Devilee, P., Runnebaum, I., Jakubowska, A., Lubinski, J., Mannermaa, A., Butzow, R., Bogdanova, N. V., Doerk, T., Pelttari, L. M., Zheng, W., Leminen, A., Anton-Culver, H., Bunker, C. H., Kristensen, V., Ness, R. B., Muir, K., Edwards, R., Meindl, A., Heitz, F., Matsuo, K., du Bois, A., Wu, A. H., Harter, P., Teo, S., Schwaab, I., Shu, X., Blot, W., Hosono, S., Kang, D., Nakanishi, T., Hartman, M., Yatabe, Y., Hamann, U., Karlan, B. Y., Sangrajrang, S., Kjaer, S. K., Gaborieau, V., Jensen, A., Eccles, D., Hogdall, E., Shen, C., Brown, J., Woo, Y. L., Shah, M., Azmi, M. A., Luben, R., Omar, S. Z., Czene, K., Vierkant, R. A., Nordestgaard, B. G., Flyger, H., Vachon, C., Olson, J. E., Wang, X., Levine, D. A., Rudolph, A., Weber, R. P., Flesch-Janys, D., Iversen, E., Nickels, S., Schildkraut, J. M., Silva, I. d., Cramer, D. W., Gibson, L., Terry, K. L., Fletcher, O., Vitonis, A. F., van der Schoot, C. E., Poole, E. M., Hogervorst, F. B., Tworoger, S. S., Liu, J., Bandera, E. V., Li, J., Olson, S. H., Humphreys, K., Row, I., Blomqvist, C., Rodriguez-Rodriguez, L., Aittomaki, K., Salvesen, H. B., Muranen, T. A., Wik, E., Brouwers, B., Krakstad, C., Wauters, E., Halle, M. K., Wildiers, H., Kiemeney, L. A., Mulot, C., Aben, K. K., Laurent-Puig, P., Altena, A. M., Therese Truong, T., Massuger, L. F., Benitez, J., Pejovic, T., Arias Perez, J. I., Hoatlin, M., Zamora, M. P., Cook, L. S., Balasubramanian, S. P., Kelemen, L. E., Schneeweiss, A., Le, N. D., Sohn, C., Brooks-Wilson, A., Tomlinson, I., Kerin, M. J., Miller, N., Cybulski, C., Henderson, B. E., Menkiszak, J., Schumacher, F., Wentzensen, N., Marchand, L. L., Yang, H. P., Mulligan, A. M., Glendon, G., Engelholm, S. A., Knight, J. A., Hogdall, C. K., Apicella, C., Gore, M., Tsimiklis, H., Song, H., Southey, M. C., Jager, A., den Ouweland, A. M., Brown, R., Martens, J. W., Flanagan, J. M., Kriege, M., Paul, J., Margolin, S., Siddiqui, N., Severi, G., Whittemore, A. S., Baglietto, L., McGuire, V., Stegmaier, C., Sieh, W., Mueller, H., Arndt, V., Labreche, F., Gao, Y., Goldberg, M. S., Yang, G., Dumont, M., McLaughlin, J. R., Hartmann, A., Ekici, A. B., Beckmann, M. W., Phelan, C. M., Lux, M. P., Permuth-Wey, J., Peissel, B., Sellers, T. A., Ficarazzi, F., Barile, M., Ziogas, A., Ashworth, A., Gentry-Maharaj, A., Jones, M., Ramus, S. J., Orr, N., Menon, U., Pearce, C. L., Bruening, T., Pike, M. C., Ko, Y., Lissowska, J., Figueroa, J., Kupryjanczyk, J., Chanock, S. J., Dansonka-Mieszkowska, A., Jukkola-Vuorinen, A., Rzepecka, I. K., Pylkas, K., Bidzinski, M., Kauppila, S., Hollestelle, A., Seynaeve, C., Tollenaar, R. A., Durda, K., Jaworska, K., Hartikainen, J. M., Kosma, V., Kataja, V., Antonenkova, N. N., Long, J., Shrubsole, M., Deming-Halverson, S., Lophatananon, A., Siriwanarangsan, P., Stewart-Brown, S., Ditsch, N., Lichtner, P., Schmutzler, R. K., Ito, H., Iwata, H., Tajima, K., Tseng, C., Stram, D. O., Van Den Berg, D., Yip, C. H., Ikrarn, M. K., Teh, Y., Cai, H., Lu, W., Signorello, L. B., Cai, Q., Noh, D., Yoo, K., Miao, H., Iau, P. T., Teo, Y. Y., McKay, J., Shapiro, C., Ademuyiwa, F., Fountzilas, G., Hsiung, C., Yu, J., Hou, M., Healey, C. S., Luccarini, C., Peock, S., Stoppa-Lyonnet, D., Peterlongo, P., Rebbeck, T. R., Piedmonte, M., Singer, C. F., friedman, e., Thomassen, M., Offit, K., Hansen, T. v., Neuhausen, S. L., Szabo, C. I., Blanco, I., Garber, J., Narod, S. A., Weitzel, J. N., Montagna, M., Olah, E., Godwin, A. K., Yannoukakos, D., Goldgar, D. E., Caldes, T., Imyanitov, E. N., Tihomirova, L., Arun, B. K., Campbell, I., Mensenkamp, A. R., van Asperen, C. J., van Roozendaa, K. E., Meijers-Heijboer, H., Collee, J. M., Oosterwijk, J. C., Hooning, M. J., Rookus, M. A., van der Luijt, R. B., Os, T. A., Evans, D. G., Frost, D., Fineberg, E., Barwell, J., Walker, L., Kennedy, M. J., Platte, R., Davidson, R., Ellis, S. D., Cole, T., Bressac-de Paillerets, B., Buecher, B., Damiola, F., Faivre, L., Frenay, M., Sinilnikova, O. M., Caron, O., Giraud, S., Mazoyer, S., Bonadona, V., Caux-Moncoutier, V., Toloczko-Grabarek, A., Gronwald, J., Byrski, T., Spurdle, A. B., Bonanni, B., Zaffaroni, D., Giannini, G., Bernard, L., Dolcetti, R., Manoukian, S., Arnold, N., Engel, C., Deissler, H., Rhiem, K., Niederacher, D., Pendl, H., Sutter, C., Wappenschmidt, B., Borg, A., Mein, B., Rantala, J., Soller, M., Nathanson, K. L., Domchek, S. M., Rodriguez, G. C., Salani, R., Kaulich, D. G., Tea, M., Paluch, S. S., Laitman, Y., Skytte, A., Kruse, T. A., Jensen, U. B., Robson, M., Gerdes, A., Ejlertsen, B., Foretova, L., Savage, S. A., Lesterm, J., Soucy, P., Kuchenbaecker, K. B., Olswold, C., Cunningham, J. M., Slager, S., Pankratz, V. S., Dicks, E., Lakhani, S. R., Couch, F. J., Hall, P., Monteiro, A. N., Gayther, S. A., Pharoah, P. D., Reddel, R. R., Goode, E. L., Greene, M. H., Easton, D. F., Berchuck, A., Antoniou, A. C., Chenevix-Trench, G., Dunning, A. M. 2013; 45 (4): 371-384

    Abstract

    TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ?480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

    View details for DOI 10.1038/ng.2566

    View details for Web of Science ID 000316840600007

    View details for PubMedID 23535731

  • GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer NATURE GENETICS Pharoah, P. D., Tsai, Y., Ramus, S. J., Phelan, C. M., Goode, E. L., Lawrenson, K., Buckley, M., Fridley, B. L., Tyrer, J. P., Shen, H., Weber, R., Karevan, R., Larson, M. C., Song, H., Tessier, D. C., Bacot, F., Vincent, D., Cunningham, J. M., Dennis, J., Dicks, E., Aben, K. K., Anton-Culver, H., Antonenkova, N., Armasu, S. M., Baglietto, L., Bandera, E. V., Beckmann, M. W., Birrer, M. J., Bloom, G., Bogdanova, N., Brenton, J. D., Brinton, L. A., Brooks-Wilson, A., Brown, R., Butzow, R., Campbell, I., Carney, M. E., Carvalho, R. S., Chang-Claude, J., Chen, Y. A., Chen, Z., Chow, W., Cicek, M. S., Coetzee, G., Cook, L. S., Cramer, D. W., Cybulski, C., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J. A., Doerk, T., du Bois, A., Duerst, M., Eccles, D., Edwards, R., Ekici, A. B., Fasching, P. A., Fenstermacher, D., Flanagan, J., Gao, Y., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G., Gjyshi, A., Gore, M., Gronwald, J., Guo, Q., Halle, M. K., Harter, P., Hein, A., Heitz, F., Hillemanns, P., Hoatlin, M., Hogdall, E., Hogdall, C. K., Hosono, S., Jakubowska, A., Jensen, A., Kalli, K. R., Karlan, B. Y., Kelemen, L. E., Kiemeney, L. A., Kjaer, S. K., Konecny, G. E., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, N., Lee, J., Leminen, A., Lim, B. K., Lissowska, J., Lubinski, J., Lundvall, L., Lurie, G., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., Menon, U., Modugno, F., Moysich, K. B., Nakanishi, T., Narod, S. A., Ness, R. B., Nevanlinna, H., Nickels, S., Noushmehr, H., Odunsi, K., Olson, S., Orlow, I., Paul, J., Pejovic, T., Pelttari, L. M., Permuth-Wey, J., Pike, M. C., Poole, E. M., Qu, X., Risch, H. A., Rodriguez-Rodriguez, L., Rossing, M. A., Rudolph, A., Runnebaum, I., Rzepecka, I. K., Salvesen, H. B., Schwaab, I., Severi, G., Shen, H., Shridhar, V., Shu, X., Sieh, W., Southey, M. C., Spellman, P., Tajima, K., Teo, S., Terry, K. L., Thompson, P. J., Timorek, A., Tworoger, S. S., van Altena, A. M., Van Den Berg, D., Vergote, I., Vierkant, R. A., Vitonis, A. F., Wang-Gohrke, S., Wentzensen, N., Whittemore, A. S., Wik, E., Winterhoff, B., Woo, Y. L., Wu, A. H., Yang, H. P., Zheng, W., Ziogas, A., Zulkifli, F., Goodman, M. T., Hall, P., Easton, D. F., Pearce, C. L., Berchuck, A., Chenevix-Trench, G., Iversen, E., Monteiro, A. N., Gayther, S. A., Schildkraut, J. M., Sellers, T. A. 2013; 45 (4): 362-370

    Abstract

    Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

    View details for DOI 10.1038/ng.2564

    View details for Web of Science ID 000316840600006

    View details for PubMedID 23535730

  • Use of antihypertensive medications and breast cancer risk CANCER CAUSES & CONTROL Saltzman, B. S., Weiss, N. S., Sieh, W., Fitzpatrick, A. L., McTiernan, A., Daling, J. R., Li, C. I. 2013; 24 (2): 365-371

    Abstract

    Use of specific antihypertensive medications (AHTs) has been hypothesized to increase breast cancer risk, but results across published studies are inconsistent.We re-evaluated the relationship between AHT use and breast cancer risk in a prospective cohort of 3,201 women ?65 years of age at recruitment now with more than double the length of follow-up (12 vs. 5 years) and substantially more breast cancer diagnoses (188 compared with 75 cases). We estimated the association between AHT use overall as well as use of specific formulations (based on data collected annually) and breast cancer risk using multivariate-adjusted Cox regression.Compared with women who reported no use of AHTs, women who had used calcium channel blockers (CCB) within the past two years had a 1.6-fold increased risk of breast cancer (95 % confidence interval (CI): 1.0-2.5), and in particular, recent users of immediate-release CCBs had a 2.4-fold increased risk (95 % CI: 1.3-4.5). Neither ever nor recent use of any other type of AHT was associated with breast cancer risk.While the observed association between immediate-release CCBs and breast cancer risk is based on a small sample size and needs to be interpreted cautiously, this result is consistent with others in the literature. However, given declines in use of these preparations in favor of sustained-release CCBs, which was not related to risk, the potential clinical and public health impact of this association is limited. This study also adds to the evidence that other commonly used AHTs are not strongly related to breast cancer risk.

    View details for DOI 10.1007/s10552-012-0122-8

    View details for Web of Science ID 000314063900018

    View details for PubMedID 23224328

  • Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31. Nature communications Permuth-Wey, J., Lawrenson, K., Shen, H. C., Velkova, A., Tyrer, J. P., Chen, Z., Lin, H., Chen, Y. A., Tsai, Y., Qu, X., Ramus, S. J., Karevan, R., Lee, J., Lee, N., Larson, M. C., Aben, K. K., Anton-Culver, H., Antonenkova, N., Antoniou, A. C., Armasu, S. M., Bacot, F., Baglietto, L., Bandera, E. V., Barnholtz-Sloan, J., Beckmann, M. W., Birrer, M. J., Bloom, G., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Brown, R., Butzow, R., Cai, Q., Campbell, I., Chang-Claude, J., Chanock, S., Chenevix-Trench, G., Cheng, J. Q., Cicek, M. S., Coetzee, G. A., Cook, L. S., Couch, F. J., Cramer, D. W., Cunningham, J. M., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J. A., Dörk, T., du Bois, A., Dürst, M., Easton, D. F., Eccles, D., Edwards, R., Ekici, A. B., Fasching, P. A., Fenstermacher, D. A., Flanagan, J. M., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G. G., Glasspool, R. M., Gonzalez-Bosquet, J., Goodman, M. T., Gore, M., Górski, B., Gronwald, J., Hall, P., Halle, M. K., Harter, P., Heitz, F., Hillemanns, P., Hoatlin, M., Høgdall, C. K., Høgdall, E., Hosono, S., Jakubowska, A., Jensen, A., Jim, H., Kalli, K. R., Karlan, B. Y., Kaye, S. B., Kelemen, L. E., Kiemeney, L. A., Kikkawa, F., Konecny, G. E., Krakstad, C., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Lancaster, J. M., Le, N. D., Leminen, A., Levine, D. A., Liang, D., Lim, B. K., Lin, J., Lissowska, J., Lu, K. H., Lubinski, J., Lurie, G., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., Menon, U., Modugno, F., Moysich, K. B., Nakanishi, T., Narod, S. A., Nedergaard, L., Ness, R. B., Nevanlinna, H., Nickels, S., Noushmehr, H., Odunsi, K., Olson, S. H., Orlow, I., Paul, J., Pearce, C. L., Pejovic, T., Pelttari, L. M., Pike, M. C., Poole, E. M., Raska, P., Renner, S. P., Risch, H. A., Rodriguez-Rodriguez, L., Rossing, M. A., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schwaab, I., Severi, G., Shridhar, V., Shu, X., Shvetsov, Y. B., Sieh, W., Song, H., Southey, M. C., Spiewankiewicz, B., Stram, D., Sutphen, R., Teo, S., Terry, K. L., Tessier, D. C., Thompson, P. J., Tworoger, S. S., van Altena, A. M., Vergote, I., Vierkant, R. A., Vincent, D., Vitonis, A. F., Wang-Gohrke, S., Palmieri Weber, R., Wentzensen, N., Whittemore, A. S., Wik, E., Wilkens, L. R., Winterhoff, B., Woo, Y. L., Wu, A. H., Xiang, Y., Yang, H. P., Zheng, W., Ziogas, A., Zulkifli, F., Phelan, C. M., Iversen, E., Schildkraut, J. M., Berchuck, A., Fridley, B. L., Goode, E. L., Pharoah, P. D., Monteiro, A. N., Sellers, T. A., Gayther, S. A. 2013; 4: 1627-?

    Abstract

    Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.

    View details for DOI 10.1038/ncomms2613

    View details for PubMedID 23535648

  • Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nature communications Shen, H., Fridley, B. L., Song, H., Lawrenson, K., Cunningham, J. M., Ramus, S. J., Cicek, M. S., Tyrer, J., Stram, D., Larson, M. C., Köbel, M., Ziogas, A., Zheng, W., Yang, H. P., Wu, A. H., Wozniak, E. L., Woo, Y. L., Winterhoff, B., Wik, E., Whittemore, A. S., Wentzensen, N., Weber, R. P., Vitonis, A. F., Vincent, D., Vierkant, R. A., Vergote, I., Van Den Berg, D., van Altena, A. M., Tworoger, S. S., Thompson, P. J., Tessier, D. C., Terry, K. L., Teo, S., Templeman, C., Stram, D. O., Southey, M. C., Sieh, W., Siddiqui, N., Shvetsov, Y. B., Shu, X., Shridhar, V., Wang-Gohrke, S., Severi, G., Schwaab, I., Salvesen, H. B., Rzepecka, I. K., Runnebaum, I. B., Rossing, M. A., Rodriguez-Rodriguez, L., Risch, H. A., Renner, S. P., Poole, E. M., Pike, M. C., Phelan, C. M., Pelttari, L. M., Pejovic, T., Paul, J., Orlow, I., Omar, S. Z., Olson, S. H., Odunsi, K., Nickels, S., Nevanlinna, H., Ness, R. B., Narod, S. A., Nakanishi, T., Moysich, K. B., Monteiro, A. N., Moes-Sosnowska, J., Modugno, F., Menon, U., McLaughlin, J. R., McGuire, V., Matsuo, K., Adenan, N. A., Massuger, L. F., Lurie, G., Lundvall, L., Lubinski, J., Lissowska, J., Levine, D. A., Leminen, A., Lee, A. W., Le, N. D., Lambrechts, S., Lambrechts, D., Kupryjanczyk, J., Krakstad, C., Konecny, G. E., Kjaer, S. K., Kiemeney, L. A., Kelemen, L. E., Keeney, G. L., Karlan, B. Y., Karevan, R., Kalli, K. R., Kajiyama, H., Ji, B., Jensen, A., Jakubowska, A., Iversen, E., Hosono, S., Høgdall, C. K., Høgdall, E., Hoatlin, M., Hillemanns, P., Heitz, F., Hein, R., Harter, P., Halle, M. K., Hall, P., Gronwald, J., Gore, M., Goodman, M. T., Giles, G. G., Gentry-Maharaj, A., Garcia-Closas, M., Flanagan, J. M., Fasching, P. A., Ekici, A. B., Edwards, R., Eccles, D., Easton, D. F., Dürst, M., du Bois, A., Dörk, T., Doherty, J. A., Despierre, E., Dansonka-Mieszkowska, A., Cybulski, C., Cramer, D. W., Cook, L. S., Chen, X., Charbonneau, B., Chang-Claude, J., Campbell, I., Butzow, R., Bunker, C. H., Brueggmann, D., Brown, R., Brooks-Wilson, A., Brinton, L. A., Bogdanova, N., Block, M. S., Benjamin, E., Beesley, J., Beckmann, M. W., Bandera, E. V., Baglietto, L., Bacot, F., Armasu, S. M., Antonenkova, N., Anton-Culver, H., Aben, K. K., Liang, D., Wu, X., Lu, K., Hildebrandt, M. A., Schildkraut, J. M., Sellers, T. A., Huntsman, D., Berchuck, A., Chenevix-Trench, G., Gayther, S. A., Pharoah, P. D., Laird, P. W., Goode, E. L., Pearce, C. L. 2013; 4: 1628-?

    Abstract

    HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

    View details for DOI 10.1038/ncomms2629

    View details for PubMedID 23535649

  • Treatment and Mortality in Men with Localized Prostate Cancer: A Population-Based Study in California. The open prostate cancer journal Sieh, W., Lichtensztajn, D. Y., Nelson, D. O., Cockburn, M., West, D. W., Brooks, J. D., Chang, E. T. 2013; 6: 1-9

    Abstract

    To provide patients and physicians with population-based estimates of mortality from prostate cancer or other causes depending upon the primary treatment modality, stratified by patient age, tumor stage and grade.We conducted a 10-year competing-risk analysis of 45,440 men diagnosed with clinically localized (T1 or T2) prostate cancer in California during 1995-1998. Information on patient characteristics, primary treatment and cause of death was obtained from the California Cancer Registry.In this population-based cohort, the most common primary treatment was surgery (40.4%), followed by radiotherapy (29.1%), conservative management (20.8%), and androgen deprivation therapy (ADT) monotherapy (9.8%). Prostate cancer mortality differed significantly (p < 0.0001) across treatment groups among patients <80 years at diagnosis with moderately or poorly differentiated disease; the 10-year disease-specific mortality rates were generally highest for men treated with ADT monotherapy [range: 3.3% (95% CI=0.8-12.5%) to 53.8% (95% CI=34.4-72.2%)], intermediate for men treated with conservative management [range: 1.7% (95% CI=0.7-4.6%) to 30.0% (95% CI=16.2-48.8%] or radiotherapy [range: 3.2% (95% CI=1.8-5.5%) to 18.3% (95% CI=15.1-22.0%)], and lowest for men treated with surgery [range: 1.2% (95% CI=0.8-1.7%) to 11.0% (95% CI=8.4-14.2%)].The cause-specific mortality estimates provided by this observational study can help patients and physicians better understand the expected long-term outcomes of localized prostate cancer given the initial treatment choice and practice patterns in the general population.

    View details for PubMedID 23997838

  • Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA. Human genetics Earp, M. A., Kelemen, L. E., Magliocco, A. M., Swenerton, K. D., Chenevix-Trench, G., Lu, Y., Hein, A., Ekici, A. B., Beckmann, M. W., Fasching, P. A., Lambrechts, D., Despierre, E., Vergote, I., Lambrechts, S., Doherty, J. A., Rossing, M. A., Chang-Claude, J., Rudolph, A., Friel, G., Moysich, K. B., Odunsi, K., Sucheston-Campbell, L., Lurie, G., Goodman, M. T., Carney, M. E., Thompson, P. J., Runnebaum, I. B., Dürst, M., Hillemanns, P., Dörk, T., Antonenkova, N., Bogdanova, N., Leminen, A., Nevanlinna, H., Pelttari, L. M., Butzow, R., Bunker, C. H., Modugno, F., Edwards, R. P., Ness, R. B., du Bois, A., Heitz, F., Schwaab, I., Harter, P., Karlan, B. Y., Walsh, C., Lester, J., Jensen, A., Kjær, S. K., Høgdall, C. K., Høgdall, E., Lundvall, L., Sellers, T. A., Fridley, B. L., Goode, E. L., Cunningham, J. M., Vierkant, R. A., Giles, G. G., Baglietto, L., Severi, G., Southey, M. C., Liang, D., Wu, X., Lu, K., Hildebrandt, M. A., Levine, D. A., Bisogna, M., Schildkraut, J. M., Iversen, E. S., Weber, R. P., Berchuck, A., Cramer, D. W., Terry, K. L., Poole, E. M., Tworoger, S. S., Bandera, E. V., Chandran, U., Orlow, I., Olson, S. H., Wik, E., Salvesen, H. B., Bjorge, L., Halle, M. K., van Altena, A. M., Aben, K. K., Kiemeney, L. A., Massuger, L. F., Pejovic, T., Bean, Y. T., Cybulski, C., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L. A., Lissowska, J., Garcia-Closas, M., Dicks, E., Dennis, J., Easton, D. F., Song, H., Tyrer, J. P., Pharoah, P. D., Eccles, D., Campbell, I. G., Whittemore, A. S., McGuire, V., Sieh, W., Rothstein, J. H., Flanagan, J. M., Paul, J., Brown, R., Phelan, C. M., Risch, H. A., McLaughlin, J. R., Narod, S. A., Ziogas, A., Anton-Culver, H., Gentry-Maharaj, A., Menon, U., Gayther, S. A., Ramus, S. J., Wu, A. H., Pearce, C. L., Pike, M. C., Dansonka-Mieszkowska, A., Rzepecka, I. K., Szafron, L. M., Kupryjanczyk, J., Cook, L. S., Le, N. D., Brooks-Wilson, A. 2013

    Abstract

    Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

    View details for DOI 10.1007/s00439-013-1383-3

    View details for PubMedID 24190013

  • Prostate Cancer Risk Profiles in Asian Americans: Disentangling the Effects of Immigration Status and Race/Ethnicity. The Journal of urology Lichtensztajn, D. Y., Gomez, S. L., Sieh, W., Chung, B. I., Cheng, I., Brooks, J. D. 2013

    Abstract

    Asian-American men with prostate cancer have been reported to present with higher grade and later stage disease than White Americans. However, Asian Americans comprise a heterogeneous population with distinct health outcomes. We compared prostate cancer risk profiles among the diverse racial and ethnic groups in California.We used data from the California Cancer Registry for 90,845 Non-Hispanic White, Non-Hispanic Black, and Asian-American men diagnosed with prostate cancer between 2004 and 2010. Patients were categorized into low, intermediate, or high-risk groups based on clinical stage, Gleason score, and PSA value at diagnosis. Using polytomous logistic regression, we estimated adjusted odds ratios for the association of race/ethnicity and nativity with risk group.In addition to Non-Hispanic Blacks, six Asian-American groups (US-born Chinese, foreign-born Chinese, US-born Japanese, foreign-born Japanese, foreign-born Filipino, and foreign-born Vietnamese) were more likely to have an unfavorable risk profile compared to Non-Hispanic Whites. The odds ratios for high vs. intermediate-risk disease ranged from 1.23 (95% CI, 1.02-1.49) for US-born Japanese to 1.45 (95% CI, 1.31-1.60) for foreign-born Filipinos. These associations appeared to be driven by higher grade and PSA values, rather than advanced clinical stage at diagnosis.In this large, ethnically diverse population-based cohort, we found that Asian-American men were more likely to have unfavorable risk profiles at diagnosis. This association varied by racial/ethnic group and nativity, and was not attributable to later stage at diagnosis, suggesting that Asian men may have biological differences that predispose to the development of more severe disease.

    View details for DOI 10.1016/j.juro.2013.10.075

    View details for PubMedID 24513166

  • Perinatal and Family Risk Factors for Hodgkin Lymphoma in Childhood Through Young Adulthood AMERICAN JOURNAL OF EPIDEMIOLOGY Crump, C., Sundquist, K., Sieh, W., Winkleby, M. A., Sundquist, J. 2012; 176 (12): 1147-1158

    Abstract

    The incidence of Hodgkin lymphoma has increased among adolescents and young adults in recent decades, but the relevant risk factors in early life are still unknown. A national cohort study was conducted of 3,571,574 individuals born in Sweden in 1973-2008 and followed up for Hodgkin lymphoma incidence through 2009, to examine perinatal and family risk factors for Hodgkin lymphoma in childhood through young adulthood (ages 0-37 years). There were 943 Hodgkin lymphoma cases identified in 66.3 million person-years of follow-up. High fetal growth was associated with an increased risk of Hodgkin lymphoma after adjustment for gestational age at birth and other potential confounders (P(trend) = 0.005). Family history of Hodgkin lymphoma in a sibling or parent also was strongly associated with an increased risk, with adjusted hazard ratios = 8.83 (95% confidence interval: 3.67, 21.30) and 7.19 (95% confidence interval: 3.58, 14.44), respectively. No association was found between gestational age at birth, birth order, twinning, parental age, or parental education and Hodgkin lymphoma. These findings did not vary by age at Hodgkin lymphoma diagnosis. Similar associations were found for nodular sclerosis and mixed cellularity subtypes. These findings suggest that perinatal factors including possible growth factor pathways may contribute to the risk of Hodgkin lymphoma in childhood through young adulthood.

    View details for DOI 10.1093/aje/kws212

    View details for Web of Science ID 000312634900011

    View details for PubMedID 23171883

  • Prediction of BRCA1 Germline Mutation Status in Women With Ovarian Cancer Using Morphology-based Criteria Identification of a BRCA1 Ovarian Cancer Phenotype AMERICAN JOURNAL OF SURGICAL PATHOLOGY Fujiwara, M., McGuire, V. A., Felberg, A., Sieh, W., Whittemore, A. S., Longacre, T. A. 2012; 36 (8): 1170-1177

    Abstract

    Specific morphologic features that may predict BRCA1 germline mutation in ovarian cancer have neither been well described nor independently tested. We identified 5 morphologic features associated with BRCA1 mutation status in a series of 20 ovarian cancers from BRCA1 mutation carriers: (1) modified Nottingham grade 3; (2) serous/undifferentiated histology; (3) prominent intraepithelial lymphocytes; (4) marked nuclear atypia with giant/bizarre forms; and (5) abundant mitotic figures. These morphologic features were then tested on 325 ovarian tumors drawn from a population-based Greater Bay Area Cancer Registry and classified into 3 categories independent of the BRCA1 status: "Compatible with BRCA1," "Possibly compatible with BRCA1," and "Not compatible with BRCA1." All "Compatible with BRCA1" tumors were additionally investigated for presence of dominant adnexal mass, fallopian tube mucosal involvement, and uterine cornu involvement. The positive and negative predictive values for "Compatible with BRCA1" were 11/42 (26.2%) and 267/283 (94.3%), respectively, whereas combining the "Compatible with BRCA1" and "Possibly compatible with BRCA1" had positive and negative predictive values of 18/85 (21.2%) and 231/240 (96.3%), respectively. Although dominant adnexal mass and uterine cornu involvement did not add further predictive value, the likelihood of BRCA1 positivity increased to 42.9% when a tumor with "Compatible with BRCA1" histology was also associated with fallopian tube mucosal involvement. The combination of modified Nottingham grade 3 serous or undifferentiated histology, prominent intraepithelial lymphocytes, marked nuclear atypia with giant/bizarre nuclei, and high mitotic index should help to identify women for BRCA1 mutational analysis in the appropriate clinical setting. Ovarian tumors lacking this specific phenotype are unlikely to be associated with BRCA1 and should not undergo mutational analysis in the absence of other indications.

    View details for DOI 10.1097/PAS.0b013e31825d9b8d

    View details for Web of Science ID 000306656500008

    View details for PubMedID 22790858

  • Gestational age at birth and risk of testicular cancer INTERNATIONAL JOURNAL OF CANCER Crump, C., Sundquist, K., Winkleby, M. A., Sieh, W., Sundquist, J. 2012; 131 (2): 446-451

    Abstract

    Most testicular germ cell tumors originate from carcinoma in situ cells in fetal life, possibly related to sex hormone imbalances in early pregnancy. Previous studies of association between gestational age at birth and testicular cancer have yielded discrepant results and have not examined extreme preterm birth. Our objective was to determine whether low gestational age at birth is independently associated with testicular cancer in later life. We conducted a national cohort study of 354,860 men born in Sweden in 1973-1979, including 19,214 born preterm (gestational age < 37 weeks) of whom 1,279 were born extremely preterm (22-29 weeks), followed for testicular cancer incidence through 2008. A total of 767 testicular cancers (296 seminomas and 471 nonseminomatous germ cell tumors) were identified in 11.2 million person-years of follow-up. Extreme preterm birth was associated with an increased risk of testicular cancer (hazard ratio = 3.95; 95% confidence interval = 1.67-9.34) after adjusting for other perinatal factors, family history of testicular cancer and cryptorchidism. Only five cases (three seminomas and two nonseminomas) occurred among men born extremely preterm, limiting the precision of risk estimates. No association was found between later preterm birth, post-term birth or low or high fetal growth and testicular cancer. These findings suggest that extreme but not later preterm birth may be independently associated with testicular cancer in later life. They are based on a small number of cases and will need confirmation in other large cohorts. Elucidation of the key prenatal etiologic factors may potentially lead to preventive interventions in early life.

    View details for DOI 10.1002/ijc.26371

    View details for Web of Science ID 000304350600036

    View details for PubMedID 22314417

  • Perinatal and Family Risk Factors for Non-Hodgkin Lymphoma in Early Life: A Swedish National Cohort Study JOURNAL OF THE NATIONAL CANCER INSTITUTE Crump, C., Sundquist, K., Sieh, W., Winkleby, M. A., Sundquist, J. 2012; 104 (12): 923-930

    Abstract

    The incidence of non-Hodgkin lymphoma (NHL) in early life has increased in recent decades, but the relevant risk factors remain largely unknown. We examined perinatal and family risk factors for NHL in childhood through young adulthood.We conducted a national cohort study of 3 571 574 individuals born in Sweden in 1973-2008 who were followed for incidence of NHL through 2009 (ages 0-37 years). Detailed information on perinatal and family characteristics and NHL diagnoses were obtained from national birth and cancer registries. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between perinatal and family variables and NHL; P values are from two-sided tests.There were 936 NHL case patients identified in 66.3 million person-years of follow-up. Independent risk factors for NHL included family history of NHL in either a sibling (adjusted HR = 9.84; 95% CI = 2.46 to 39.41; P = .001) or parent (adjusted HR = 2.36; 95% CI = 1.27 to 4.38; P = .007); high fetal growth (for ? 2 SDs relative to 0 to <1 SD from the mean: adjusted HR = 1.64; 95% CI = 1.19 to 2.25; P = .002); older maternal age (adjusted HR for each 5-year increment = 1.11; 95% CI = 1.04 to 1.19; P (trend) = .004); low birth order (adjusted HR for each increment of one birth = 0.91; 95% CI = 0.84 to 0.99; P (trend) = .02); and male sex (adjusted HR = 1.58; 95% CI = 1.38 to 1.80; P < .001). Male sex was associated with onset of NHL before 15 years of age but not with later-onset NHL, whereas the other risk factors did not vary by age at diagnosis. No association was found between gestational age at birth, twinning, paternal age, or parental education and NHL.In this large national cohort study, family history of NHL, high fetal growth, older maternal age, low birth order, and male sex were independent risk factors for NHL in early life.

    View details for DOI 10.1093/jnci/djs225

    View details for Web of Science ID 000306067700009

    View details for PubMedID 22623506

  • Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Bolton, K. L., Chenevix-Trench, G., Goh, C., Sadetzki, S., Ramus, S. J., Karlan, B. Y., Lambrechts, D., Despierre, E., Barrowdale, D., McGuffog, L., Healey, S., Easton, D. F., Sinilnikova, O., Benitez, J., Garcia, M. J., Neuhausen, S., Gail, M. H., Hartge, P., Peock, S., Frost, D., Evans, G., Eeles, R., Godwin, A. K., Daly, M. B., Kwong, A., Ma, E. S., Lazaro, C., Blanco, I., Montagna, M., D'Andrea, E., Nicoletto, M. O., Johnatty, S. E., Krueger, S., Jensen, A., Hogdall, E., Goode, E. L., Fridley, B. L., Loud, J. T., Greene, M. H., Mai, P. L., Chetrit, A., Lubin, F., Hirsh-Yechezkel, G., Glendon, G., Andrulis, I. L., Toland, A. E., Senter, L., Gore, M. E., Gourley, C., Michie, C. O., Song, H., Tyrer, J., Whittemore, A. S., McGuire, V., Sieh, W., Kristoffersson, U., Olsson, H., Borg, A., Levine, D. A., Steele, L., Beattie, M. S., Chan, S., Nussbaum, R. L., Moysich, K. B., Gross, J., Cass, I., Walsh, C., Li, A. J., Leuchter, R., Gordon, O., Garcia-Closas, M., Gayther, S. A., Chanock, S. J., Antoniou, A. C., Pharoah, P. D. 2012; 307 (4): 382-390

    Abstract

    Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear.To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns.A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998).Five-year overall mortality.The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003).Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.

    View details for Web of Science ID 000299464000024

    View details for PubMedID 22274685

  • Estrogen Receptor Beta rs1271572 Polymorphism and Invasive Ovarian Carcinoma Risk: Pooled Analysis within the Ovarian Cancer Association Consortium PLOS ONE Lurie, G., Wilkens, L. R., Thompson, P. J., Shvetsov, Y. B., Matsuno, R. K., Carney, M. E., Palmieri, R. T., Wu, A. H., Pike, M. C., Pearce, C. L., Menon, U., Gentry-Maharaj, A., Gayther, S. A., Ramus, S. J., Whittemore, A. S., McGuire, V., Sieh, W., Pharoah, P. D., Song, H., Gronwald, J., Jakubowska, A., Cybulski, C., Lubinski, J., Schildkraut, J. M., Berchuck, A., Kjaer, S. K., Hogdall, E., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Hein, A., Chenevix-Trench, G., Webb, P. M., Beesley, J., Goodman, M. T. 2011; 6 (6)

    Abstract

    The association of ovarian carcinoma risk with the polymorphism rs1271572 in the estrogen receptor beta (ESR2) gene was examined in 4946 women with primary invasive ovarian carcinoma and 6582 controls in a pooled analysis of ten case-control studies within the Ovarian Cancer Association Consortium (OCAC). All participants were non-Hispanic white women. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression adjusted for site and age. Women with the TT genotype were at increased risk of ovarian carcinoma compared to carriers of the G allele (OR?=?1.10; 95%; CI: 1.01-1.21; p?=?0.04); the OR was 1.09 (CI: 0.99-1.20; p?=?0.07) after excluding data from the center (Hawaii) that nominated this SNP for OCAC genotyping A stronger association of rs1271572 TT versus GT/GG with risk was observed among women aged ?50 years versus older women (OR?=?1.35; CI: 1.12-1.62; p?=?0.002; p for interaction?=?0.02) that remained statistically significant after excluding Hawaii data (OR?=?1.34; CI: 1.11-1.61; p?=?0.009). No heterogeneity of the association was observed by study, menopausal status, gravidity, parity, use of contraceptive or menopausal hormones, tumor histological type, or stage at diagnosis. This pooled analysis suggests that rs1271572 might influence the risk of ovarian cancer, in particular among younger women.

    View details for DOI 10.1371/journal.pone.0020703

    View details for Web of Science ID 000291356400020

    View details for PubMedID 21673961

  • Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk HUMAN MOLECULAR GENETICS Pearce, C. L., Doherty, J. A., Van den Berg, D. J., Moysich, K., Hsu, C., Cushing-Haugen, K. L., Conti, D. V., Ramus, S. J., Gentry-Maharaj, A., Menon, U., Gayther, S. A., Pharoah, P. D., Song, H., Kjaer, S. K., Hogdall, E., Hogdall, C., Whittemore, A. S., McGuire, V., Sieh, W., Gronwald, J., Medrek, K., Jakubowska, A., Lubinski, J., Chenevix-Trench, G., Beesley, J., Webb, P. M., Berchuck, A., Schildkraut, J. M., Iversen, E. S., Moorman, P. G., Edlund, C. K., Stram, D. O., Pike, M. C., Ness, R. B., Rossing, M. A., Wu, A. H. 2011; 20 (11): 2263-2272

    Abstract

    The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial ovarian cancer and 321 women with borderline epithelial ovarian tumors was carried out to test the association between tag single-nucleotide polymorphisms (tSNPs) (n=58) in this pathway and risk of ovarian cancer. We found no association between variation in IGF1, IGFBP1 or IGFBP3 and risk of invasive disease, whereas five tSNPs in IGF2 were associated with risk of invasive epithelial ovarian cancer at P<0.05 and followed-up one of the associated SNPs. We conducted genotyping in 3216 additional non-Hispanic white cases and 5382 additional controls and were able to independently replicate our initial findings. In the combined set of studies, rs4320932 was associated with a 13% decreased risk of ovarian cancer per copy of the minor allele carried (95% confidence interval 0.81-0.93, P-trend=7.4 × 10(-5)). No heterogeneity of effect across study centers was observed (p(het)=0.25). IGF2 is emerging as an important gene for ovarian cancer; additional genotyping is warranted to further confirm these associations with IGF2 and to narrow down the region harboring the causal SNP.

    View details for DOI 10.1093/hmg/ddr087

    View details for Web of Science ID 000290589800016

    View details for PubMedID 21422097

  • Prostate Cancer Susceptibility Polymorphism rs2660753 Is Not Associated with Invasive Ovarian Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Amankwah, E. K., Kelemen, L. E., Wang, Q., Song, H., Chenevix-Trench, G., Beesley, J., Webb, P. M., Pearce, C. L., Wu, A. H., Pike, M. C., Stram, D. O., Chang-Claude, J., Wang-Gohrke, S., Ness, R. B., Goode, E. L., Cunningham, J. M., Fridley, B. L., Vierkant, R. A., Tworoger, S. S., Whittemore, A. S., McGuire, V., Sieh, W., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Rossing, M. A., Doherty, J. A., Goodman, M. T., Carney, M. E., Lurie, G., Wilkens, L. R., Kjaer, S. K., Hogdall, E., Cramer, D. W., Terry, K. L., Garcia-Closas, M., Yang, H., Lissowska, J., Anton-Culver, H., Ziogas, A., Schildkraut, J. M., Berchuck, A., Pharoah, P. D. 2011; 20 (5): 1028-1031

    Abstract

    We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC; OR = 1.2, 95% CI=1.0-1.4, P(trend) = 0.01) that showed a stronger association with the serous histological subtype (OR = 1.3, 95% CI = 1.1-1.5, P(trend) = 0.003).We sought to replicate this association in 12 other studies comprising 4,482 cases and 6,894 controls of white non-Hispanic ancestry in the Ovarian Cancer Association Consortium.No evidence for an association with all cancers or serous cancers was observed in a combined analysis of data from the replication studies (all: OR = 1.0, 95% CI = 0.9-1.1, P(trend) = 0.61; serous: OR = 1.0, 95% CI = 0.9-1.1, P(trend) = 0.85) or from the combined analysis of discovery and replication studies (all: OR = 1.0, 95% CI = 1.0-1.1, P(trend) = 0.28; serous: OR = 1.1, 95% CI = 1.0-1.2, P(trend) = 0.11). There was no evidence for statistical heterogeneity in ORs across the studies.Although rs2660753 is a strong prostate cancer susceptibility polymorphism, the association with another hormonally related cancer, invasive EOC, is not supported by this replication study.Our findings, based on a larger sample size, emphasize the importance of replicating potentially promising genetic risk associations.

    View details for DOI 10.1158/1055-9965.EPI-11-0053

    View details for Web of Science ID 000290251000036

    View details for PubMedID 21415361

  • Common variants at 19p13 are associated with susceptibility to ovarian cancer NATURE GENETICS Bolton, K. L., Tyrer, J., Song, H., Ramus, S. J., Notaridou, M., Jones, C., Sher, T. 3., Gentry-Maharaj, A., Wozniak, E., Tsai, Y., Weidhaas, J., Paik, D., Van den Berg, D. J., Stram, D. O., Pearce, C. L., Wu, A. H., Brewster, W., Anton-Culver, H., Ziogas, A., Narod, S. A., Levine, D. A., Kaye, S. B., Brown, R., Paul, J., Flanagan, J., Sieh, W., McGuire, V., Whittemore, A. S., Campbell, I., Gore, M. E., Lissowska, J., Yang, H. P., Medrek, K., Gronwald, J., Lubinski, J., Jakubowska, A., Le, N. D., Cook, L. S., Kelemen, L. E., Brook-Wilson, A., Massuger, L. F., Kiemeney, L. A., Aben, K. K., van Altena, A. M., Houlston, R., Tomlinson, I., Palmieri, R. T., Moorman, P. G., Schildkraut, J., Iversen, E. S., Phelan, C., Vierkant, R. A., Cunningham, J. M., Goode, E. L., Fridley, B. L., Kruger-Kjaer, S., Blaeker, J., Hogdall, E., Hogdall, C., Gross, J., Karlan, B. Y., Ness, R. B., Edwards, R. P., Odunsi, K., Moyisch, K. B., Baker, J. A., Modugno, F., Heikkinenen, T., Butzow, R., Nevanlinna, H., Leminen, A., Bogdanova, N., Antonenkova, N., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I., Thompson, P. J., Carney, M. E., Goodman, M. T., Lurie, G., Wang-Gohrke, S., Hein, R., Chang-Claude, J., Rossing, M. A., Cushing-Haugen, K. L., Doherty, J., Chen, C., Rafnar, T., Besenbacher, S., Sulem, P., Stefansson, K., Birrer, M. J., Terry, K. L., Hernandez, D., Cramer, D. W., Vergote, I., Amant, F., Lambrechts, D., Despierre, E., Fasching, P. A., Beckmann, M. W., Thiel, F. C., Ekici, A. B., Chen, X., Johnatty, S. E., Webb, P. M., Beesley, J., Chanock, S., Garcia-Closas, M., Sellers, T., Easton, D. F., Berchuck, A., Chenevix-Trench, G., Pharoah, P. D., Gayther, S. A. 2010; 42 (10): 880-?

    Abstract

    Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10?? and P = 6 × 10??, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10?? and P = 4 × 10?¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

    View details for DOI 10.1038/ng.666

    View details for Web of Science ID 000282276600019

    View details for PubMedID 20852633

  • A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24 NATURE GENETICS Goode, L. L., Chenevix-Trench, G., Song, H., Ramus, S. J., Notaridou, M., Lawrenson, K., Widschwendter, M., Vierkant, R. A., Larson, M. C., Kjaer, S. K., Birrer, M. J., Berchuck, A., Schildkraut, J., Tomlinson, I., Kiemeney, L. A., Cook, L. S., Gronwald, J., Garcia-Closas, M., Gore, M. E., Campbell, I., Whittemore, A. S., Sutphen, R., Phelan, C., Anton-Culver, H., Pearce, C. L., Lambrechts, D., Rossing, M. A., Chang-Claude, J., Moysich, K. B., Goodman, M. T., Doerk, T., Nevanlinna, H., Ness, R. B., Rafnar, T., Hogdall, C., Hogdall, E., Fridley, B. L., Cunningham, J. M., Sieh, W., McGuire, V., Godwin, A. K., Cramer, D. W., Hernandez, D., Levine, D., Lu, K., Iversen, E. S., Palmieri, R. T., Houlston, R., van Altena, A. M., Aben, K. K., Massuger, L. F., Brooks-Wilson, A., Kelemen, L. E., Le, N. D., Jakubowska, A., Lubinski, J., Medrek, K., Stafford, A., Easton, D. F., Tyrer, J., Bolton, K. L., Harrington, P., Eccles, D., Chen, A., Molina, A. N., Davila, B. N., Arango, H., Tsai, Y., Chen, Z., Risch, H. A., McLaughlin, J., Narod, S. A., Ziogas, A., Brewster, W., Gentry-Maharaj, A., Menon, U., Wu, A. H., Stram, D. O., Pike, M. C., Beesley, J., Webb, P. M., Chen, X., Ekici, A. B., Thiel, F. C., Beckmann, M. W., Yang, H., Wentzensen, N., Lissowska, J., Fasching, P. A., Despierre, E., Amant, F., Vergote, I., Doherty, J., Hein, R., Wang-Gohrke, S., Lurie, G., Carney, M. E., Thompson, P. J., Runnebaum, I., Hillemanns, P., Duerst, M., Antonenkova, N., Bogdanova, N., Leminen, A., Butzow, R., Heikkinen, T., Stefansson, K., Sulem, P., Besenbacher, S., Sellers, T. A., Gayther, S. A., Pharoah, P. D. 2010; 42 (10): 874-?

    Abstract

    Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P ? 10??) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P ? 5 × 10?? (8q24, P = 8.0 × 10?¹? and 2q31, P = 3.8 × 10?¹?) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10?? and 17q21, P = 1.4 × 10??). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.

    View details for DOI 10.1038/ng.668

    View details for Web of Science ID 000282276600018

    View details for PubMedID 20852632

  • Lipophilic Statin Use and Risk of Breast Cancer Subtypes CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Woditschka, S., Habel, L. A., Udaltsova, N., Friedman, G. D., Sieh, W. 2010; 19 (10): 2479-2487

    Abstract

    Statins are widely used and of high interest as potential chemopreventive agents for cancer. Preclinical studies suggest that lipophilic statins have anticancer properties targeting hormone receptor (HR)-negative breast cancer. Few epidemiologic studies have investigated the relationship between lipophilic statin use and risk for breast cancer, stratified by HR status. We conducted a large case-control study within Kaiser Permanente of Northern California (KPNC) to determine whether chronic use of lipophilic statins is associated with decreased risk of HR-negative breast cancer or other breast cancer subtypes.We identified 22,488 breast cancer cases diagnosed from 1997 to 2007, and 224,860 controls matched to cases based upon birth year and duration of KPNC pharmacy coverage. Use of lipophilic statins was ascertained using the comprehensive electronic pharmacy records of KPNC.We found no association between lipophilic statin use (?2 y versus never) and overall breast cancer risk (odds ratio(adj), 1.02; 95% CI, 0.97-1.08) in conditional logistic regression models adjusted for oral contraceptive and hormone therapy use. Women who used lipophilic statins did not have a decreased risk of HR-negative breast cancer (odds ratio(adj), 0.98; 95% CI, 0.84-1.14) nor altered risk of HR-positive disease (odds ratio(adj), 1.03; 95% CI, 0.97-1.10). Furthermore, lipophilic statin use was not associated with risk of any of the intrinsic subtypes, luminal A, luminal B, human epidermal growth factor receptor 2 positive/estrogen receptor negative, or triple negative.Our results do not support an association of lipophilic statin use with the risk for breast cancer in general or with risks of HR-negative or other breast cancer subtypes specifically.These findings do not confirm previous reports of a possible preventive association.

    View details for DOI 10.1158/1055-9965.EPI-10-0524

    View details for Web of Science ID 000282590500009

    View details for PubMedID 20729289

  • Cancer linked to Alzheimer disease but not vascular dementia NEUROLOGY Roe, C. M., Fitzpatrick, A. L., Xiong, C., Sieh, W., Kuller, L., Miller, J. P., Williams, M. M., Kopan, R., Behrens, M. I., Morris, J. C. 2010; 74 (2): 106-112

    Abstract

    To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD).Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer.The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD.In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.

    View details for DOI 10.1212/WNL.0b013e3181c91873

    View details for Web of Science ID 000273563600004

    View details for PubMedID 20032288

  • Prevalence of Cancer in Female Orthopedic Surgeons in the United States JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME Chou, L. B., Cox, C. A., Tung, J. J., Harris, A. H., Brooks-Terrell, D., Sieh, W. 2010; 92A (1): 240-244
  • Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia HUMAN MOLECULAR GENETICS Sundar, P. D., Yu, C., Sieh, W., Steinbart, E., Garruto, R. M., Oyanagi, K., Craig, U., Bird, T. D., Wijsman, E. M., Galasko, D. R., Schellenberg, G. D. 2007; 16 (3): 295-306

    Abstract

    Unusual forms of amyotrophic lateral sclerosis (ALS-G), Parkinsonism dementia complex (PDC-G) and Guam dementia (GD) are found in Chamorros, the indigenous people of Guam. Neurofibrillary tangles composed of hyperphosphorylated tau are a neuropathologic feature of these closely related disorders. To determine if variation in the gene that encodes microtubule-associated protein tau gene (MAPT) contributes to risk for these disorders, we genotyped nine single nucleotide polymorphism (SNP) sites and one insertion/deletion in the 5' end of MAPT in 54 ALS-G, 135 PDC-G, 153 GD and 258 control subjects, all of whom are Chamorros. Variation at three SNPs (sites 2, 6 and 9) influenced risk for ALS-G, PDC-G and GD. SNP2 acts through a dominant mechanism and is independent of the risk conferred by SNPs 6 and 9, the latter two acting by a recessive mechanism. Persons with the high-risk SNP6 and SNP9 AC/AC diplotype had an increased risk of 3-fold [95% confidence interval (CI)=1.10-8.25] for GD, 4-fold (95% CI=1.40-11.64) for PDC-G and 6-fold (95% CI=1.44-32.14) for ALS-G, compared to persons with other diplotypes after adjusting for SNP2. Carriers of the SNP2 G allele had an increased risk of 1.6-fold (95% CI=1.00-2.62) for GD, 2-fold (95% CI=1.28-3.66) for PDC-G, and 1.5-fold (95% CI=0.74-3.00) for ALS-G, compared to non-carriers after adjusting for SNPs 6 and 9. Others have shown that SNP6 is also associated with risk for progressive supranuclear palsy. These two independent cis-acting sites presumably influence risk for Guam neuro-degenerative disorders by regulating MAPT expression.

    View details for DOI 10.1093/hmg/ddl463

    View details for Web of Science ID 000244126000006

    View details for PubMedID 17185385

  • Accounting for linkage disequilibrium among markers in linkage analysis: Impact of haplotype frequency estimation and molecular haplotypes for a gene in a candidate region for Alzheimer's disease HUMAN HEREDITY Sieh, W., Yu, C., Bird, T. D., Schellenberg, G. D., Wijsman, E. M. 2007; 63 (1): 26-34

    Abstract

    Linkage disequilibrium (LD) between closely spaced SNPs can be accommodated in linkage analysis by specifying the multi-SNP haplotype frequencies, if known. Phased haplotypes in candidate regions can provide gold standard haplotype frequency estimates, and may be of inherent interest as markers. We evaluated the effects of different methods of haplotype frequency estimation, and the use of marker phase information, on linkage analysis of a multi-SNP cluster in a candidate region for Alzheimer's disease (AD).We performed parametric linkage analysis of a five-SNP cluster in extended pedigrees to compare the use of: (1) haplotype frequencies estimated by molecular phase determination, maximum likelihood estimation, or by assuming linkage equilibrium (LE); (2) AD families or controls as the frequency source; and (3) unphased or molecularly phased SNP data.There was moderate to strong pairwise LD among the five SNPs. Falsely assuming LE substantially inflated the LOD score, but the method of haplotype frequency estimation and particular sample used made little difference provided that LD was accommodated. Use of phased haplotypes produced a modest increase in the LOD score over unphased SNPs.Ignoring LD between markers can lead to substantially inflated evidence for linkage in LOD score analysis of extended pedigrees with missing data. Use of marker phase information in linkage analysis may be important in disease studies where the costs of family recruitment and phenotyping greatly exceed the costs of phase determination.

    View details for DOI 10.1159/000098459

    View details for Web of Science ID 000243564800003

    View details for PubMedID 17215579

  • Comparison of multipoint linkage analyses for quantitative traits in the CEPH data: parametric LOD scores, variance components LOD scores, and Bayes factors. BMC proceedings Sung, Y. J., Di, Y., Fu, A. Q., Rothstein, J. H., Sieh, W., Tong, L., Thompson, E. A., Wijsman, E. M. 2007; 1: S93-?

    Abstract

    We performed multipoint linkage analyses with multiple programs and models for several gene expression traits in the Centre d'Etude du Polymorphisme Humain families. All analyses provided consistent results for both peak location and shape. Variance-components (VC) analysis gave wider peaks and Bayes factors gave fewer peaks. Among programs from the MORGAN package, lm_multiple performed better than lm_markers, resulting in less Markov-chain Monte Carlo (MCMC) variability between runs, and the program lm_twoqtl provided higher LOD scores by also including either a polygenic component or an additional quantitative trait locus.

    View details for PubMedID 18466597

  • Genetic susceptibility to prostate cancer: prostate-specific antigen and its interaction with the androgen receptor (United States) CANCER CAUSES & CONTROL Sieh, W., Edwards, K. L., Fitzpatrick, A. L., Srinouanprachanh, S. L., Farin, F. M., Monks, S. A., Kronmal, R. A., Eaton, D. L. 2006; 17 (2): 187-197

    Abstract

    To determine whether directly observed prostate-specific antigen (PSA) promoter diploid haplotype, either alone or in conjunction with androgen receptor (AR) genotype, is associated with prostate cancer risk.We conducted a case-control study nested within the US population-based Cardiovascular Health Study cohort. Incident prostate cancers were identified by linkage to cancer registry records for the years 1989-2000. We genotyped 193 cases and 391 controls for the PSA -252 G/A and -158 G/A SNPs and the AR CAG microsatellite, and developed methods to directly determine proximal PSA promoter haplotypes. Exact logistic regression was used to estimate odds ratios and significance levels.No significant associations were observed between PSA diplotype and prostate cancer overall. Short (< 20) AR CAG repeat lengths were associated with modest increases in the risk of prostate cancer (OR, 1.46; 95% CI, 0.97-2.19; p = 0.071) that were significant for advanced disease (OR, 1.82; 95% CI, 1.02-3.26; p = 0.044). Men who possessed two copies of the PSA*2 (-252G/-158G) haplotype and short AR CAG repeat lengths had a 4-fold (95% CI, 1.05-20.75; exact p = 0.040) increased risk of prostate cancer, and a 7-fold (95% CI, 1.25-39.78; exact p = 0.026) increased risk of advanced disease.We found evidence that the PSA*2*2 diplotype in combination with short AR CAG alleles increases a man's risk of developing prostate cancer. These findings support an etiologic role in prostate cancer of genetic interactions between polymorphisms that increase AR transactivation strength and those that alter the regulatory regions of target genes such as PSA that are responsive to androgen stimulation.

    View details for DOI 10.1007/s10552-005-0454-8

    View details for Web of Science ID 000234754500008

    View details for PubMedID 16425097

  • Comparison of marker types and map assumptions using Markov chain Monte Carlo-based linkage analysis of COGA data BMC GENETICS Sieh, W., Basu, S., Fu, A. Q., Rothstein, J. H., Scheet, P. A., Stewart, W. C., Sung, Y. J., Thompson, E. A., Wijsman, E. M. 2005; 6

    Abstract

    We performed multipoint linkage analysis of the electrophysiological trait ECB21 on chromosome 4 in the full pedigrees provided by the Collaborative Study on the Genetics of Alcoholism (COGA). Three Markov chain Monte Carlo (MCMC)-based approaches were applied to the provided and re-estimated genetic maps and to five different marker panels consisting of microsatellite (STRP) and/or SNP markers at various densities. We found evidence of linkage near the GABRB1 STRP using all methods, maps, and marker panels. Difficulties encountered with SNP panels included convergence problems and demanding computations.

    View details for DOI 10.1186/1471-2156-6-S1-S11

    View details for Web of Science ID 000236103400011

    View details for PubMedID 16451566

  • Familial risks of squamous cell carcinoma of the head and neck: Retrospective case-control study BRITISH MEDICAL JOURNAL Foulkes, W. D., Brunet, J. S., Sieh, W., Black, M. J., Shenouda, G., Narod, S. A. 1996; 313 (7059): 716-721

    Abstract

    To determine the contribution of inheritance to the incidence of squamous cell carcinoma of the head and neck.Historical cohort study. First degree relatives of cases with squamous cell carcinoma of the head and neck made up the exposed cohort and first degree relatives of spouses of cases made up the comparison unexposed cohort.Ear, nose, and throat clinic in a large metropolitan teaching hospital.1429 first degree relatives of 242 index cases of squamous cell carcinoma of the head and neck; as controls, 934 first degree relatives of the spouses of 156 index cases.Relative risk of developing squamous cell carcinoma in first degree relatives of cases compared with risk in first degree relatives of spouses.The adjusted relative risk for developing head and neck cancer if the index case had squamous cell carcinoma of the head and neck was 3.79 (95% confidence interval 1.11 to 13.0). There were no significantly increased risks associated with a family history of cancer at other sites. The adjusted relative risk for squamous cell carcinoma of the head and neck was 7.89 (1.50 to 41.6) in first degree relatives of patients with multiple primary head and neck tumours.These data suggest that genetic factors are important in the aetiology of head and neck cancer, in particular for patients with multiple primary cancers. Given the prolonged exposure of these subjects to carcinogens, these genetic factors may have a role in modifying carcinogen activity or in host resistance to carcinogens. Inherited factors may be important in persons with environmentally induced cancers.

    View details for Web of Science ID A1996VJ44100021

    View details for PubMedID 8819440

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