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Academic Appointments


Research & Scholarship

Current Research and Scholarly Interests


Cancers of the prostate, breast and ovary account for a major proportion of new cancer cases and cancer deaths in the U.S. each year. We conduct population-based epidemiologic field studies aimed at understanding the etiologies of these cancers. The primary focus concerns the joint effects of genetic predisposition and modifiable lifestyle characteristics on cancer risk. We currently are analyzing data from a large case-control study of prostate cancer in black, white and Asian-American men. We are attempting to delineate the effects on prostate cancer risk of diet, body size, physical activity and family history of prostate cancer. We have established population-based registries of families with multiple cases of prostate cancer, and families with multiple cases of breast and/or ovarian cancer. We are using these registries for linkage analysis in search of cancer-susceptibility genes, for the study of gene-environment interactions, and for estimates of the proportions of cancers attributable to specific genes. Our recent research focus has been on developing improved statistical methods for the design and conduct of studies involving hereditary predisposition and modifiable lifestyle characteristics in the etiologies of site-specific cancers.

Teaching

2013-14 Courses


Publications

Journal Articles


  • 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

  • Two-stage sampling designs for external validation of personal risk models. Statistical methods in medical research Whittemore, A. S., Halpern, J. 2013

    Abstract

    We propose a cost-effective sampling design and estimating procedure for validating personal risk models using right-censored cohort data. Validation involves using each subject's covariates, as ascertained at cohort entry, in a risk model (specified independently of the data) to assign him/her a probability of an adverse outcome within a future time period. Subjects are then grouped according to the magnitudes of their assigned risks, and within each group, the mean assigned risk is compared with the probability of outcome occurrence as estimated using the follow-up data. Such validation presents two complications. First, in the presence of right-censoring, estimating the probability of developing the outcomes before death requires competing risk analysis. Second, for rare outcomes, validation using the full cohort requires assembling covariates and assigning risks to thousands of subjects. This can be costly when some covariates involve analyzing biological specimens. A two-stage sampling design addresses this problem by assembling covariates and assigning risks only to those subjects most informative for estimating key parameters. We use this design to estimate the outcome probabilities needed to evaluate model performance and we provide theoretical and bootstrap estimates of their variances. We also describe how to choose two-stage designs with minimal efficiency loss for a parameter of interest when the quantities determining optimality are unknown at the time of design. We illustrate these methods by using subjects in the California Teachers Study to validate ovarian cancer risk models. We find that a design with optimal efficiency for one performance parameter need not be so for others, and trade-offs will be required. A two-stage design that samples all outcome-positive subjects and more outcome-negative than censored subjects will perform well in most circumstances. The methods are implemented in Risk Model Assessment Program, an R program freely available at http://med.stanford.edu/epidemiology/two-stage.html.

    View details for PubMedID 23592716

  • Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. The 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): 853-62

    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 PubMedID 23845225

  • 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

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

    Abstract

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

    View details for DOI 10.1200/JCO.2010.34.4440

    View details for Web of Science ID 000298136500016

    View details for PubMedID 22042950

  • Optimal Methods for Meta-Analysis of Genome-Wide Association Studies GENETIC EPIDEMIOLOGY Zhou, B., Shi, J., Whittemore, A. S. 2011; 35 (7): 581-591

    Abstract

    Meta-analysis of genome-wide association studies involves testing single nucleotide polymorphisms (SNPs) using summary statistics that are weighted sums of site-specific score or Wald statistics. This approach avoids having to pool individual-level data. We describe the weights that maximize the power of the summary statistics. For small effect-sizes, any choice of weights yields summary Wald and score statistics with the same power, and the optimal weights are proportional to the square roots of the sites' Fisher information for the SNP's regression coefficient. When SNP effect size is constant across sites, the optimal summary Wald statistic is the well-known inverse-variance-weighted combination of estimated regression coefficients, divided by its standard deviation. We give simple approximations to the optimal weights for various phenotypes, and show that weights proportional to the square roots of study sizes are suboptimal for data from case-control studies with varying case-control ratios, for quantitative trait data when the trait variance differs across sites, for count data when the site-specific mean counts differ, and for survival data with different proportions of failing subjects. Simulations suggest that weights that accommodate intersite variation in imputation error give little power gain compared to those obtained ignoring imputation uncertainties. We note advantages to combining site-specific score statistics, and we show how they can be used to assess effect-size heterogeneity across sites. The utility of the summary score statistic is illustrated by application to a meta-analysis of schizophrenia data in which only site-specific P-values and directions of association are available.

    View details for DOI 10.1002/gepi.20603

    View details for Web of Science ID 000296846900001

    View details for PubMedID 21922536

  • The potential value of sibling controls compared with population controls for association studies of lifestyle-related risk factors: an example from the Breast Cancer Family Registry INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Milne, R. L., John, E. M., Knight, J. A., Dite, G. S., Southey, M. C., Giles, G. G., Apicella, C., West, D. W., Andrulis, I. L., Whittemore, A. S., Hopper, J. L. 2011; 40 (5): 1342-1354

    Abstract

    A previous Australian population-based breast cancer case-control study found indirect evidence that control participation, although high, was not random. We hypothesized that unaffected sisters may provide a more appropriate comparison group than unrelated population controls.Three population-based case-control-family studies of breast cancer in women of white European origin were carried out by the Australian, Ontario and Northern California sites of the Breast Cancer Family Registry. We compared risk factors between 3643 cases, 2444 of their unaffected sisters and 2877 population controls and conducted separate case-control analyses based on population and sister controls using unconditional multivariable logistic regression.Compared with sister controls, population controls were more highly educated, had an earlier age at menarche, fewer births, their first birth at a later age and their last birth more recently. The established breast cancer associations detected using sister controls, but not detected using population controls, were decreasing risk with each of later age at menarche, more births, younger age at first birth and greater time since last birth.Since participation of population controls might be unintentionally related to some risk factors, we hypothesize that sister controls could provide more valid relative risk estimates and be recruited at lower cost. Given declining study participation by population controls, this contention is highly relevant to epidemiologic research.

    View details for DOI 10.1093/ije/dyr110

    View details for Web of Science ID 000296634900025

    View details for PubMedID 21771852

  • Evaluating health risk models STATISTICS IN MEDICINE Whittemore, A. S. 2010; 29 (23): 2438-2452

    Abstract

    Interest in targeted disease prevention has stimulated development of models that assign risks to individuals, using their personal covariates. We need to evaluate these models and quantify the gains achieved by expanding a model to include additional covariates. This paper reviews several performance measures and shows how they are related. Examples are used to show that appropriate performance criteria for a risk model depend upon how the model is used. Application of the performance measures to risk models for hypothetical populations and for US women at risk of breast cancer illustrate two additional points. First, model performance is constrained by the distribution of risk-determining covariates in the population. This complicates the comparison of two models when applied to populations with different covariate distributions. Second, all summary performance measures obscure model features of relevance to its utility for the application at hand, such as performance in specific subgroups of the population. In particular, the precision gained by adding covariates to a model can be small overall, but large in certain subgroups. We propose new ways to identify these subgroups and to quantify how much they gain by measuring the additional covariates. Those with largest gains could be targeted for cost-efficient covariate assessment.

    View details for DOI 10.1002/sim.3991

    View details for Web of Science ID 000282622200006

    View details for PubMedID 20623821

  • Genetic Variation in TYMS in the One-Carbon Transfer Pathway Is Associated with Ovarian Carcinoma Types in the Ovarian Cancer Association Consortium CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kelemen, L. E., Goodman, M. T., McGuire, V., Rossing, M. A., Webb, P. M., Koebel, M., Anton-Culver, H., Beesley, J., Berchuck, A., Brar, S., Carney, M. E., Chang-Claude, J., Chenevix-Trench, G., Cramer, D. W., Cunningham, J. M., DiCioccio, R. A., Doherty, J. A., Easton, D. F., Fredericksen, Z. S., Fridley, B. L., Gates, M. A., Gayther, S. A., Gentry-Maharaj, A., Hogdall, E., Kjaer, S. K., Lurie, G., Menon, U., Moorman, P. G., Moysich, K., Ness, R. B., Palmieri, R. T., Pearce, C. L., Pharoah, P. D., Ramus, S. J., Song, H., Stram, D. O., Tworoger, S. S., Van Den Berg, D., Vierkant, R. A., Wang-Gohrke, S., Whittemore, A. S., Wilkens, L. R., Wu, A. H., Schildkraut, J. M., Sellers, T. A., Goode, E. L. 2010; 19 (7): 1822-1830

    Abstract

    We previously reported the risks of ovarian carcinoma for common polymorphisms in one-carbon transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990, and TYMS rs495139 with risk of ovarian carcinoma overall and to use the large sample of assembled cases to investigate associations by histologic type.Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and study site.The five polymorphisms were not associated with ovarian carcinoma overall (P(trend) > 0.13); however, associations for the minor allele at TYMS rs495139 were observed for carcinomas of mucinous type (OR, 1.19; 95% CI, 1.03-1.39; P = 0.02), clear cell type (OR, 0.86; 95% CI, 0.75-0.99; P = 0.04), and endometrioid type (OR, 0.90; 95% CI, 0.81-0.99; P = 0.04; P(heterogeneity) = 0.001). Restriction to low-grade mucinous carcinomas further strengthened the association for the mucinous type (OR, 1.32; 95% CI, 1.07-1.62; P = 0.01). TYMS rs495139 was not associated with serous type (OR, 1.06; 95% CI, 1.00-1.13; P = 0.05).TYMS rs495139 may be associated with a differential risk of ovarian carcinoma types, indicating the importance of accurate histopathologic classification.Biomarkers that distinguish ovarian carcinoma types are few, and TYMS rs495139 may provide a novel clue to type etiology.

    View details for DOI 10.1158/1055-9965.EPI-09-1317

    View details for Web of Science ID 000279590100018

    View details for PubMedID 20570913

  • Estimating Gene Penetrance From Family Data GENETIC EPIDEMIOLOGY Gong, G., Hannon, N., Whittemore, A. S. 2010; 34 (4): 373-381

    Abstract

    Family data are useful for estimating disease risk in carriers of specific genotypes of a given gene (penetrance). Penetrance is frequently estimated assuming that relatives' phenotypes are independent, given their genotypes for the gene of interest. This assumption is unrealistic when multiple shared risk factors contribute to disease risk. In this setting, the phenotypes of relatives are correlated even after adjustment for the genotypes of any one gene (residual correlation). Many methods have been proposed to address this problem, but their performance has not been evaluated systematically. In simulations we generated genotypes for a rare (frequency 0.35%) allele of moderate penetrance, and a common (frequency 15%) allele of low penetrance, and then generated correlated disease survival times using the Clayton-Oakes copula model. We ascertained families using both population and clinic designs. We then compared the estimates of several methods to the optimal ones obtained from the model used to generate the data. We found that penetrance estimates for common low-risk genotypes were more robust to model misspecification than those for rare, moderate-risk genotypes. For the latter, penetrance estimates obtained ignoring residual disease correlation had large biases. Also biased were estimates based only on families that segregate the risk allele. In contrast, a method for accommodating phenotype correlation by assuming the presence of genetic heterogeneity performed nearly optimally, even when the survival data were coded as binary outcomes. We conclude that penetrance estimates that accommodate residual phenotype correlation (even only approximately) outperform those that ignore it, and that coding censored survival outcomes as binary does not substantially increase the mean-square error of the estimates, provided the censoring is not extensive.

    View details for DOI 10.1002/gepi.20493

    View details for Web of Science ID 000277642800010

    View details for PubMedID 20397150

  • Second Malignant Neoplasms in Survivors of Pediatric Hodgkin's Lymphoma Treated With Low-Dose Radiation and Chemotherapy JOURNAL OF CLINICAL ONCOLOGY O'Brien, M. M., Donaldson, S. S., Balise, R. R., Whittemore, A. S., Link, M. P. 2010; 28 (7): 1232-1239

    Abstract

    Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation.Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires.One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (+/- SE) 5-year disease-free and overall survival were 76% +/- 12% and 85% +/- 10% with median follow-up 5 years from SMN diagnosis.Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.

    View details for DOI 10.1200/JCO.2009.24.8062

    View details for Web of Science ID 000274892500025

    View details for PubMedID 20124178

  • No evidence of familial correlation in breast cancer metastasis BREAST CANCER RESEARCH AND TREATMENT Whittemore, A. S., Stearman, B., Venne, V., Halpern, J., Felberg, A., McGuire, V., Daly, M., Buys, S. S. 2009; 118 (3): 575-581

    Abstract

    Animal experiments support the hypothesis that the metastatic potential of breast cancer is a heritable trait of the host. Our objective was to evaluate correlations in metastasis occurrence in large families with multiple cases of breast cancer. We evaluated correlation among pairs of relatives in the occurrence and timing of distant metastasis using retrospective cohort data from 743 female breast cancer patients in 242 families. We adjusted for correlation in their age at diagnosis, year of diagnosis, educational level, lymph node involvement, and estrogen receptor status. Distant metastasis occurred in 255 patients (34.3%) during mean followup of 11.7 years. None of the correlation coefficients for metastasis in blood relatives differed significantly from zero. The estimated correlation coefficient in first-degree relatives was -0.03 (95% confidence interval -0.11 to 0.06). These findings suggest that a family history of metastatic breast cancer does not contribute substantially to risk of metastasis for breast cancer patients.

    View details for DOI 10.1007/s10549-009-0368-3

    View details for Web of Science ID 000271640900015

    View details for PubMedID 19296215

  • An Admixture Scan in 1,484 African American Women with Breast Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Fejerman, L., Haiman, C. A., Reich, D., Tandon, A., Deo, R. C., John, E. M., Ingles, S. A., Ambrosone, C. B., Bovbjerg, D. H., Jandorf, L. H., Davis, W., Ciupak, G., Whittemore, A. S., Press, M. F., Ursin, G., Bernstein, L., Huntsman, S., Henderson, B. E., Ziv, E., Freedman, M. L. 2009; 18 (11): 3110-3117

    Abstract

    African American women with breast cancer present more commonly with aggressive tumors that do not express the estrogen receptor (ER) and progesterone receptor (PR) compared with European American women. Whether this disparity is the result of inherited factors has not been established. We did an admixture-based genome-wide scan to search for risk alleles for breast cancer that are highly differentiated in frequency between African American and European American women, and may contribute to specific breast cancer phenotypes, such as ER-negative (ER-) disease. African American women with invasive breast cancer (n = 1,484) were pooled from six population-based studies and typed at approximately 1,500 ancestry-informative markers. We investigated global genetic ancestry and did a whole genome admixture scan searching for breast cancer-predisposing loci in association with disease phenotypes. We found a significant difference in ancestry between ER+PR+ and ER-PR- women, with higher European ancestry among ER+PR+ individuals, after controlling for possible confounders (odds ratios for a 0 to 1 change in European ancestry proportion, 2.84; 95% confidence interval, 1.13-7.14; P = 0.026). Women with localized tumors had higher European ancestry than women with non-localized tumors (odds ratios, 2.65; 95% confidence interval, 1.11-6.35; P = 0.029). No genome-wide statistically significant associations were observed between European or African ancestry at any specific locus and breast cancer, or in analyses stratified by ER/PR status, stage, or grade. In summary, in African American women, genetic ancestry is associated with ER/PR status and disease stage. However, we found little evidence that genetic ancestry at any one region contributes significantly to breast cancer risk or hormone receptor status.

    View details for DOI 10.1158/1055-9965.EPI-09-0464

    View details for Web of Science ID 000271562600045

    View details for PubMedID 19843668

  • Family history of breast cancer and all-cause mortality after breast cancer diagnosis in the Breast Cancer Family Registry BREAST CANCER RESEARCH AND TREATMENT Chang, E. T., Milne, R. L., Phillips, K., Figueiredo, J. C., Sangaramoorthy, M., Keegan, T. H., Andrulis, I. L., Hopper, J. L., Goodwin, P. J., O'Malley, F. P., Weerasooriya, N., Apicella, C., Southey, M. C., Friedlander, M. L., Giles, G. G., Whittemore, A. S., West, D. W., John, E. M. 2009; 117 (1): 167-176

    Abstract

    Although having a family history of breast cancer is a well established breast cancer risk factor, it is not known whether it influences mortality after breast cancer diagnosis. We studied 4,153 women with first primary incident invasive breast cancer diagnosed between 1991 and 2000, and enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. Cases were oversampled for younger age at diagnosis and/or family history of breast cancer. Carriers of germline mutations in BRCA1 or BRCA2 were excluded. Cases and their relatives completed structured questionnaires assessing breast cancer risk factors and family history of cancer. Cases were followed for a median of 6.5 years, during which 725 deaths occurred. Cox proportional hazards regression was used to evaluate associations between family history of breast cancer at the time of diagnosis and risk of all-cause mortality after breast cancer diagnosis, adjusting for established prognostic factors. The hazard ratios for all-cause mortality were 0.98 (95% confidence interval [CI] = 0.84-1.15) for having at least one first- or second-degree relative with breast cancer, and 0.85 (95% CI = 0.70-1.02) for having at least one first-degree relative with breast cancer, compared with having no such family history. Estimates did not vary appreciably when stratified by case or tumor characteristics. In conclusion, family history of breast cancer is not associated with all-cause mortality after breast cancer diagnosis for women without a known germline mutation in BRCA1 or BRCA2. Therefore, clinical management should not depend on family history of breast cancer.

    View details for DOI 10.1007/s10549-008-0255-3

    View details for Web of Science ID 000269005400020

    View details for PubMedID 19034644

  • Common variants on chromosome 6p22.1 are associated with schizophrenia NATURE Shi, J., Levinson, D. F., Duan, J., Sanders, A. R., Zheng, Y., Pe'er, I., Dudbridge, F., Holmans, P. A., Whittemore, A. S., Mowry, B. J., Olincy, A., Amin, F., Cloninger, C. R., Silverman, J. M., Buccola, N. G., Byerley, W. F., Black, D. W., Crowe, R. R., Oksenberg, J. R., Mirel, D. B., Kendler, K. S., Freedman, R., Gejman, P. V. 2009; 460 (7256): 753-757

    Abstract

    Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x 10(-9)). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.

    View details for DOI 10.1038/nature08192

    View details for Web of Science ID 000268670300042

    View details for PubMedID 19571809

  • Performance of Prediction Models for BRCA Mutation Carriage in Three Racial/Ethnic Groups: Findings from the Northern California Breast Cancer Family Registry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kurian, A. W., Gong, G. D., John, E. M., Miron, A., Felberg, A., Phipps, A. I., West, D. W., Whittemore, A. S. 2009; 18 (4): 1084-1091

    Abstract

    Patients with early-onset breast and/or ovarian cancer frequently wish to know if they inherited a mutation in one of the cancer susceptibility genes, BRCA1 or BRCA2. Accurate carrier prediction models are needed to target costly testing. Two widely used models, BRCAPRO and BOADICEA, were developed using data from non-Hispanic Whites (NHW), but their accuracies have not been evaluated in other racial/ethnic populations.We evaluated the BRCAPRO and BOADICEA models in a population-based series of African American, Hispanic, and NHW breast cancer patients tested for BRCA1 and BRCA2 mutations. We assessed model calibration by evaluating observed versus predicted mutations and attribute diagrams, and model discrimination using areas under the receiver operating characteristic curves.Both models were well-calibrated within each racial/ethnic group, with some exceptions. BOADICEA overpredicted mutations in African Americans and older NHWs, and BRCAPRO underpredicted in Hispanics. In all racial/ethnic groups, the models overpredicted in cases whose personal and family histories indicated >80% probability of carriage. The two models showed similar discrimination in each racial/ethnic group, discriminating least well in Hispanics. For example, BRCAPRO's areas under the receiver operating characteristic curves were 83% (95% confidence interval, 63-93%) for NHWs, compared with 74% (59-85%) for African Americans and 58% (45-70%) for Hispanics.The poor performance of the model for Hispanics may be due to model misspecification in this racial/ethnic group. However, it may also reflect racial/ethnic differences in the distributions of personal and family histories among breast cancer cases in the Northern California population.

    View details for DOI 10.1158/1055-9965.EPI-08-1090

    View details for Web of Science ID 000265125000009

    View details for PubMedID 19336551

  • Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer BRITISH JOURNAL OF CANCER Quaye, L., Song, H., Ramus, S. J., Gentry-Maharaj, A., Hogdall, E., DiCioccio, R. A., McGuire, V., Wu, A. H., Van den Berg, D. J., Pike, M. C., Wozniak, E., Doherty, J. A., Rossing, M. A., Ness, R. B., Moysich, K. B., Hogdall, C., Blaakaer, J., Easton, D. F., Ponder, B. A., Jacobs, I. J., Menon, U., Whittemore, A. S., Kruger-Kjaer, S., Pearce, C. L., Pharoah, P. D., Gayther, S. A. 2009; 100 (6): 993-1001

    Abstract

    Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

    View details for DOI 10.1038/sj.bjc.6604947

    View details for Web of Science ID 000264306400019

    View details for PubMedID 19240718

  • Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer CANCER RESEARCH Schildkraut, J. M., Goode, E. L., Clyde, M. A., Iversen, E. S., Moorman, P. G., Berchuck, A., Marks, J. R., Lissowska, J., Brinton, L., Peplonska, B., Cunningham, J. M., Vierkant, R. A., Rider, D. N., Chenevix-Trench, G., Webb, P. M., Beesley, J., Chen, X., Phelan, C., Sutphen, R., Sellers, T. A., Pearce, L., Wu, A. H., Van Den Berg, D., Conti, D., Elund, C. K., Anderson, R., Goodman, M. T., Lurie, G., Carney, M. E., Thompson, P. J., Gayther, S. A., Ramus, S. J., Jacobs, I., Kjaer, S. K., Hogdall, E., Blaakaer, J., Hogdall, C., Easton, D. F., Song, H., Pharoah, P. D., Whittemore, A. S., McGuire, V., Quaye, L., Anton-Culver, H., Ziogas, A., Terry, K. L., Cramer, D. W., Hankinson, S. E., Tworoger, S. S., Calingaert, B., Chanock, S., Sherman, M., Garcia-Closas, M. 2009; 69 (6): 2349-2357

    Abstract

    The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r(2) = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07-1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01-1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region.

    View details for DOI 10.1158/0008-5472.CAN-08-2902

    View details for Web of Science ID 000264541300027

    View details for PubMedID 19276375

  • Candidate Gene Analysis Using Imputed Genotypes: Cell Cycle Single-Nucleotide Polymorphisms and Ovarian Cancer Risk CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Goode, E. L., Fridley, B. L., Vierkant, R. A., Cunningham, J. M., Phelan, C. M., Anderson, S., Rider, D. N., White, K. L., Pankratz, V. S., Song, H., Hogdall, E., Kjaer, S. K., Whittemore, A. S., DiCioccio, R., Ramus, S. J., Gayther, S. A., Schildkraut, J. M., Pharaoh, P. P., Sellers, T. A. 2009; 18 (3): 935-944

    Abstract

    Polymorphisms in genes critical to cell cycle control are outstanding candidates for association with ovarian cancer risk; numerous genes have been interrogated by multiple research groups using differing tagging single-nucleotide polymorphism (SNP) sets. To maximize information gleaned from existing genotype data, we conducted a combined analysis of five independent studies of invasive epithelial ovarian cancer. Up to 2,120 cases and 3,382 controls were genotyped in the course of two collaborations at a variety of SNPs in 11 cell cycle genes (CDKN2C, CDKN1A, CCND3, CCND1, CCND2, CDKN1B, CDK2, CDK4, RB1, CDKN2D, and CCNE1) and one gene region (CDKN2A-CDKN2B). Because of the semi-overlapping nature of the 123 assayed tagging SNPs, we performed multiple imputation based on fastPHASE using data from White non-Hispanic study participants and participants in the international HapMap Consortium and National Institute of Environmental Health Sciences SNPs Program. Logistic regression assuming a log-additive model was done on combined and imputed data. We observed strengthened signals in imputation-based analyses at several SNPs, particularly CDKN2A-CDKN2B rs3731239; CCND1 rs602652, rs3212879, rs649392, and rs3212891; CDK2 rs2069391, rs2069414, and rs17528736; and CCNE1 rs3218036. These results exemplify the utility of imputation in candidate gene studies and lend evidence to a role of cell cycle genes in ovarian cancer etiology, suggest a reduced set of SNPs to target in additional cases and controls.

    View details for DOI 10.1158/1055-9965.EPI-08-0860

    View details for Web of Science ID 000264226100034

    View details for PubMedID 19258477

  • Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium BRITISH JOURNAL OF CANCER Pearce, C. L., Near, A. M., Van den Berg, D. J., Ramus, S. J., Gentry-Maharaj, A., Menon, U., Gayther, S. A., Anderson, A. R., Edlund, C. K., Wu, A. H., Chen, X., Beesley, J., Webb, P. M., Holt, S. K., Chen, C., Doherty, J. A., Rossing, M. A., Whittemore, A. S., McGuire, V., DiCioccio, R. A., Goodman, M. T., Lurie, G., Carney, M. E., Wilkens, L. R., Ness, R. B., Moysich, K. B., Edwards, R., JENNISON, E., Kjaer, S. K., Hogdall, E., Hogdall, C. K., Goode, E. L., Sellers, T. A., Vierkant, R. A., Cunningham, J. C., Schildkraut, J. M., Berchuck, A., Moorman, P. G., Iversen, E. S., Cramer, D. W., Terry, K. L., Vitonis, A. F., Titus-Ernstoff, L., Song, H., Pharoah, P. D., Spurdle, A. B., Anton-Culver, H., Ziogas, A., Brewster, W., Galitovskiy, V., Chenevix-Trench, G. 2009; 100 (2): 412-420

    Abstract

    The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

    View details for DOI 10.1038/sj.bjc.6604820

    View details for Web of Science ID 000262637800028

    View details for PubMedID 19127255

  • Polymorphism in the IL18 Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Palmieri, R. T., Wilson, M. A., Iversen, E. S., Clyde, M. A., Calingaert, B., Moorman, P. G., Poole, C., Anderson, A. R., Anderson, S., Anton-Culver, H., Beesley, J., Hogdall, E., Brewster, W., Carney, M. E., Chen, X., Chenevix-Trench, G., Chang-Claude, J., Cunningham, J. M., DiCioccio, R. A., Doherty, J. A., Easton, D. F., Edlund, C. K., Gayther, S. A., Gentry-Maharaj, A., Goode, E. L., Goodman, M. T., Kjaer, S. K., Hogdall, C. K., Hopkins, M. P., Jenison, E. L., Blaakaer, J., Lurie, G., McGuire, V., Menon, U., Moysich, K. B., Ness, R. B., Pearce, C. L., Pharoah, P. D., Pike, M. C., Ramus, S. J., Rossing, M. A., Song, H., Terada, K. Y., VanDenBerg, D., Vierkant, R. A., Wang-Gohrke, S., Webb, P. M., Whittemore, A. S., Wu, A. H., Ziogas, A., Berchuck, A., Schildkraut, J. M. 2008; 17 (12): 3567-3572

    Abstract

    Over 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States, but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low-penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNP) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (P = 0.002) with a <25% chance of being a false-positive finding (q value = 0.240). Using a multivariate model search algorithm over 11 IL18 tagging SNPs, we found that the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (odds ratio, 1.24; 95% confidence interval, 1.06-1.45). In a replication stage, 12 independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (odds ratio, 0.99; 95% confidence interval, 0.94-1.05) when data from the 12 OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial North Carolina Ovarian Cancer Study data. This analysis shows the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3567-72).

    View details for DOI 10.1158/1055-9965.EPI-08-0548

    View details for Web of Science ID 000261724000038

    View details for PubMedID 19064572

  • Association Study of Prostate Cancer Susceptibility Variants with Risks of Invasive Ovarian, Breast, and Colorectal Cancer CANCER RESEARCH Song, H., Koessler, T., Ahmed, S., Ramus, S. J., Kjaer, S. K., DiCioccio, R. A., Wozniak, E., Hogdall, E., Whittemore, A. S., McGuire, V., Ponder, B. A., Turnbull, C., Hines, S., Rahman, N., Eeles, R. A., Easton, D. F., Gayther, S. A., Dunning, A. M., Pharoah, P. D. 2008; 68 (21): 8837-8842

    Abstract

    Several prostate cancer susceptibility loci have recently been identified by genome-wide association studies. These loci are candidates for susceptibility to other epithelial cancers. The aim of this study was to test these tag single nucleotide polymorphisms (SNP) for association with invasive ovarian, colorectal, and breast cancer. Twelve prostate cancer-associated tag SNPs were genotyped in ovarian (2,087 cases/3,491 controls), colorectal (2,148 cases/2,265 controls) and breast (first set, 4,339 cases/4,552 controls; second set, 3,800 cases/3,995 controls) case-control studies. The primary test of association was a comparison of genotype frequencies between cases and controls, and a test for trend stratified by study where appropriate. Genotype-specific odds ratios (OR) were estimated by logistic regression. SNP rs2660753 (chromosome 3p12) showed evidence of association with ovarian cancer [per minor allele OR, 1.19; 95% confidence interval (95% CI), 1.04-1.37; P(trend) = 0.012]. This association was stronger for the serous histologic subtype (OR, 1.29; 95% CI, 1.09-1.53; P = 0.003). SNP rs7931342 (chromosome 11q13) showed some evidence of association with breast cancer (per minor allele OR, 0.95; 95% CI, 0.91-0.99; P(trend) = 0.028). This association was somewhat stronger for estrogen receptor-positive tumors (OR, 0.92; 95% CI, 0.87-0.98; P = 0.011). None of these tag SNPs were associated with risk of colorectal cancer. In conclusion, loci associated with risk of prostate cancer may also be associated with ovarian and breast cancer susceptibility. However, the effects are modest and warrant replication in larger studies.

    View details for DOI 10.1158/0008-5472.CAN-08-2363

    View details for Web of Science ID 000260698900025

    View details for PubMedID 18974127

  • Performance of BRCA1/2 mutation prediction models in Asian Americans JOURNAL OF CLINICAL ONCOLOGY Kurian, A. W., Gong, G. D., Chun, N. M., Mills, M. A., Staton, A. D., Kingham, K. E., Crawford, B. B., Lee, R., Chan, S., Donlon, S. S., Ridge, Y., Panabaker, K., West, D. W., Whittemore, A. S., Ford, J. M. 2008; 26 (29): 4752-4758

    Abstract

    There are established differences in breast cancer epidemiology between Asian and white individuals, but little is known about hereditary breast cancer in Asian populations. Although increasing numbers of Asian individuals are clinically tested for BRCA1/2 mutations, it is not known whether computer models that predict mutations work accurately in Asian individuals. We compared the performance in Asian and white individuals of two widely used BRCA1/2 mutation prediction models, BRCAPRO and Myriad II.We evaluated BRCAPRO and Myriad II in 200 Asian individuals and a matched control group of 200 white individuals who were tested for BRCA1/2 mutations at four cancer genetics clinics, by comparing numbers of observed versus predicted mutation carriers and by evaluating area under the receiver operating characteristic curve (AUC) for each model.BRCAPRO and Myriad II accurately predicted the number of white BRCA1/2 mutation carriers (25 observed v 24 predicted by BRCAPRO; 25 predicted by Myriad II, P > or = .69), but underpredicted Asian carriers by two-fold (49 observed v 25 predicted by BRCAPRO; 26 predicted by Myriad II; P < or = 3 x 10(-7)). For BRCAPRO, this racial difference reflects substantial underprediction of Asian BRCA2 mutation carriers (26 observed v 4 predicted; P = 1 x 10(-30)); for Myriad II, separate mutation predictions were not available. For both models, AUCs were nonsignificantly lower in Asian than white individuals, suggesting less accurate discrimination between Asian carriers and noncarriers.Both BRCAPRO and Myriad II underestimated the proportion of BRCA1/2 mutation carriers, and discriminated carriers from noncarriers less well, in Asian compared with white individuals.

    View details for DOI 10.1200/JCO.2008.16.8310

    View details for Web of Science ID 000259902800011

    View details for PubMedID 18779604

  • Mismatch repair gene polymorphisms and survival in invasive ovarian cancer patients EUROPEAN JOURNAL OF CANCER Mann, A., Hogdall, E., Ramus, S. J., DiCioccio, R. A., Hogdall, C., Quaye, L., McGuire, V., Whittemore, A. S., Shah, M., Greenberg, D., Easton, D. F., Ponder, B. A., Kjaer, S. K., Gayther, S. A., Thompson, D. J., Pharoah, P. D., Song, H. 2008; 44 (15): 2259-2265

    Abstract

    Inherited genetic factors may help partially explain variability of survival length amongst ovarian cancer patients. Of particular interest are genes involved in DNA repair, specifically those involved in mismatch repair (MMR). The aim of this study was to investigate the possible association between the common variants in MMR genes and invasive ovarian cancer overall survival.We examined associations between 44 variants that tag the known common variants (minor allele frequency 0.05) in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2) and survival of invasive ovarian cancer patients in three case-control studies from United Kingdom (UK), Denmark and California of United States of America (USA). DNA from up to 1495 women were genotyped. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis stratified by study. A nominally significant association (P=0.04) between genotype and ovarian cancer survival was observed for rs2228006 in PMS2. The per-rare allele hazard ratio (HR 95%CI) was 0.84 (0.71-0.99), however, it was not significant after adjusting for multiple covariants (P=0.47). When the analyses were restricted to serous type ovarian cancer, two SNPs showed marginal significant associations; the per-rare allele HR was 1.3 (1.05-1.6) (P=0.02) for rs1799977 in MLH1 and 1.4 (1.03-1.9) (P=0.04) for rs6151662 in MSH3. Neither was significant after adjusting for multiple covariants.It is unlikely that common variants in the MMR pathways examined have moderate effects on survival after diagnosis with ovarian cancer. Much larger studies would be needed to exclude common variants with small effects.

    View details for DOI 10.1016/j.ejca.2008.07.010

    View details for Web of Science ID 000261020800025

    View details for PubMedID 18723338

  • The effects of common genetic variants in oncogenes on ovarian cancer survival CLINICAL CANCER RESEARCH Quaye, L., Gayther, S. A., Ramus, S. J., Di Cioccio, R. A., McGuire, V., Hogdall, E., Hogdall, C., Blaakr, J., Easton, D. F., Ponder, B. A., Jacobs, I., Kjaer, S. K., Whittemore, A. S., Pearce, C. L., Pharoah, P. D., Song, H. 2008; 14 (18): 5833-5839

    Abstract

    The 5-year survival rate for invasive epithelial ovarian cancer is <35%. It has been suggested that common, germline genetic variation may influence survival after cancer diagnoses, which might enable the prediction of response to treatment and survival in the clinical setting. The aim of this study was to evaluate associations between common germline genetic variants in the oncogenes BRAF, ERBB2, KRAS, NMI, and PIK3CA, and survival after a diagnosis of epithelial ovarian cancer.We evaluated the association between 34 tagging single nucleotide polymorphisms and survival in 1,480 cases of invasive epithelial ovarian cancer cases from three different studies. Cox regression analysis, stratified by study, was used to estimate per rare allele hazard ratios (HR).The minor allele rs6944385 in BRAF was significantly associated with poor survival [HR, 1.19; 95% confidence intervals (95% CI), 1.02-1.39; P = 0.024]. The association remained after adjusting for prognostic factors (adjusted HR, 1.20; 95 CI, 1.03-1.40; P = 0.018). A haplotype of BRAF was also associated with poor survival (HR, 1.24; 95% CI, 1.02-1.51; P = 0.029) and was more significant after adjustment (HR, 1.44; 95% CI, 1.15-1.81; P = 0.001). We also found evidence of an association between a KRAS haplotype and poor survival in serous subtype (HR, 1.69; 95% CI, 1.21-2.38; P = 0.002), but this was no longer significant after adjustment. Finally, when analyses were restricted to the serous histologic subtype, the rare allele rs10842513 in KRAS, was associated with poor survival (HR, 1.40; 95% CI, 1.10-1.78; P = 0.007).Common genetic variants in the BRAF and KRAS oncogenes may be important in the prediction of survival in patients with invasive epithelial ovarian cancer.

    View details for DOI 10.1158/1078-0432.CCR-08-0819

    View details for Web of Science ID 000259347600027

    View details for PubMedID 18794094

  • Facility factors dominate the ability to achieve target haemoglobin levels in haemodialysis patients NEPHROLOGY DIALYSIS TRANSPLANTATION Chan, K. E., Lafayette, R. A., Whittemore, A. S., Hlatky, M. A., Moran, J. 2008; 23 (9): 2948-2956

    Abstract

    Our objective was to determine whether patient factors, processes of care and measures of erythropoietin (EPO) responsiveness were associated with successful anemia management at the individual patient level.We retrospectively reviewed laboratory and demographic data from 1499 patients receiving hemodialysis in 15 units operated by the same dialysis provider. We performed univariate and multivariate logistic regression analysis to determine predictors of an average 3-month hemoglobin level below or above the target interval of 11.0-12.5 g/dL. To explain the effect of facility on anemia performance, we calculated correlations between measures of EPO responsiveness and the probability of achieving the target interval by facility.Patients above the target hemoglobin range demonstrated an association with parathyroid hormone (PTH) (OR = 0.96 per 100 pg/mL increase), female gender (OR = 0.68), EPO protocol use (OR = 0.94 per 10% increase in use) and facility (range of OR = 0.26-2.59 for 15 participating sites). Patients below the target hemoglobin range demonstrated an association with CRP (OR = 1.10 per mg/L increase), PTH (OR = 1.07 per 100 pg/mL increase), iron deficiency (OR = 1.07 per 10% increase), EPO protocol use (OR = 0.89 per 10% increase in use), iron protocol use (OR = 0.93 per 10% increase in use) and facility (range of OR = 0.58-3.41 over 15 units). EPO index (r = 0.71), EPO dose (r = 0.73), hemoglobin (r = -0.60) and EPO per unit weight (r = 0.76) were significantly correlated with the probability of achieving the target hemoglobin by facility.The facility significantly influences the outcome of anemia management in patients with ESRD. In part, this is due to the patients' EPO responsiveness, which may be influenced by facility care patterns.

    View details for DOI 10.1093/ndt/gfn172

    View details for Web of Science ID 000259372400039

    View details for PubMedID 18469314

  • Consortium analysis of 7 candidate SNPs for ovarian cancer INTERNATIONAL JOURNAL OF CANCER Ramus, S. J., Vierkant, R. A., Johnatty, S. E., Pike, M. C., Van den Berg, D. J., Wu, A. H., Pearce, C. L., Menon, U., Gentry-Maharaj, A., Gayther, S. A., DiCioccio, R. A., McGuire, V., Whittemore, A. S., Song, H., Easton, D. F., Pharoah, P. D., Garcia-Closas, M., Chanock, S., Lissowska, J., Brinton, L., Terry, K. L., Cramer, D. W., Tworoger, S. S., Hankinson, S. E., Berchuck, A., Moorman, P. G., Schildkraut, J. M., Cunningham, J. M., Liebow, M., Kjaer, S. K., Hogdall, E., Hogdall, C., Blaakaer, J., Ness, R. B., Moysich, K. B., Edwards, R. P., Carney, M. E., Lurie, G., Goodman, M. T., Wang-Gohrke, S., Kropp, S., Chang-Claude, J., Webb, P. M., Chen, X., Beesley, J., Chenevix-Trench, G., Goode, E. L. 2008; 123 (2): 380-388

    Abstract

    The Ovarian Cancer Association Consortium selected 7 candidate single nucleotide polymorphisms (SNPs), for which there is evidence from previous studies of an association with variation in ovarian cancer or breast cancer risks. The SNPs selected for analysis were F31I (rs2273535) in AURKA, N372H (rs144848) in BRCA2, rs2854344 in intron 17 of RB1, rs2811712 5' flanking CDKN2A, rs523349 in the 3' UTR of SRD5A2, D302H (rs1045485) in CASP8 and L10P (rs1982073) in TGFB1. Fourteen studies genotyped 4,624 invasive epithelial ovarian cancer cases and 8,113 controls of white non-Hispanic origin. A marginally significant association was found for RB1 when all studies were included [ordinal odds ratio (OR) 0.88 (95% confidence interval (CI) 0.79-1.00) p = 0.041 and dominant OR 0.87 (95% CI 0.76-0.98) p = 0.025]; when the studies that originally suggested an association were excluded, the result was suggestive although no longer statistically significant (ordinal OR 0.92, 95% CI 0.79-1.06). This SNP has also been shown to have an association with decreased risk in breast cancer. There was a suggestion of an association for AURKA, when one study that caused significant study heterogeneity was excluded [ordinal OR 1.10 (95% CI 1.01-1.20) p = 0.027; dominant OR 1.12 (95% CI 1.01-1.24) p = 0.03]. The other 5 SNPs in BRCA2, CDKN2A, SRD5A2, CASP8 and TGFB1 showed no association with ovarian cancer risk; given the large sample size, these results can also be considered to be informative. These null results for SNPs identified from relatively large initial studies shows the importance of replicating associations by a consortium approach.

    View details for DOI 10.1002/ijc.23448

    View details for Web of Science ID 000256760300018

    View details for PubMedID 18431743

  • Multiple loci with different cancer specificities within the 8q24 gene desert JOURNAL OF THE NATIONAL CANCER INSTITUTE Ghoussaini, M., Song, H., Koessler, T., Al Olama, A. A., Kote-Jarai, Z., Driver, K. E., Pooley, K. A., Ramus, S. J., Kjaer, S. K., Hogdall, E., DiCioccio, R. A., Whittemore, A. S., Gayther, S. A., Giles, G. G., Guy, M., Edwards, S. M., Morrison, J., Donovan, J. L., Hamdy, F. C., Dearnaley, D. P., Ardern-Jones, A. T., Hall, A. L., O'Brien, L. T., Gehr-Swain, B. N., Wilkinson, R. A., Brown, P. M., Hopper, J. L., Neal, D. E., Pharoah, P. D., Ponder, B. A., Eeles, R. A., Easton, D. F., Dunning, A. M. 2008; 100 (13): 962-966

    Abstract

    Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case-control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.

    View details for DOI 10.1093/jnci/djn190

    View details for Web of Science ID 000257403100010

    View details for PubMedID 18577746

  • Significance levels for studies with correlated test statistics BIOSTATISTICS Shi, J., Levinson, D. F., Whittemore, A. S. 2008; 9 (3): 458-466

    Abstract

    When testing large numbers of null hypotheses, one needs to assess the evidence against the global null hypothesis that none of the hypotheses is false. Such evidence typically is based on the test statistic of the largest magnitude, whose statistical significance is evaluated by permuting the sample units to simulate its null distribution. Efron (2007) has noted that correlation among the test statistics can induce substantial interstudy variation in the shapes of their histograms, which may cause misleading tail counts. Here, we show that permutation-based estimates of the overall significance level also can be misleading when the test statistics are correlated. We propose that such estimates be conditioned on a simple measure of the spread of the observed histogram, and we provide a method for obtaining conditional significance levels. We justify this conditioning using the conditionality principle described by Cox and Hinkley (1974). Application of the method to gene expression data illustrates the circumstances when conditional significance levels are needed.

    View details for DOI 10.1093/biostatistics/kxm047

    View details for Web of Science ID 000256977000007

    View details for PubMedID 18089626

  • Ovarian cysts and breast cancer: results from the Women's Contraceptive and Reproductive Experiences Study BREAST CANCER RESEARCH AND TREATMENT Knight, J. A., Lesosky, M., Blackmore, K. M., Voigt, L. F., Holt, V. L., Bernstein, L., Marchbanks, P. A., Burkman, R. T., Daling, J. R., Whittemore, A. S. 2008; 109 (1): 157-164

    Abstract

    A diagnosis of ovarian cysts is likely an indicator of hormonal milieu and thus may be related to breast cancer risk. Recent studies have reported an inverse relationship between prior ovarian cyst diagnosis and breast cancer risk. We evaluated this relationship in the Women's Contraceptive and Reproductive Experiences (CARE) Study, a population-based case-control study conducted in Atlanta, Detroit, Philadelphia, Los Angeles, and Seattle. Cases had first primary invasive breast cancer diagnosed between 1994 and 1998 at ages 35-64 years. African American women were over-sampled. Controls were identified through random digit dialling and were frequency matched to cases on centre, race, and five-year age group. A total of 4575 cases and 4682 controls were interviewed. We used unconditional logistic regression adjusted for age and study centre within racial groups to estimate the odds ratio (OR) and 95% confidence interval (CI) for the relationship between prior ovarian cysts and breast cancer. Ovarian cyst diagnosis was associated with a significantly reduced risk among Caucasians (OR=0.85, 95% CI 0.76-0.96) and among African Americans (OR=0.68, 95% CI 0.57-0.81). The association in Caucasians was not significant within subgroups defined by menopausal status, hormone use, or gynecological surgery while the OR estimates in African Americans were consistently lower and frequently significant. These data are consistent with the previously reported inverse association between ovarian cysts and breast cancer, but the evidence for a relationship was stronger in African Americans than Caucasians. Additional studies are required to determine the specific cyst type(s) responsible for the observed relationship.

    View details for DOI 10.1007/s10549-007-9634-4

    View details for Web of Science ID 000255031000016

    View details for PubMedID 17616808

  • Effects of common germ-line genetic variation in cell cycle genes on ovarian cancer survival CLINICAL CANCER RESEARCH Song, H., Hogdall, E., Ramus, S. J., DiCioccio, R. A., Hogdall, C., Quaye, L., McGuire, V., Whittemore, A. S., Shah, M., Greenberg, D., Easton, D., Kjaer, S. K., Pharoah, P. D., Gayther, S. A. 2008; 14 (4): 1090-1095

    Abstract

    Somatic alterations have been shown to correlate with ovarian cancer prognosis and survival, but less is known about the effects on survival of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division and could plausibly influence clinical characteristics of multiple tumors types.We examined associations between common germ-line genetic variation in 14 genes involved in cell cycle pathway (CCND1, CCND2, CCND3, CCNE1, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CDK2, CDK4, CDK6, and RB1) and survival among women with invasive ovarian cancer participating in a multicenter case-control study from United Kingdom, Denmark, and United States. DNAs from up to 1,499 women were genotyped for 97 single-nucleotide polymorphisms that tagged the known common variants (minor allele frequency > or = 0.05) in these genes. The genotypes of each polymorphism were tested for association with survival by Cox regression analysis.A nominally statistically significant association between genotype and ovarian cancer survival was observed for polymorphisms in CCND2 and CCNE1. The per-allele hazard ratios (95% confidence intervals) were 1.16 (1.03-1.31; P = 0.02) for rs3217933, 1.14 (1.02-1.27; P = 0.024) for rs3217901, and 0.85 (0.73-1.00; P = 0.043) for rs3217862 in CCND2 and 1.39 (1.04-1.85; P = 0.033) for rs3218038 in CCNE1. However, these were not significant after adjusting for multiple hypothesis tests.It is unlikely that common variants in cell cycle pathways examined above associated with moderate effect in survival after diagnosis of ovarian cancer. Much larger studies will be needed to exclude common variants with small effects.

    View details for DOI 10.1158/1078-0432.CCR-07-1195

    View details for Web of Science ID 000253449700018

    View details for PubMedID 18281541

  • Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the ovarian cancer association consortium pooled analysis BRITISH JOURNAL OF CANCER Pearce, C. L., Wu, A. H., Gayther, S. A., Bale, A. E., Beck, P. A., Beesley, J., Chanock, S., Cramer, D. W., DiCioccio, R., Edwards, R., Fredericksen, Z. S., Garcia-Closas, M., Goode, E. L., Green, A. C., Hartmann, L. C., Hogdall, E., Kjaer, S. K., Lissowska, J., McGuire, V., Modugno, F., Moysich, K., Ness, R. B., Ramus, S. J., Risch, H. A., Sellers, T. A., Song, H., Stram, D. O., Terry, K. L., Webb, P. M., Whiteman, D. C., Whittemore, A. S., Zheng, W., Pharoah, P. D., Chenevix-Trench, G., Pike, M. C., Schildkraut, J., Berchuck, A. 2008; 98 (2): 282-288

    Abstract

    There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.

    View details for DOI 10.1038/sj.bjc.6604170

    View details for Web of Science ID 000252933400007

    View details for PubMedID 18219286

  • Prostate cancer risk in relation to insulin-like growth factor (IGF)-I and IGF-binding protein-3: A prospective multiethnic study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Borugian, M. J., Spinelli, J. J., Sun, Z., Kolonel, L. N., Oakley-Girvan, I., Pollak, M. D., Whittemore, A. S., Wu, A. H., Gallagher, R. P. 2008; 17 (1): 252-254
  • Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION John, E. M., Miron, A., Gong, G., Phipps, A. I., Felberg, A., Li, F. P., West, D. W., Whittemore, A. S. 2007; 298 (24): 2869-2876

    Abstract

    Information on the prevalence of pathogenic BRCA1 mutation carriers in racial/ethnic minority populations is limited.To estimate BRCA1 carrier prevalence in Hispanic, African American, and Asian American female breast cancer patients compared with non-Hispanic white patients with and without Ashkenazi Jewish ancestry.We estimated race/ethnicity-specific prevalence of BRCA1 in a population-based, multiethnic series of female breast cancer patients younger than 65 years at diagnosis who were enrolled at the Northern California site of the Breast Cancer Family Registry during the period 1996-2005. Race/ethnicity and religious ancestry were based on self-report. Weighted estimates of prevalence and 95% confidence intervals (CIs) were based on Horvitz-Thompson estimating equations.Estimates of BRCA1 prevalence.Estimates of BRCA1 prevalence were 3.5% (95% CI, 2.1%-5.8%) in Hispanic patients (n = 393), 1.3% (95% CI, 0.6%-2.6%) in African American patients (n = 341), and 0.5% (95% CI, 0.1%-2.0%) in Asian American patients (n = 444), compared with 8.3% (95% CI, 3.1%-20.1%) in Ashkenazi Jewish patients (n = 41) and 2.2% (95% CI, 0.7%-6.9%) in other non-Hispanic white patients (n = 508). Prevalence was particularly high in young (<35 years) African American patients (5/30 patients [16.7%]; 95% CI, 7.1%-34.3%). 185delAG was the most common mutation in Hispanics, found in 5 of 21 carriers (24%).Among African American, Asian American, and Hispanic patients in the Northern California Breast Cancer Family Registry, the prevalence of BRCA1 mutation carriers was highest in Hispanics and lowest in Asian Americans. The higher carrier prevalence in Hispanics may reflect the presence of unrecognized Jewish ancestry in this population.

    View details for Web of Science ID 000251816000019

    View details for PubMedID 18159056

  • Association between single-nucleotide polymorphisms in hormone metabolism and DNA repair genes and epithelial ovarian cancer: Results from two Australian studies and an additional validation set CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Beesley, J., Jordan, S. J., Spurdle, A. B., Song, H., Ramus, S. J., Kjaer, S. K., Hogdall, E., DiCioccio, R. A., McGuire, V., Whittemore, A. S., Gayther, S. A., Pharoah, P. D., Webb, P. M., Chenevix-Trench, G. 2007; 16 (12): 2557-2565

    Abstract

    Although some high-risk ovarian cancer genes have been identified, it is likely that common low penetrance alleles exist that confer some increase in ovarian cancer risk. We have genotyped nine putative functional single-nucleotide polymorphisms (SNP) in genes involved in steroid hormone synthesis (SRD5A2, CYP19A1, HSB17B1, and HSD17B4) and DNA repair (XRCC2, XRCC3, BRCA2, and RAD52) using two Australian ovarian cancer case-control studies, comprising a total of 1,466 cases and 1,821 controls of Caucasian origin. Genotype frequencies in cases and controls were compared using logistic regression. The only SNP we found to be associated with ovarian cancer risk in both of these two studies was SRD5A2 V89L (rs523349), which showed a significant trend of increasing risk per rare allele (P = 0.00002). We then genotyped another SNP in this gene (rs632148; r(2) = 0.945 with V89L) in an attempt to validate this finding in an independent set of 1,479 cases and 2,452 controls from United Kingdom, United States, and Denmark. There was no association between rs632148 and ovarian cancer risk in the validation samples, and overall, there was no significant heterogeneity between the results of the five studies. Further analyses of SNPs in this gene are therefore warranted to determine whether SRD5A2 plays a role in ovarian cancer predisposition.

    View details for DOI 10.1158/1055-9965.EPI-07-0542

    View details for Web of Science ID 000251856100006

    View details for PubMedID 18086758

  • Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer HUMAN MUTATION Ramus, S. J., Harrington, P. A., Pye, C., DiCioccio, R. A., Cox, M. J., Garlinghouse-Jones, K., Oakley-Girvan, I., Jacobs, I. J., Hardy, R. M., Whittemore, A. S., Ponder, B. A., Piver, M. S., Pharoah, P. D., Gayther, S. A. 2007; 28 (12): 1207-1215

    Abstract

    A total of 283 epithelial ovarian cancer families from the United Kingdom (UK) and the United States (US) were screened for coding sequence changes and large genomic alterations (rearrangements and deletions) in the BRCA1 and BRCA2 genes. Deleterious BRCA1 mutations were identified in 104 families (37%) and BRCA2 mutations in 25 families (9%). Of the 104 BRCA1 mutations, 12 were large genomic alterations; thus this type of change represented 12% of all BRCA1 mutations. Six families carried a previously described exon 13 duplication, known to be a UK founder mutation. The remaining six BRCA1 genomic alterations were previously unreported and comprised five deletions and an amplification of exon 15. One of the 25 BRCA2 mutations identified was a large genomic deletion of exons 19-20. The prevalence of BRCA1/2 mutations correlated with the extent of ovarian and breast cancer in families. Of 37 families containing more than two ovarian cancer cases and at least one breast cancer case with diagnosis at less than 60 years of age, 30 (81%) had a BRCA1/2 mutation. The mutation prevalence was appreciably less in families without breast cancer; mutations were found in only 38 out of 141 families (27%) containing two ovarian cancer cases only, and in 37 out of 59 families (63%) containing three or more ovarian cancer cases. These data indicate that BRCA1 and BRCA2 are the major susceptibility genes for ovarian cancer but that other susceptibility genes may exist. Finally, it is likely that these data will be of clinical importance for individuals in families with a history of epithelial ovarian cancer, in providing accurate estimates of their disease risks.

    View details for DOI 10.1002/humu.20599

    View details for Web of Science ID 000251534700008

    View details for PubMedID 17688236

  • Comparison of admixture and association mapping in admixed families GENETIC EPIDEMIOLOGY Clarke, G., Whittemore, A. S. 2007; 31 (7): 763-775

    Abstract

    The family-based admixture mapping test (AMT) identifies disease-related genes using family data from admixed individuals with the disease of interest (cases). The cases' genotypes at a set of markers are used to infer their DNA ancestry as it varies in blocks along the chromosomes. The test compares the cases' inferred ancestries to those expected from their family histories. Deviation between observed and expected ancestries in a region suggests the presence of a disease gene. We use a likelihood-based development of the AMT to compare it with the transmission disequilibrium test (TDT) as applied to admixed populations. The two tests have a common framework but differ significantly when the disease locus is untyped. The TDT infers disease-locus genotypes using the markers with which it is in linkage disequilibrium (LD). In contrast, the AMT infers disease locus ancestries using those of its linked markers. Thus, TDT power depends on LD between disease and marker loci, while AMT power depends on the lengths of the ancestry blocks containing the disease locus. We compare the power of the two tests when applied to cases with descent from two ancestral populations. The AMT outperforms the TDT when case marker ancestries are correctly specified and LD between disease and marker loci is less than one-third its maximal value (Delta' < 1/3). However, the TDT performs better in the presence of uncertain marker ancestries, even for weak LD between disease and marker loci (Delta' = 0.1). These findings have implications for the design of studies using admixed populations.

    View details for DOI 10.1002/gepi.20239

    View details for Web of Science ID 000250904800009

    View details for PubMedID 17508341

  • Prediagnostic C-peptide and risk of prostate cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Borugian, M. J., Spinelli, J. J., Sun, Z., Kolonel, L. N., Oakley-Girvan, I., Pollak, M. D., Whittemore, A. S., Wu, A. H., Gallagher, R. P. 2007; 16 (10): 2164-2165
  • UDP-glucuronosyltransferase 1A1 gene polymorphisms and total bilirubin levels in an ethnically diverse cohort of women DRUG METABOLISM AND DISPOSITION Hong, A. L., Huo, D., Kim, H., Niu, Q., Fackenthal, D. L., Cummings, S. A., John, E. M., West, D. W., Whittemore, A. S., Das, S., Olopade, O. I. 2007; 35 (8): 1254-1261

    Abstract

    The objective of this study was to investigate variations in UGT1A1 polymorphisms and haplotypes among African-American and Caucasian women and to assess whether variants other than UGT1A1*28 are associated with total serum bilirubin levels. The (TA)(n) repeats and 14 single nucleotide polymorphisms (SNPs) in the UGT1A1 gene were genotyped in 335 African Americans and 181 Caucasians. Total serum bilirubin levels were available in a subset of 125 women. Allele frequencies of all SNPs and (TA)(n) repeats were significantly different between African Americans and Caucasians. In Caucasians, three common haplotypes accounted for 71.8% of chromosomes, whereas five common haplotypes accounted for only 46.6% of chromosomes in African Americans. Mean total serum bilirubin levels were significantly lower (p = 0.005) in African Americans (0.36 mg/dl) than in Caucasians (0.44 mg/dl). The (TA)(n) repeats explained a significant amount of variation in total bilirubin levels (R(2) = 0.27, p < 0.0001), whereas other SNPs were less correlative. Thus, significant variations in UGT1A1 haplotype structure exist between African Americans and Caucasians in this relatively large cohort of women. The correlation of UGT1A1 with total bilirubin levels was mainly due to (TA)(n) repeats in Caucasians but a clear correlation was not observed in African Americans because of the high diversity of haplotypes and the small sample size. These data have implications for the design of epidemiologic studies of cancer susceptibility and pharmacogenetic studies for adverse drug reactions in populations of African ancestry.

    View details for DOI 10.1124/dmd.106.014183

    View details for Web of Science ID 000248200000003

    View details for PubMedID 17478602

  • Medical radiation exposure and breast cancer risk: Findings from the Breast Cancer Family Registry INTERNATIONAL JOURNAL OF CANCER John, E. M., Phipps, A. I., Knight, J. A., Milne, R. L., Dite, G. S., Hopper, J. L., Andrulis, I. L., Southey, M., Giles, G. G., West, D. W., Whittemore, A. S. 2007; 121 (2): 386-394

    Abstract

    Moderate to high-dose radiotherapy is known to increase the risk of breast cancer. Uncertainties remain about the effects of low-dose chest X-rays, particularly in individuals at increased genetic risk. We analyzed case-control data from the Breast Cancer Family Registry. Self-reported data on therapeutic and diagnostic radiation exposures to the chest were available for 2,254 breast cancer cases and 3,431 controls (1,556 unaffected sisters and 1,875 unrelated population controls). We used unconditional logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with radiation exposure, after adjusting for age, study center, country of birth, and education. Increased risks for breast cancer were found for women who had radiotherapy for a previous cancer (OR=3.55, CI=1.47-8.54) and diagnostic chest X-rays for tuberculosis (OR=2.49, CI=1.82-3.40) or pneumonia (OR=2.19, CI=1.38-3.47). Risks were highest for women with a large number of exposures at a young age or exposed in earlier calendar years. There was no evidence of increased risk associated with other diagnostic chest X-rays (not including tuberculosis or pneumonia), both in women with and without indicators of increased genetic risk (i.e., diagnosed at age <40 years or family history of breast cancer). Given the widespread and increasing use of medical diagnostic radiation, continued surveillance of breast cancer risk is warranted, particularly in women at specific genetic risk, such as those carrying mutations in BRCA1 or BRCA2.

    View details for DOI 10.1002/ijc.22668

    View details for Web of Science ID 000247155000021

    View details for PubMedID 17372900

  • Compelling evidence for a prostate cancer gene at 22q12.3 by the International Consortium for Prostate Cancer Genetics HUMAN MOLECULAR GENETICS Camp, N. J., Cannon-Albright, L. A., Farnham, J. M., Baffoe-Bonnie, A. B., George, A., Powell, I., Bailey-Wilson, J. E., Carpten, J. D., Giles, G. G., Hopper, J. L., Severi, G., English, D. R., Foulkes, W. D., Maehle, L., Moller, P., Eeles, R., Easton, D., Badzioch, M. D., Whittemore, A. S., Oakley-Girvan, I., Hsieh, C., Dimitrov, L., Xu, J., Stanford, J. L., Johanneson, B., Deutsch, K., McIntosh, L., Ostrander, E. A., Wiley, K. E., Isaacs, S. D., Walsh, P. C., Thibodeau, S. N., McDonnell, S. K., Hebbring, S., Schaid, D. J., Lange, E. M., Cooney, K. A., Tammela, T. L., Schleutker, J., Paiss, T., Maier, C., Gronberg, H., Wiklund, F., Emanuelsson, M., Isaacs, W. B. 2007; 16 (11): 1271-1278

    Abstract

    Previously, an analysis of 14 extended, high-risk Utah pedigrees localized in the chromosome 22q linkage region to 3.2 Mb at 22q12.3-13.1 (flanked on each side by three recombinants) contained 31 annotated genes. In this large, multi-centered, collaborative study, we performed statistical recombinant mapping in 54 pedigrees selected to be informative for recombinant mapping from nine member groups of the International Consortium for Prostate Cancer Genetics (ICPCG). These 54 pedigrees included the 14 extended pedigrees from Utah and 40 pedigrees from eight other ICPCG member groups. The additional 40 pedigrees were selected from a total pool of 1213 such that each pedigree was required to contain both at least four prostate cancer (PRCA) cases and exhibit evidence for linkage to the chromosome 22q region. The recombinant events in these 40 independent pedigrees confirmed the previously proposed region. Further, when all 54 pedigrees were considered, the three-recombinant consensus region was narrowed down by more than a megabase to 2.2 Mb at chromosome 22q12.3 flanked by D22S281 and D22S683. This narrower region eliminated 20 annotated genes from that previously proposed, leaving only 11 genes. This region at 22q12.3 is the most consistently identified and smallest linkage region for PRCA. This collaborative study by the ICPCG illustrates the value of consortium efforts and the continued utility of linkage analysis using informative pedigrees to localize genes for complex diseases.

    View details for DOI 10.1093/hmg/ddm075

    View details for Web of Science ID 000248053300001

    View details for PubMedID 17478474

  • Multiple regions within 8q24 independently affect risk for prostate cancer NATURE GENETICS Haiman, C. A., Patterson, N., Freedman, M. L., Myers, S. R., Pike, M. C., Waliszewska, A., Neubauer, J., Tandon, A., Schirmer, C., McDonald, G. J., Greenway, S. C., Stram, D. O., Le Marchand, L., Kolonel, L. N., Frasco, M., Wong, D., Pooler, L. C., Ardlie, K., Oakley-Girvan, I., Whittemore, A. S., Cooney, K. A., John, E. M., Ingles, S. A., Altshuler, D., Henderson, B. E., Reich, D. 2007; 39 (5): 638-644

    Abstract

    After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.

    View details for DOI 10.1038/ng2015

    View details for Web of Science ID 000245971300019

    View details for PubMedID 17401364

  • Screening for the BRCA1-ins6kbEx13 mutation: potential for misdiagnosis. Mutation in brief #964. Online. Human mutation Ramus, S. J., Harrington, P. A., Pye, C., Peock, S., Cook, M. R., Cox, M. J., Jacobs, I. J., DiCioccio, R. A., Whittemore, A. S., Piver, M. S., EMBRACE, Easton, D. F., Ponder, B. A., Pharoah, P. D., Gayther, S. A. 2007; 28 (5): 525-526

    Abstract

    Misdiagnosis of a germline mutation associated with an inherited disease syndrome can have serious implications for the clinical management of patients. A false negative diagnosis (mutation missed by genetic screening) limits decision making about intervention strategies within families. More serious is the consequence of a false positive diagnosis (genetic test suggesting a mutation is present when it is not). This could lead to an individual, falsely diagnosed as a mutation carrier, undergoing unnecessary clinical intervention, possibly involving risk-reducing surgery. As part of screening 283 ovarian cancer families for BRCA1 mutations, we used two different methods (mutation specific PCR and multiplex ligation-dependent probe amplification) to screen for a known rearrangement mutation L78833.1:g.44369_50449dup (ins6kbEx13). We found false positive and false negative results in several families. We then tested 61 known carriers or non-carriers from an epidemiological study of BRCA1 and BRCA2 mutation carriers (the EMBRACE study). These data highlight the need for caution when interpreting analyses of the ins6kbEx13 mutation and similar mutations, where characterising the exact sequence alteration for a deleterious mutation is not a part of the routine genetic test.

    View details for PubMedID 17397054

  • Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer CANCER RESEARCH Gayther, S. A., Song, H., Ramus, S. J., Kjaer, S. K., Whittemore, A. S., Quaye, L., Tyrer, J., Shadforth, D., Hogdall, E., Hogdall, C., Blaeker, J., DiCioccio, R., McGuire, V., Webb, P. M., Beesley, J., Green, A. C., Whiteman, D. C., Goodman, M. T., Lurie, G., Carney, M. E., Modugno, F., Ness, R. B., Edwards, R. P., Moysich, K. B., Goode, E. L., Couch, F. J., Cunningham, J. M., Sellers, T. A., Wu, A. H., Pike, M. C., Iversen, E. S., Marks, J. R., Garcia-Closas, M., Brinton, L., Lissowska, J., Peplonska, B., Easton, D. F., Jacobs, I., Ponder, B. A., Schildkraut, J., Pearce, C. L., Chenevix-Trench, G., Berchuck, A., Pharoah, P. D. 2007; 67 (7): 3027-3035

    Abstract

    High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)-tagging approach to evaluate common variants in 13 genes involved in cell cycle control-CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D-and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark ( approximately 1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States ( approximately 2,000 cases and approximately 3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85-0.98) for rs3731257; and OR, 0.93 (0.87-0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies.

    View details for DOI 10.1158/0008-5472.CAN-06-3261

    View details for Web of Science ID 000245622900019

    View details for PubMedID 17409409

  • Tagging Single Nucleotide Polymorphisms in the BRIP1 Gene and Susceptibility to Breast and Ovarian Cancer PLOS ONE Song, H., Ramus, S. J., Kjaer, S. K., Hogdall, E., DiCioccio, R. A., Whittemore, A. S., McGuire, V., Hogdall, C., Jacobs, I. J., Easton, D. F., Ponder, B. A., Dunning, A. M., Gayther, S. A., Pharoah, P. D. 2007; 2 (3)

    Abstract

    BRIP1 interacts with BRCA1 and functions in regulating DNA double strand break repair pathways. Germline BRIP1 mutations are associated with breast cancer and Fanconi anemia. Thus, common variants in the BRIP1 are candidates for breast and ovarian cancer susceptibility.We used a SNP tagging approach to evaluate the association between common variants (minor allele frequency>or=0.05) in BRIP1 and the risks of breast cancer and invasive ovarian cancer. 12 tagging SNPs (tSNPs) in the gene were identified and genotyped in up to 2,270 breast cancer cases and 2,280 controls from the UK and up to 1,513 invasive ovarian cancer cases and 2,515 controls from the UK, Denmark and USA. Genotype frequencies in cases and controls were compared using logistic regression.Two tSNPs showed a marginal significant association with ovarian cancer: Carriers of the minor allele of rs2191249 were at reduced risk compared with the common homozygotes (Odds Ratio (OR) = 0.90 (95% CI, 0.82-1.0), P-trend = 0.045) and the minor allele of rs4988344 was associated with increased risk (OR = 1.15 (95%CI, 1.02-1.30), P-trend = 0.02). When the analyses were restricted to serous ovarian cancers, these effects became slightly stronger. These results were not significant at the 5% level after adjusting for multiple testing. None of the tSNPs was associated with breast cancer.It is unlikely that common variants in BRIP1 contribute significantly to breast cancer susceptibility. The possible association of rs2191249 and rs4988344 with ovarian cancer risks warrant confirmation in independent case-control studies.

    View details for DOI 10.1371/journal.pone.0000268

    View details for Web of Science ID 000207444700003

    View details for PubMedID 17342202

  • BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays AMERICAN JOURNAL OF SURGICAL PATHOLOGY Bane, A. L., Beck, J. C., Bleiweiss, I., Buys, S. S., Catalano, E., Daly, M. B., Giles, G., Godwin, A. K., Hibshoosh, H., Hopper, J. L., John, E. M., Layfield, L., Longacre, T., Miron, A., Senie, R., Southey, M. C., West, D. W., Whittemore, A. S., Wu, H., Andrulis, I. L., O'Malley, F. P. 2007; 31 (1): 121-128

    Abstract

    A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.

    View details for Web of Science ID 000243236000015

    View details for PubMedID 17197928

  • Assessing environmental modifiers of disease risk associated with rare mutations HUMAN HEREDITY Whittemore, A. S. 2007; 63 (2): 134-143

    Abstract

    As disease-predisposing mutations are increasingly identified, there is growing need to assess the effects of lifestyle and environmental factors on disease risks in mutation carriers. Such assessment is difficult when the mutations are rare and evaluating them in large population samples is costly.This paper describes four study designs for evaluating the effects of environmental exposures in carriers of rare disease-predisposing mutations.The strengths and weaknesses of the designs are assessed, and strategies for analyzing the data obtained from such designs are considered.When exposure effects in noncarriers are well-established and exposure is independent of carrier status in the population of disease-free controls, the case-only design provides a feasible and efficient method for inferring effects in carriers. When exposure effects in noncarriers are not well established, the most feasible design options are those that compare exposures in carrier cases to either untyped controls or to carrier controls. These two designs have complementary strengths and weaknesses; thus inferences are stronger when measures of association estimated using the two designs are consistent.

    View details for DOI 10.1159/000099185

    View details for Web of Science ID 000244256500008

    View details for PubMedID 17283442

  • Imputation of missing ages in pedigree data HUMAN HEREDITY Balise, R. R., Chen, Y., Dite, G., Felberg, A., Sun, L., Ziogas, A., Whittemore, A. S. 2007; 63 (3-4): 168-174

    Abstract

    In human pedigree data age at disease occurrence frequently is missing and is imputed using various methods. However, little is known about the performance of these methods when applied to families. In particular, there is little information about the level of agreement between imputed and actual values of temporal data and their effects on inferences.We performed two evaluations of five imputation methods used to generate complete data for repositories to be shared by many investigators. Two of the methods are mean substitution methods, two are regression methods and one is a multiple imputation method based on one of the regression methods. To evaluate the methods, we randomly deleted the years of disease diagnosis of some men in a sample of pedigrees ascertained as part of a prostate cancer study. In the first evaluation, we used the five methods to impute the missing diagnosis years and evaluated agreement between imputed and actual values. In the second evaluation, we compared agreement between regression coefficients estimated using imputed diagnosis years with those estimated using the actual years.For both evaluations, we found optimal or near-optimal performance from a regression method that imputes a man's diagnosis year based on the year of birth and year of last observation of all affected men with complete data. The multiple imputation analogue of this method also performed well.

    View details for DOI 10.1159/000099829

    View details for Web of Science ID 000244952500003

    View details for PubMedID 17310126

  • Sex steroid hormones in young manhood and the risk of subsequent prostate cancer: a longitudinal study in African-Americans and Caucasians (United States) CANCER CAUSES & CONTROL Tsai, C. J., Cohn, B. A., Cirillo, P. M., Feldman, D., Stanczyk, F. Z., Whittemore, A. S. 2006; 17 (10): 1237-1244

    Abstract

    To investigate the relation of sex hormone levels in young adults to subsequent prostate cancer risk.From 1959 to 1967, the Child Health and Development Studies collected sera from 10,442 men (median age: 34 years) and followed them for a median of 32 years. In this analysis, we selected 119 African-Americans and 206 Caucasians diagnosed with prostate cancer during the follow-up period. Two prostate cancer-free men were chosen to match each prostate cancer case on race and birth year. We compared the levels of testosterone, estradiol, and sex hormone-binding globulin in cases to those of their matched controls using conditional logistic regression.There was no significant association between absolute levels of sex hormones in youth and prostate cancer risk in either race. However, among Caucasians, but not African-Americans, prostate cancer risk was positively associated with the ratio of total testosterone to total estradiol (odds ratio relating the fourth to the first quartile: 3.01; 95% confidence interval: 1.42-6.39).The association between testosterone to estradiol ratio and prostate cancer risk in young Caucasians is consistent with similar findings in older Caucasians. The absence of this association in African-Americans needs confirmation in other data involving larger numbers of African-Americans.

    View details for DOI 10.1007/s10552-006-0052-4

    View details for Web of Science ID 000242145700003

    View details for PubMedID 17111254

  • Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics HUMAN GENETICS Schaid, D. J. 2006; 120 (4): 471-485

    Abstract

    While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives.

    View details for DOI 10.1007/s00439-006-0219-9

    View details for Web of Science ID 000241791900003

    View details for PubMedID 16932970

  • Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T > G and c.1066-6T > G (IVS10-6T > G) from the breast cancer family registry HUMAN MUTATION Bernstein, J. L., Teraoka, S., Southey, M. C., Jenkins, M. A., Andrulis, I. L., Knight, J. A., John, E. M., Lapinski, R., Wolitzer, A. L., Whittemore, A. S., West, D., Seminara, D., Olson, E. R., Spurdle, A. B., Chenevix-Trench, G., Giles, G. G., Hopper, J. L., Concannon, P. 2006; 27 (11): 1122-1128

    Abstract

    The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.

    View details for DOI 10.1002/humu.20415

    View details for Web of Science ID 000241529500007

    View details for PubMedID 16958054

  • Common variants in mismatch repair genes and risk of invasive ovarian cancer CARCINOGENESIS Song, H., Ramus, S. J., Quaye, L., DiCioccio, R. A., Tyrer, J., Lomas, E., Shadforth, D., Hogdall, E., Hogdall, C., McGuire, V., Whittemore, A. S., Easton, D. F., Ponder, B. A., Kjaer, S. K., Pharoah, P. D., Gayther, S. A. 2006; 27 (11): 2235-2242

    Abstract

    Mismatch repair (MMR) is important for repairing of nucleotide mismatches during DNA replication. Germline mutations in MMR genes are associated with hereditary non-polyposis colorectal cancer (HNPCC). Ovarian cancer occurs as part of the HNPCC phenotype, and so common variants in MMR genes are candidates for ovarian cancer susceptibility. We performed a large multicentre case-control study to investigate associations of common variations in MMR genes and ovarian cancer using a single nucleotide polymorphism (SNP) tagging approach. A total of 2570 controls and 1531 cases from three separate studies were genotyped for 44 tagging SNPs (stSNP) in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2). Genotype frequencies were marginally different between cases and controls for PMS2 rs7797466 (P(2df) = 0.046) with a 1.17-fold (95% CI 1.03-1.33) increase in risk for each 'a' allele carried (P-trend = 0.013). Haplotype analysis of PMS2 also showed significant differences in frequencies between cases and controls (P(7df) = 0.005), with one haplotype accounting for most of the effect. There was also marginal evidence for a recessive protective effect with common homozygote as the baseline comparator for two SNPs--MSH6 rs3136245 (OR 0.67; 95% CI 0.46-0.98) and MSH3 rs6151662 (OR 0.28; 95% CI 0.08-0.91)--but the comparisons of genotype frequencies for these variants were not significant (P = 0.10 and 0.054). In conclusion, it is unlikely that common variants in MLH1, MLH3, PMS1, MSH2, MSH3 and MSH6 contribute significantly to ovarian cancer susceptibility. The observed association of PMS2 rs7797466 with ovarian cancer warrants confirmation in an independent study.

    View details for DOI 10.1093/carcin/bg1089

    View details for Web of Science ID 000241629700011

    View details for PubMedID 16774946

  • Common variants in RB1 gene and risk of invasive ovarian cancer CANCER RESEARCH Song, H., Ramus, S. J., Shadforth, D., Quaye, L., Kjaer, S. K., DiCioccio, R. A., Dunning, A. M., Hogdall, E., Hogdall, C., Whittemore, A. S., McGuire, V., Lesueur, F., Easton, D. F., Jacobs, I. J., Ponder, B. A., Gayther, S. A., Pharoah, P. D. 2006; 66 (20): 10220-10226

    Abstract

    Somatic alteration of the RB1 gene is common in several types of cancer, and germ-line variants are implicated in others. We have used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between common variants (SNP) in RB1 and risks of invasive ovarian cancer. We genotyped 11 tagging SNPs in three ovarian case-control studies from the United Kingdom, United States, and Denmark, comprising >1500 cases and 4,800 controls. Two SNPs showed significant association with ovarian cancer risk: carriers of the minor allele of rs2854344 were at reduced risk compared with the common homozygotes [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.61-0.89; P = 0.0009 dominant model]. Similarly, the minor allele of rs4151620 was found to be associated with reduced risk (rare versus common homozygote; OR, 0.19; 95% CI, 0.07-0.53; P = 0.00005 recessive model). After adjusting for multiple testing, the most significant association (rs4151620) was P = 0.001. A global test comparing common haplotype frequencies in cases and controls was of borderline significance (P(8df) = 0.04). There are no common coding SNPs in the RB1 gene. However, intron 17 of RB1 contains the open reading frame for the P2RY5 gene, and rs4151620 is perfectly correlated with rs2227311, which is located in the 5'-untranslated region of P2RY5 and is predicted to affect P2RY5 transcription. rs2854344 has been reported previously to be associated with breast cancer risk. The possible associations of rs2854344 and rs4151620 with ovarian cancer risk warrant confirmation in independent case-control studies before studies on their biological mode of action.

    View details for DOI 10.1158/0008-5472.CAN-06-2222

    View details for Web of Science ID 000241392700053

    View details for PubMedID 17047088

  • BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50 CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Haile, R. W., Thomas, D. C., McGuire, V., Felberg, A., John, E. M., Milne, R. L., Hopper, J. L., Jenkins, M. A., Levine, A. J., Daly, M. M., Buys, S. S., Senie, R. T., Andrulis, I. L., Knight, J. A., Godwin, A. K., Southey, M., McCredie, M. R., Giles, G. G., Andrews, L., Tucker, K., Miron, A., Apicella, C., Tesoriero, A., Bane, A., Pike, M. C., Whittemore, A. S. 2006; 15 (10): 1863-1870

    Abstract

    Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice.We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years.For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P(trend) = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (OR(trend) per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later.We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue.

    View details for DOI 10.1158/1055-9965.EPI-06-0258

    View details for Web of Science ID 000241616800019

    View details for PubMedID 17021353

  • Getting more from digital SNP data STATISTICS IN MEDICINE El Karoui, N., Zhou, W., Whittemore, A. S. 2006; 25 (18): 3124-3133

    Abstract

    The digital SNP method has been proposed for identifying loss of heterozygosity (LOH) in tumour tissue and correlating it with patients' clinical characteristics. The method evaluates a tumour's allelic count at a single nucleotide polymorphism (SNP) for which the patient's normal tissue is heterozygous. The count is used to classify the tumour as positive or negative for LOH, using the sequential probability ratio test (SPRT). However, the SPRT was not developed for analysing digital SNP experiments. When applied to digital SNP data, the SPRT has several anomalies that can result in both loss of data and tumour misclassification. The anomalies are caused by discrepancies between the design of digital SNP experiments and the setting for which SPRT was developed. We propose an alternative classification scheme based on the false discovery rate, and show that it outperforms the SPRT when applied to Digital SNP data.

    View details for DOI 10.1002/sim.2379

    View details for Web of Science ID 000240568100005

    View details for PubMedID 16397858

  • Predicting and preventing hereditary colorectal cancer JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ford, J. M., Whittemore, A. S. 2006; 296 (12): 1521-1523

    View details for Web of Science ID 000240770000029

    View details for PubMedID 17003401

  • Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Freedman, M. L., Haiman, C. A., Patterson, N., McDonald, G. J., Tandon, A., Waliszewska, A., Penney, K., Steen, R. G., Ardlie, K., John, E. M., Clakley-Girvan, I., Whitternore, A. S., Cooney, K. A., Ingles, S. A., Altshuler, D., Henderson, B. E., Reich, D. 2006; 103 (38): 14068-14073

    Abstract

    A whole-genome admixture scan in 1,597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer [logarithm of odds (LOD) = 7.1]. The increased risk because of inheriting African ancestry is greater in men diagnosed before 72 years of age (P < 0.00032) and may contribute to the epidemiological observation that the higher risk for prostate cancer in African Americans is greatest in younger men (and attenuates with older age). The same region was recently identified through linkage analysis of prostate cancer, followed by fine-mapping. We strongly replicated this association (P < 4.2 x 10(-9)) but find that the previously described alleles do not explain more than a fraction of the admixture signal. Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it.

    View details for DOI 10.1073/pnas.0605832103

    View details for Web of Science ID 000240746600031

    View details for PubMedID 16945910

  • Patterns and progress in ovarian cancer over 14 years OBSTETRICS AND GYNECOLOGY Chan, J. K., Cheung, M. K., Husain, A., Teng, N. N., West, D., Whittemore, A. S., Berek, J. S., Osann, K. 2006; 108 (3): 521-528

    Abstract

    To estimate the change in survival rates of women with ovarian cancer during the past 14 years.Women diagnosed with epithelial, germ cell, sarcomas, and sex-cord stromal ovarian tumors were identified from the Surveillance Epidemiology and End Results Database. Demographic and clinicopathologic factors, and survival information were extracted and tested using chi 2 and Kaplan-Meier and Cox regression analyses.A total of 30,246 women were diagnosed with ovarian cancer, including 26,753 non-clear cell epithelial, 1,411 clear cell, 818 sarcoma, 778 germ cell, and 486 sex-cord stromal tumors. The 5-year disease-specific survival rate across 1988-1992 and 1993-1997 improved from 45.4% to 48.6% (P < .001). The corresponding estimates show increases for non-clear cell epithelial carcinoma from 42.5% to 45.8% (P < .001), and for sarcomas from 33.5% to 38.8% (P = .07). However, improvements were not observed in those with clear cell, 64.3% to 63.9% (P = .82), and sex-cord stromal, 89.7% to 85.7% (P = .18), tumors of the ovary. In multivariable analyses, younger age, early stage, favorable histologic cell types, low-grade tumors, standard surgery, and recent time interval from 1993-1997 were independent prognostic factors for improved survival.In this large population-based study, there has been some improvement in the overall survival of women with ovarian cancers during a 14-year period. However, new treatment strategies are warranted for those with epithelial cancer and sarcomas of the ovary, given their overall poor prognosis. These results from our updated analyses might help to counsel women diagnosed with ovarian cancers.

    View details for Web of Science ID 000246769000008

    View details for PubMedID 16946210

  • Breast cancer followed by corpus cancer: Is there a higher risk for aggressive histologic subtypes? GYNECOLOGIC ONCOLOGY Chan, J. K., Manuel, M. R., Cheung, M. K., Osann, K., Husain, A., Teng, N. N., Rao, A., Carlson, R. W., Whittemore, A. S. 2006; 102 (3): 508-512

    Abstract

    To analyze corpus cancer patients with a breast cancer history for risk of developing aggressive uterine histologic types.Corpus cancer patients with a history of breast cancer were identified from the Surveillance Epidemiology and End Results database from 1988 to 2001. Demographics, clinico-pathologic, and survival data were analyzed using Kaplan-Meier and logistic regression analyses.Of 52,109 women diagnosed with corpus cancer, 1922 had a history of breast cancer. Women with a history of breast cancer had a significantly higher proportion of uterine papillary serous carcinomas (UPSC) and sarcomas compared to those without a breast cancer history (9.4% vs. 6.3% for UPSC and 10.3% vs. 8.4% for sarcoma; P < 0.001). Patients with endometrioid or sarcoma of the uterus after breast cancer had significantly worse 5-year survivals than patients without a breast cancer history (84.4% vs. 90.5%; P < 0.001 and 49.0% vs. 63.6%, P < 0.001, respectively). Older age, advanced stage, lack of surgery and radiation treatment, poor histologic types, and history of breast cancer were independent prognostic factors for poorer survival.In this study, the proportional incidence of UPSC and sarcoma was significantly higher in women with a breast cancer history. These findings highlight the association of breast cancer and high-risk corpus cancer subtypes.

    View details for DOI 10.1016/j.ygyno.2006.01.014

    View details for Web of Science ID 000240871000017

    View details for PubMedID 16483640

  • No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages < 50 years CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION McGuire, V., John, E. M., Felberg, A., Haile, R. W., Boyd, N. F., Thomas, D. C., Jenkins, M. A., Milne, R. L., Daly, M. B., Ward, J., Terry, M. B., Andrulis, I. L., Knight, J. A., Godwin, A. K., Giles, G. G., Southey, M., West, D. W., Hopper, J. L., Whittemore, A. S. 2006; 15 (8): 1565-1567
  • Nonparametric linkage analysis using person-specific covariates GENETIC EPIDEMIOLOGY Whittemore, A. S., Halpern, J. 2006; 30 (5): 369-379

    Abstract

    Linkage analysis provides an important tool for mapping genes for complex disease. However its usefulness has been limited by inadequate marker density, inadequate sample sizes and the possibility that different genes account for different subtypes of the disease (phenotypic heterogeneity). The first two limitations can be addressed by high-density single nucleotide polymorphism (SNP) genotyping and the pooling of large sets of multiple-case families. Phenotypic heterogeneity can be addressed by analyses that weigh the contributions of affected family members according to characteristics of their disease phenotypes. Here we introduce a method for including such person-specific weights in nonparametric linkage analysis. We show with simulations that such weighting can provide stronger linkage signals when a causal polymorphism affects some manifestations of the disease more than others. We applied the method to prostate cancer linkage data in a region on chromosome 19p, and obtained higher lod scores by assigning weights of one to men with early-onset aggressive cancers, weights of zero to those with late-onset nonaggressive cancers, and intermediate weights to all other affected men. We have developed a modified version of GENEHUNTER that allows inclusion of person-specific weights in the nonparametric analyses. This program is freely available at http://med.stanford.edu/epidemiology/statisticalSoftware/weightedKAC.

    View details for DOI 10.1002/gepi.20153

    View details for Web of Science ID 000238690600001

    View details for PubMedID 16671107

  • Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Lee, J. S., John, E. M., McGuire, V., Felberg, A., Ostrow, K. L., DiCioccio, R. A., Li, F. P., Miron, A., West, D. W., Whittemore, A. S. 2006; 15 (2): 359-363

    Abstract

    First-degree relatives of patients with breast or ovarian cancer have increased risks for these cancers. Little is known about how their risks vary with the patient's cancer site, carrier status for predisposing genetic mutations, or age at cancer diagnosis.We evaluated breast and ovarian cancer incidence in 2,935 female first-degree relatives of non-Hispanic White female patients with incident invasive cancers of the breast (n = 669) or ovary (n = 339) who were recruited from a population-based cancer registry in northern California. Breast cancer patients were tested for BRCA1 and BRCA2 mutations. Ovarian cancer patients were tested for BRCA1 mutations. We estimated standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) for breast and ovarian cancer among the relatives according to the patient's mutation status, cancer site, and age at cancer diagnosis.In families of patients who were negative or untested for BRCA1 or BRCA2 mutations, risks were elevated only for the patient's cancer site. The breast cancer SIR was 1.5 (95% CI, 1.2-1.8) for relatives of breast cancer patients, compared with 1.1 (95% CI, 0.8-1.6) for relatives of ovarian cancer patients (P = 0.12 for difference by patient's cancer site). The ovarian cancer SIR was 0.9 (95% CI, 0.5-1.4) for relatives of breast cancer patients, compared with 1.9 (95% CI, 1.0-4.0) for relatives of ovarian cancer patients (P = 0.04 for difference by site). In families of BRCA1-positive patients, relatives' risks also correlated with the patient's cancer site. The breast cancer SIR was 10.6 (95% CI, 5.2-21.6) for relatives of breast cancer patients, compared with 3.3 (95% CI, 1.4-7.3) for relatives of ovarian cancer patients (two-sided P = 0.02 for difference by site). The ovarian cancer SIR was 7.9 (95% CI, 1.2-53.0) for relatives of breast cancer patients, compared with 11.3 (3.6-35.9) for relatives of ovarian cancer patients (two-sided P = 0.37 for difference by site). Relatives' risks were independent of patients' ages at diagnosis, with one exception: In families ascertained through a breast cancer patient without BRCA mutations, breast cancer risks were higher if the patient had been diagnosed before age 40 years.In families of patients with and without BRCA1 mutations, breast and ovarian cancer risks correlate with the patient's cancer site. Moreover, in families of breast cancer patients without BRCA mutations, breast cancer risk depends on the patient's age at diagnosis. These patterns support the presence of genes that modify risk specific to cancer site, in both carriers and noncarriers of BRCA1 and BRCA2 mutations.

    View details for DOI 10.1158/1055-9965.EPI-05-0687

    View details for Web of Science ID 000235587200026

    View details for PubMedID 16492929

  • Improved survival of Asians with corpus cancer compared with whites - An analysis of underlying factors OBSTETRICS AND GYNECOLOGY Zhang, M. M., Cheung, M. K., Osann, K., Lee, M. M., Gomez, S. S., Whittemore, A. S., Husain, A., Teng, N. N., Chan, J. K. 2006; 107 (2): 329-335

    Abstract

    To compare the clinicopathologic prognosticators and survival of Asians and whites with corpus cancer.Demographic, clinicopathologic, and survival data were obtained from the 1992-2001 Surveillance, Epidemiology, and End Results Program. Statistical analyses were performed by Kaplan-Meier methods and Cox proportional hazards model.A total of 2,144 Asians and 32,999 whites with corpus cancer were identified. The age-adjusted incidence of uterine cancer in Asians compared with whites was 16.8 compared with 26.1 per 100,000. Asians presented at a younger age (mean 58.4 years compared with 65.1; P < .01) and with more advanced stage disease than whites (21.5% compared with 15.4%; P < .01). The 5-year survival rate for Asians was 79.4% compared with 75.2% for whites (P < .01). Asians with stage I-II and III-IV cancers had 5-year survival rates of 89.3% and 41.2% compared with 82.3% and 34.0% for the whites, respectively (P < .01, early stage; P < .01, advanced stage). The survival advantage of Asians persists in endometrioid (P < .01) and uterine papillary serous carcinomas (P < .01), but not in clear cell carcinoma (P = .62) or sarcomas (P = .78). In multivariate analysis, younger age (P < .01), earlier stage (P < .01), favorable histology (P < .01), and lower grade (P < .01) remained as significant independent prognosticators for improved survival. However, race was not an important prognosticator.The overall survival advantage experienced by Asians with uterine cancer is attributable to their younger age at diagnosis. Because Asian women present at a younger age with more advanced disease, physicians should have an increased index of suspicion for malignancy in young Asian women with suspicious symptoms and consider a lower age threshold for biopsy in this group.II-2.

    View details for Web of Science ID 000241295400019

    View details for PubMedID 16449120

  • The CHEK2*1100de/C allelic variant and risk of breast cancer: Screening results from the breast cancer family registry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Bernstein, J. L., Teraoka, S. N., John, E. M., Andrulis, I. L., Knight, J. A., Lapinski, R., Olson, E. R., Wolitzer, A. L., Seminara, D., Whittemore, A. S., Concannon, P. 2006; 15 (2): 348-352

    Abstract

    CHEK2, a serine-threonine kinase, is activated in response to agents, such as ionizing radiation, which induce DNA double-strand breaks. Activation of CHEK2 can result in cell cycle checkpoint arrest or apoptosis. One specific variant, CHEK2*1100delC, has been associated with an increased risk of breast cancer. In this population-based study, we screened 2,311 female breast cancer cases and 496 general population controls enrolled in the Ontario and Northern California Breast Cancer Family Registries for this variant (all controls were Canadian). Overall, 30 cases and one control carried the 1100delC allele. In Ontario, the weighted mutation carrier frequency among cases and controls was 1.34% and 0.20%, respectively [odds ratio (OR), 6.65; 95% confidence interval (95% CI), 2.37-18.68]. In California, the weighted population mutation carrier frequency in cases was 0.40%. Across all cases, 1 of 524 non-Caucasians (0.19%) and 29 of 1,775 Caucasians (1.63%) were mutation carriers (OR, 0.12; 95% CI, 0.02-0.89). Among Caucasian cases >45 years age at diagnosis, carrier status was associated with history of benign breast disease (OR, 3.18; 95% CI, 1.30-7.80) and exposure to diagnostic ionizing radiation (excluding mammography; OR, 3.21; 95% CI, 1.13-9.14); compared with women without exposure to ionizing radiation, the association was strongest among women exposed >15 years before diagnosis (OR, 4.28; 95% CI, 1.50-12.20) and among those who received two or more chest X-rays (OR, 3.63; 95% CI, 1.25-10.52). These data supporting the biological relevance of CHEK2 in breast carcinogenesis suggest that further studies examining the joint roles of CHEK2*1100delC carrier status and radiation exposure may be warranted.

    View details for DOI 10.1158/1055-9965.EPI-05-0557

    View details for Web of Science ID 000235587200024

    View details for PubMedID 16492927

  • Short-term chloral hydrate administration and cancer in humans DRUG SAFETY Haselkorn, T., Whittemore, A. S., Udaltsova, N., Friedman, G. D. 2006; 29 (1): 67-77

    Abstract

    Chloral hydrate, used as a hypnosedative in adults and children, has been shown to be genotoxic and carcinogenic in animal studies. We investigated the potential causal association between chloral hydrate exposure and cancer risk in humans.Cancer incidence was previously determined via biennial screening analyses of the 215 most commonly used drugs between 1976 and 1998 for a cohort of 143,574 outpatients at Kaiser Permanente who had prescriptions filled between 1969 and 1973. Among users of chloral hydrate, statistically significant elevations in standardised morbidity ratios were observed during various years for cancer at five anatomical sites, including the lung, stomach, prostate, skin melanoma and mouth floor. In this analysis, these associations were investigated using: (i) a dose-response analysis among exposed subjects; and (ii) a two-stage design with exposed and non-exposed persons.There was evidence of an increasing risk of prostate cancer with increasing number of dispensings of chloral hydrate, which persisted after controlling for benign prostatic hypertrophy, vasectomy and obesity; however, the trend was not statistically significant. There was no evidence of a dose-response relationship between chloral hydrate and risk of any of the other four cancers. In the two-stage design, analyses comparing exposed and unexposed subjects showed no increased risk of cancer after controlling for confounding variables; however, the data were suggestive for prostate cancer, where the increased risk associated with chloral hydrate exposure after adjustment for confounding variables persisted. No dose-response relationship was seen for any of the other four cancer sites.To our knowledge, this is the first study to examine the relationship between chloral hydrate exposure and cancer risk in humans. There was no persuasive evidence to support a causal relationship between chloral hydrate exposure in humans and the development of cancer. However, statistical power was low for weak associations, particularly for some of the individual cancer sites. Although animal data using much higher doses of chloral hydrate have demonstrated its genotoxicity and carcinogenicity, the effects of chloral hydrate in humans are still uncertain.

    View details for Web of Science ID 000235639000005

    View details for PubMedID 16454535

  • An inverse association between ovarian cysts and breast cancer in the Breast Cancer Family Registry INTERNATIONAL JOURNAL OF CANCER Knight, J. A., John, E. M., Milne, R. L., Dite, G. S., Balbuena, R., Shi, E. J., Giles, G. G., Ziogas, A., Andrulis, I. L., Whittemore, A. S., Hopper, J. L. 2006; 118 (1): 197-202

    Abstract

    Ovarian cysts of several types are common in women of reproductive age. Their etiology is not well understood but is likely related to perturbations in the hypothalamic-pituitary-gonadal axis. The relationship of ovarian cysts to breast cancer risk is not known, although a negative association with polycystic ovarian syndrome has been reported. Incident, invasive female breast cancer cases, population-based controls and unaffected sisters of cases were studied from 3 countries participating in the Breast Cancer Family Registry: Melbourne and Sydney, Australia; the San Francisco Bay Area, USA; and Ontario, Canada. Using the same questionnaire, information was collected on self-reported history of ovarian cysts and other risk factors. Analyses were based on 3,049 cases, 2,344 population controls and 1,934 sister controls from all sites combined. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using both unconditional and conditional logistic regression using an offset term to account for sampling fractions at 2 of the sites. A significantly reduced risk of breast cancer was observed for women reporting a history of ovarian cysts (OR = 0.70, 95% CI 0.59-0.82, among all cases and all controls). This risk estimate was similar regardless of control group used, within all 3 sites and in both premenopausal and postmenopausal women (ORs ranging from 0.68-0.75, all 95% CI excluded 1.00). A self-reported history of ovarian cysts was strongly and consistently associated with a reduced risk of breast cancer. Further study of ovarian cysts may increase our understanding of hormonal and other mechanisms of breast cancer etiology.

    View details for DOI 10.1002/ijc.21298

    View details for Web of Science ID 000233376000027

    View details for PubMedID 16032703

  • Disengagement and social support moderate distress among women with a family history of breast cancer BREAST JOURNAL Turner-Cobb, J. M., Bloor, L. E., Whittemore, A. S., West, D., Spiegel, D. 2006; 12 (1): 7-15

    Abstract

    Using a cross-sectional, exploratory design, this pilot study analyzed the relationships between familial history of breast cancer and psychological distress in order to evaluate who is more distressed and to assess the possible need for intervention. Coping style, social support, and family relations were investigated as potential moderators of these relationships. Participants were 45 women with a familial history of breast cancer recruited from the Family Registry for Breast Cancer (FRBC) at the Northern California Cancer Center (NCCC). Contrary to previous reports of similar cohorts, the overall level of psychological distress in this cohort was comparable to normative samples. The number of relatives with breast cancer was related to distress as measured by the State-Trait Anxiety Inventory (STAI) scale, but there was no significant differentiation in distress associated with the number of first-degree as compared to second- and third-degree relatives with breast cancer. Having more relatives that had died from breast cancer was associated with greater distress on a number of measures. The number of first-degree relative deaths, including maternal death, was also associated with distress. Positive and network support, disengagement coping responses, and family cohesion were each significant moderators of the impact of family history on distress. This association between distress and disengagement is similar to that found in metastatic breast cancer patients themselves, and the findings suggest a subgroup that merits and might respond to more intensive intervention to provide support and facilitate emotional expression.

    View details for Web of Science ID 000235532900003

    View details for PubMedID 16409581

  • Polymorphisms in DNA repair genes and epithelial ovarian cancer risk INTERNATIONAL JOURNAL OF CANCER Auranen, A., Song, H. L., Waterfall, C., DiCioccio, R. A., Kuschel, B., Kjaer, S. K., Hogdall, E., Hogdall, C., Stratton, J., Whittemore, A. S., Easton, D. F., Ponder, B. A., Novik, K. L., Dunning, A. M., Gayther, S., Pharoah, P. D. 2005; 117 (4): 611-618

    Abstract

    DNA repair gene polymorphisms and mutations are known to influence cancer risk. We studied whether polymorphisms in DNA double strand break (DSB) repair genes are associated with epithelial ovarian cancer (EOC) risk. Up to 1,600 cases and 4,241 controls from 4 separate genetic association studies from 3 countries were genotyped for 13 single nucleotide polymorphisms (SNP) in 6 genes (BRCA1, NBS1, RAD51, RAD52, XRCC2 and XRCC3) involved in homologous recombination of DNA double strand breaks. Genotype specific risks were estimated as odds ratios (OR) by unconditional logistic regression. No association was detected between EOC risk and BRCA1 Q356R, BRCA1 P871L, RAD51 g135c, RAD51 g172t, RAD52 c2259t, NBS1 L34L, NBS1 E185Q, NBS1 A399A, NBS1 P672P, XRCC2 g4324c, XRCC2 c41657t and XRCC3 T241M. The XRCC2 R188H polymorphism was associated with a modest reduction in EOC risk: OR for heterozygotes was 0.8 (95% confidence interval [CI] = 0.7-1.0) and for rare homozygotes 0.3 (0.1-0.9). The XRCC3 a4541g polymorphism, situated in the 5'UTR, and the intronic XRCC3 a17893g polymorphism were not associated with EOC risk in general, but when the serous EOC subset only was analysed, the OR for heterozygotes for a4541g was 1.0 (0.9-1.2) and for the rare homozygotes 0.5 (0.3-0.9). For the XRCC3 a17893g polymorphism, the OR for the heterozygotes and the rare homozygotes were 0.8 (0.7-0.9) and 0.9 (0.7-1.2), respectively. In our study, some polymorphisms in XRCC2 and XRCC3 genes were associated with EOC risk. Further research on the role of these genes on epithelial ovarian cancer is warranted.

    View details for DOI 10.1002/ijc.21047

    View details for Web of Science ID 000232666500012

    View details for PubMedID 15924337

  • Incidence of small bowel cancer in the United States and worldwide: geographic, temporal, and racial differences CANCER CAUSES & CONTROL Haselkorn, T., Whittemore, A. S., Lilienfeld, D. E. 2005; 16 (7): 781-787

    Abstract

    To examine the demographic and geographic patterns of small bowel cancer incidence in the United States and worldwide.Incidence data from the Surveillance, Epidemiology, and End Results (SEER) program between 1973 to 2000 were used to analyze the four histologic types of small bowel cancer, adenocarcinomas, carcinoid tumors, lymphomas, and sarcomas. International comparisons were made using data from Cancer Incidence in Five Continents (CIVIII). Geographic correlations between small bowel and both large bowel and stomach cancer incidence, were performed.Men had higher rates than women for all types of small bowel cancer. Blacks had almost double the incidence of carcinomas and carcinoid tumors compared to whites (10.6 vs. 5.6 per million people; 9.2 vs. 5.4 per million people, respectively). Small bowel cancer incidence has risen, with the greatest increase for carcinoid tumors (21%) and black men (120%). A geographic correlation between small and large bowel cancer incidence, but not small bowel and stomach cancer, were observed.Small bowel cancer incidence in the U.S. is higher in blacks compared to whites, particularly for carcinomas and carcinoid tumors. Small bowel cancer incidence is rising, particularly in black men. The geographic correlation between large and small bowel cancer suggests shared etiologies.

    View details for DOI 10.1007/s10552-005-3635-6

    View details for Web of Science ID 000231220800002

    View details for PubMedID 16132788

  • Prostate specific antigen levels in young adulthood predict prostate cancer risk: Results from a cohort of black and white Americans JOURNAL OF UROLOGY Whittemore, A. S., Cirillo, P. M., Feldman, D., Cohn, B. A. 2005; 174 (3): 872-876

    Abstract

    Prostate specific antigen (PSA) is a serine protease produced by normal and malignant prostate epithelial cells. Serum PSA increases with age, due largely to age related increases in the prevalence of benign prostatic disease. Little is known about PSA distribution in young adulthood, when benign and malignant prostatic diseases are rare, or about how PSA within the normal range in youth relates to subsequent prostate cancer risk.We evaluated serum PSA and subsequent prostate cancer occurrence in a cohort of young black and white American men with a median age at blood draw of 34 years, who in 1959 to 1966 participated as the fathers of newborns enrolled in the Child Health and Development Study, and who were followed for several decades for prostate cancer. We examined associations between PSA in young adulthood and subsequent prostate cancer risk using a nested case-control design based on 119 black and 206 white cases with 2 control men matched to each case on race and year of birth.Prostate cancer risk increased with increasing PSA in black and white men. The OR comparing risk in the highest to lowest quartiles of PSA was 4.4 (95% CI 2.0 to 9.6) in black men and 3.5 (95% CI 2.0 to 6.1) in white men. ORs relating risk to PSA were higher when analysis was restricted to cases diagnosed before age 65 years.These findings suggest that PSA levels in young adulthood indicate increased risk of prostate cancer and, thus, they may be useful for targeting men for screening and early diagnosis.

    View details for DOI 10.1097/01.ju.0000169262.18000.8a

    View details for Web of Science ID 000231274700019

    View details for PubMedID 16093978

  • A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics AMERICAN JOURNAL OF HUMAN GENETICS Xu, J. F., Dimitrov, L., Chang, B. L., Adams, T. S., Turner, A. R., Meyers, D. A., Eeles, R. A., Easton, D. F., Foulkes, W. D., Simard, J., Giles, G. G., Hopper, J. L., Mahle, L., Moller, P., Bishop, T., Evans, C., Edwards, S., Meitz, J., Bullock, S., Hope, Q., Hsieh, C. L., Halpern, J., Balise, R. N., Oakley-Girvan, I., Whittemore, A. S., Ewing, C. M., Gielzak, M., Isaacs, S. D., Walsh, P. C., Wiley, K. E., Isaacs, W. B., Thibodeau, S. N., McDonnell, S. K., Cunningham, J. M., Zarfas, K. E., Hebbring, S., Schaid, D. J., Friedrichsen, D. M., Deutsch, K., Kolb, S., Badzioch, M., Jarvik, G. P., Janer, M., Hood, L., Ostrander, E. A., Stanford, J. L., Lange, E. M., Beebe-Dimmer, J. L., Mohai, C. E., Cooney, K. A., Ikonen, T., Baffoe-Bonnie, A., Fredriksson, H., Matikainen, M. P., Tammela, T. L., Bailey-Wilson, J., Schleutker, J., Maier, C., Herkommer, K., Hoegel, J. J., Vogel, W., Paiss, T., Wiklund, F., Emanuelsson, M., Stenman, E., Jonsson, B. A., Gronberg, H., Camp, N. J., Farnham, J., Cannon-Albright, L. A., Seminara, D. 2005; 77 (2): 219-229

    Abstract

    Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

    View details for Web of Science ID 000230387200004

    View details for PubMedID 15988677

  • Genetic association studies: Time for a new paradigm? CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Whittemore, A. S. 2005; 14 (6): 1359-1360

    View details for Web of Science ID 000229766600003

    View details for PubMedID 15941936

  • Covariate adjustment in family-based association studies GENETIC EPIDEMIOLOGY Whittemore, A. S., Halpern, J., Ahsan, H. 2005; 28 (3): 244-255

    Abstract

    Family-based tests of association between a candidate locus and a disease evaluate how often a variant allele at the locus is transmitted from parents to offspring. These tests assume that in the absence of association, an affected offspring is equally likely to have inherited either one of the two homologous alleles carried by a parent. However, transmission distortion was documented in families in which the offspring are unselected for phenotype. Moreover, if offspring genotypes are associated with a risk factor for the disease, transmission distortion to affected offspring can occur in the absence of a causal relation between gene and disease risk. We discuss the appropriateness of adjusting for established risk factors when evaluating association in family-based studies. We present methods for adjusting the transmission/disequilibrium test for risk factors when warranted, and we apply them to data on CYP19 (aromatase) genotypes in nuclear families with multiple cases of breast cancer. Simulations show that when genotypes are correlated with risk factors, the unadjusted test statistics have inflated size, while the adjusted ones do not. The covariate-adjusted tests are less powerful than the unadjusted ones, suggesting the need to check the relationship between genotypes and known risk factors to verify that adjustment is needed. The adjusted tests are most useful for data containing a large proportion of families that lack disease-discordant sibships, i.e., data for which multiple logistic regression of matched sibships would have little power. Software for performing the covariate-adjusted tests is available at http://www.stanford.edu/dept/HRP/epidemiology/COVTDT.

    View details for DOI 10.1002/gepi.20055

    View details for Web of Science ID 000227898400005

    View details for PubMedID 15593089

  • Re: Reason for late-stage breast cancer: Absence of screening or detection, or breakdown in follow-up? JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S. 2005; 97 (5): 400-400

    View details for DOI 10.1093/jnci/dji062

    View details for Web of Science ID 000227352800016

    View details for PubMedID 15741577

  • Histologic types of epithelial ovarian cancer: have they different risk factors? GYNECOLOGIC ONCOLOGY Kurian, A. W., Balise, R. R., McGuire, V., Whittemore, A. S. 2005; 96 (2): 520-530

    Abstract

    The histologic types of epithelial ovarian cancer differ in clinical behavior, descriptive epidemiology, and genetic origins. The goals of the current study were to characterize further the relation of histologic-specific ovarian cancer risks to reproductive and lifestyle attributes.The authors conducted a pooled analysis of 10 case-control studies of ovarian cancer in US White women, involving 1834 patients with invasive epithelial ovarian cancer (1067 serous, 254 mucinous, 373 endometrioid, and 140 clear cell) and 7484 control women.Risks of all four histological types were inversely associated with parity and oral contraceptive use, but the histologic types showed different associations with nonreproductive factors. Unique associations include an inverse relation of serous cancer risk to body mass index, a positive relation of mucinous cancer risk to cigarette smoking, and a weakly positive relation of endometrioid cancer risk to body mass index. Risk of all histologic types was unassociated with age at menarche, age at menopause, a history of infertility, noncontraceptive estrogen use, and alcohol consumption.The most important modifiers of ovarian cancer risk (parity and oral contraceptive use) showed similar associations across the histologies. Nevertheless, the unique associations seen for other modifiers support the conjecture that the histologic types of epithelial ovarian cancer have different etiologies, which should be addressed in future investigations of the molecular basis of ovarian cancers and their responses to therapies.

    View details for DOI 10.1016/j.gygno.2004.10.037

    View details for Web of Science ID 000226636600041

    View details for PubMedID 15661246

  • Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Milne, R. L., Knight, J. A., John, E. M., Dite, G. S., Balbuena, R., Ziogas, A., Andrulis, I. L., West, D. W., Li, F. P., Southey, M. C., Giles, G. G., McCredie, M. R., Hopper, J. L., Whittemore, A. S. 2005; 14 (2): 350-356

    Abstract

    Recent oral contraceptive use has been associated with a small increase in breast cancer risk and a substantial decrease in ovarian cancer risk. The effects on risks for women with germ line mutations in BRCA1 or BRCA2 are unclear.Subjects were population-based samples of Caucasian women that comprised 1,156 incident cases of invasive breast cancer diagnosed before age 40 (including 47 BRCA1 and 36 BRCA2 mutation carriers) and 815 controls from the San Francisco Bay area, California, Ontario, Canada, and Melbourne and Sydney, Australia. Relative risks by carrier status were estimated using unconditional logistic regression, comparing oral contraceptive use in case groups defined by mutation status with that in controls.After adjustment for potential confounders, oral contraceptive use for at least 12 months was associated with decreased breast cancer risk for BRCA1 mutation carriers [odds ratio (OR), 0.22; 95% confidence interval (CI), 0.10-0.49; P < 0.001], but not for BRCA2 mutation carriers (OR, 1.02; 95% CI, 0.34-3.09) or noncarriers (OR, 0.93; 95% CI, 0.69-1.24). First use during or before 1975 was associated with increased risk for noncarriers (OR, 1.52 per year of use before 1976; 95% CI, 1.22-1.91; P < 0.001).There was no evidence that use of current low-dose oral contraceptive formulations increases risk of early-onset breast cancer for mutation carriers, and there may be a reduced risk for BRCA1 mutation carriers. Because current formulations of oral contraceptives may reduce, or at least not exacerbate, ovarian cancer risk for mutation carriers, they should not be contraindicated for a woman with a germ line mutation in BRCA1 or BRCA2.

    View details for Web of Science ID 000227113800010

    View details for PubMedID 15734957

  • Response to C. Bosetti et al. (Trends in colorectal cancer mortality in Japan, 1970-2000) INTERNATIONAL JOURNAL OF CANCER Yin, H. Y., Whittemore, A. S., Shibata, A. 2005; 113 (2): 342-342

    View details for DOI 10.1002/ijc.20554

    View details for Web of Science ID 000225717500025

    View details for PubMedID 15476198

  • Variants in estrogen-biosynthesis genes CYP17 and CYP19 and breast cancer risk: a family-based genetic association study BREAST CANCER RESEARCH Ahsan, H., Whittemore, A. S., Chen, Y., Senie, R. T., Hamilton, S. P., Wang, Q., Gurvich, I., Santella, R. M. 2005; 7 (1): R71-R81

    Abstract

    Case-control studies have reported inconsistent results concerning breast cancer risk and polymorphisms in genes that control endogenous estrogen biosynthesis. We report findings from the first family-based association study examining associations between female breast cancer risk and polymorphisms in two key estrogen-biosynthesis genes CYP17 (T-->C promoter polymorphism) and CYP19 (TTTA repeat polymorphism).We conducted the study among 278 nuclear families containing one or more daughters with breast cancer, with a total of 1123 family members (702 with available constitutional DNA and questionnaire data and 421 without them). These nuclear families were selected from breast cancer families participating in the Metropolitan New York Registry, one of the six centers of the National Cancer Institute's Breast Cancer Family Registry. We used likelihood-based statistical methods to examine allelic associations.We found the CYP19 allele with 11 TTTA repeats to be associated with breast cancer risk in these families. We also found that maternal (but not paternal) carrier status of CYP19 alleles with 11 repeats tended to be associated with breast cancer risk in daughters (independently of the daughters' own genotype), suggesting a possible in utero effect of CYP19. We found no association of a woman's breast cancer risk either with her own or with her mother's CYP17 genotype.This family-based study indicates that a woman's personal and maternal carrier status of CYP19 11 TTTA repeat allele might be related to increased breast cancer risk. However, because this is the first study to report an association between CYP19 11 TTTA repeat allele and breast cancer, and because multiple comparisons have been made, the associations should be interpreted with caution and need confirmation in future family-based studies.

    View details for DOI 10.1186/bcr951

    View details for Web of Science ID 000226247000019

    View details for PubMedID 15642171

  • Breast cancer risks for BRCA1/2 carriers SCIENCE Easton, D. F., Hopper, J. L., Thomas, D. C., Antoniou, A., Pharoah, P. D., Whittemore, A. S., Haile, R. W. 2004; 306 (5705): 2187-2188

    View details for Web of Science ID 000225950000015

    View details for PubMedID 15622557

  • Prevalence of BRCA1 mutation carriers among US non-Hispanic Whites CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Whittemore, A. S., Gong, G., John, E. M., McGuire, V., Li, F. P., Ostrow, K. L., DiCioccio, R., Felberg, A., West, D. W. 2004; 13 (12): 2078-2083

    Abstract

    Data from several countries indicate that 1% to 2% of Ashkenazi Jews carry a pathogenic ancestral mutation of the tumor suppressor gene BRCA1. However, the prevalence of BRCA1 mutations among non-Ashkenazi Whites is uncertain. We estimated mutation carrier prevalence in U.S. non-Hispanic Whites, specific for Ashkenazi status, using data from two population-based series of San Francisco Bay Area patients with invasive cancers of the breast or ovary, and data on breast and ovarian cancer risks in Ashkenazi and non-Ashkenazi carriers. Assuming that 90% of the BRCA1 mutations were detected, we estimate a carrier prevalence of 0.24% (95% confidence interval, 0.15-0.39%) in non-Ashkenazi Whites, and 1.2% (95% confidence interval, 0.5-2.6%) in Ashkenazim. When combined with U.S. White census counts, these prevalence estimates suggest that approximately 550,513 U.S. Whites (506,206 non-Ashkenazim and 44,307 Ashkenazim) carry germ line BRCA1 mutations. These estimates may be useful in guiding resource allocation for genetic testing and genetic counseling and in planning preventive interventions.

    View details for Web of Science ID 000226077100015

    View details for PubMedID 15598764

  • Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations BRITISH JOURNAL OF CANCER Whittemore, A. S., Balise, R. R., Pharoah, P. D., DiCioccio, R. A., Oakley-Girvan, I., Ramus, S. J., Daly, M., Usinowicz, M. B., Garlinghouse-Jones, K., Ponder, B. A., Buys, S., Senie, R., Andrulis, I., John, E., Hopper, J. L., Piver, M. S. 2004; 91 (11): 1911-1915

    Abstract

    Women with mutations of the genes BRCA1 or BRCA2 are at increased risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they protect against the disease in carriers of these mutations. We obtained self-reported lifetime histories of oral contraceptive use from 451 women who carried mutations of BRCA1 or BRCA2. We used conditional logistic regression to estimate the odds ratios associated with oral contraceptive use, comparing the histories of 147 women with ovarian cancer (cases) to those of 304 women without ovarian cancer (controls) who were matched to cases on year of birth, country of residence and gene (BRCA1 vs BRCA2). Reference ages for controls had to exceed the ages at diagnosis of their matched cases. After adjusting for parity, the odds-ratio for ovarian cancer associated with use of oral contraceptives for at least 1 year was 0.85 (95 percent confidence interval, 0.53-1.36). The risk decreased by 5% (1-9%) with each year of use (P for trend=0.01). Use for 6 or more years was associated with an odds-ratio of 0.62 (0.35-1.09). These data support the hypothesis that long-term oral contraceptive use reduces the risk of ovarian cancer among women who carry mutations of BRCA1 or BRCA2.

    View details for DOI 10.1038/sj.bjc.6602239

    View details for Web of Science ID 000225301700010

    View details for PubMedID 15545966

  • Classifying disease chromosomes arising from multiple founders, with application to fine-scale haplotype mapping GENETIC EPIDEMIOLOGY Yu, K., MARTIN, R. B., Whittemore, A. S. 2004; 27 (3): 173-181

    Abstract

    The availability of high-density haplotype data has motivated several fine-scale linkage disequilibrium mapping methods for locating disease-causing mutations. These methods identify loci around which haplotypes of case chromosomes exhibit greater similarity than do those of control chromosomes. A difficulty arising in such mapping is the possibility that case chromosomes have inherited disease-causing mutations from different ancestral chromosomes (founder heterogeneity). Such heterogeneity dilutes measures of case haplotype similarity. This dilution can be mitigated by separating case chromosomes into subsets according to their putative mutation origin, and searching for an area with excessive haplotype similarity within each subset. We propose a nonparametric method for identifying subsets of case chromosomes likely to share a common ancestral progenitor. By simulation studies and application to published data, we show that the method accurately identifies relatively large subsets of chromosomes that share a common founder. We also show that the method allows more precise estimates of the disease mutation loci than obtained by other fine-scale mapping methods.

    View details for DOI 10.1002/gepi.20016

    View details for Web of Science ID 000224813200001

    View details for PubMedID 15389930

  • Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations AMERICAN JOURNAL OF EPIDEMIOLOGY McGuire, V., Felberg, A., Mills, M., Ostrow, K. L., DiCioccio, R., John, E. M., West, D. W., Whittemore, A. S. 2004; 160 (7): 613-618

    Abstract

    In the general population, ovarian cancer risk is inversely associated with oral contraceptive use, tubal ligation, and childbearing. Among carriers of BRCA1 gene mutations, the data are conflicting. The authors identified women diagnosed with incident invasive epithelial ovarian cancer in the San Francisco Bay Area of California from March 1997 through July 2001. They compared the contraceptive and reproductive histories of 36 carrier cases and 381 noncarrier cases with those of 568 controls identified by random digit dialing who were frequency matched to cases on age and race/ethnicity. In both carriers and noncarriers, reduced risk was associated with ever use of oral contraceptives (odds ratio = 0.54 (95% confidence interval (CI): 0.26, 1.13) for carriers and 0.55 (95% CI: 0.41, 0.73) for noncarriers), duration of oral contraceptive use (risk reduction per year = 13% (p = 0.01) for carriers and 6% (p < 0.001) for noncarriers), history of tubal ligation (odds ratio = 0.68 (95% CI: 0.25, 1.90) for carriers and 0.65 (95% CI: 0.45, 0.95) for noncarriers), and increasing parity (risk reduction per childbirth = 16% (p = 0.26) for carriers and 24% (p < 0.001) for noncarriers). These data suggest that BRCA1 mutation carriers and noncarriers have similar risk reductions associated with oral contraceptive use, tubal ligation, and parity.

    View details for Web of Science ID 000224083700001

    View details for PubMedID 15383404

  • STK15 polymorphisms and association with risk of invasive ovarian cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION DiCioccio, R. A., Song, H. L., Waterfall, C., Kimura, M. T., Nagase, H., McGuire, V., Hogdall, E., Shah, M. N., Luben, R. N., Easton, D. F., Jacobs, I. J., Ponder, B. A., Whittemore, A. S., Gayther, S. A., Pharoah, P. D., Kruger-Kjaer, S. 2004; 13 (10): 1589-1594

    Abstract

    STK15 is a putative oncogene that codes for a centrosome-associated, serine/threonine kinase, the normal function of which is to ensure accurate segregation of chromosomes during mitosis. Amplification of STK15 has been reported in ovarian tumors, suggesting a role in ovarian cancer pathology. STK15 is polymorphic with two single nucleotide substitutions (449t/a and 527g/a) in evolutionarily conserved regions causing amino acid changes (F31I and V57I). Two other nucleotide substitutions (287c/g and 1891g/c) of unknown significance are in 5' and 3' untranslated regions (UTR), respectively. To learn more about the involvement of STK15 in ovarian cancer, we genotyped and haplotyped these polymorphisms in three population-based ovarian cancer case-control studies from the United Kingdom, United States, and Denmark with 1,821 combined cases and 2,467 combined controls and calculated risks for developing ovarian cancer. Genotypes of individual polymorphisms in control groups of the United Kingdom, United States, and Denmark conformed to Hardy-Weinberg equilibrium. In combined cases and combined controls, rare allele frequencies were 0.23 and 0.21 for I31, 0.16 and 0.17 for I57, 0.08 and 0.07 for 5' UTR g, and 0.25 and 0.24 for 3' UTR c, respectively. Using FF common homozygotes of F31I as comparator, there was increased ovarian cancer risk to FI heterozygotes (odds ratio, 1.18; 95% confidence interval, 1.01-1.36), II homozygotes (odds ratio, 1.25; 95% confidence interval, 0.89-1.75), and I31 allele carriers (odds ratio, 1.17; 95% confidence interval, 1.02-1.35) in the combined group data. For either V57I, 5' UTR C/G, or 3' UTR G/C, all genotypic ovarian cancer risks were essentially in unity relative to their respective common homozygotes, VV, cc, or gg. Haplotype analysis of combined group data revealed seven haplotypes with frequencies between 0.02 and 0.5, with c-F-V-g the most common. None of the haplotype-specific risks significantly differed from unity relative to c-F-V-g. These results suggest a model of dominant inheritance of ovarian cancer risk by the I31 allele of F31I and that the I31 allele may be a common ovarian cancer susceptibility allele of low penetrance.

    View details for Web of Science ID 000224453700008

    View details for PubMedID 15466974

  • The effects of BRCA1 missense variants V1804D and M1628T on transcriptional activity CANCER GENETICS AND CYTOGENETICS Ostrow, K. L., McGuire, V., Whittemore, A. S., DiCioccio, R. A. 2004; 153 (2): 177-180

    Abstract

    Many families with multiple cases of ovarian cancer, breast cancer, or both segregate inherited mutations in one allele of the tumor suppressor gene BRCA1. Genetic testing is used to assess cancer risk; however, testing can detect missense DNA alterations, called unclassified variants, of unknown functional and biological significance with uncertain risk implications. Some missense variants at the transcriptional activation domain of BRCA1 of cancer patients inactivate transcriptional activity of BRCA1, providing evidence that they are deleterious. We identified the variants V1804D and M1628T at the transcriptional activation domain of BRCA1 of two ovarian cancer patients without a family history of ovarian or breast cancer. To test if these residues are critical for transcriptional activation, we created V1804D and M1628T independently in BRCA1 cDNA via site-directed mutagenesis in a mammalian expression vector, pcDNA3.1. Wild-type, mutant, and empty vector constructs were tested in human kidney 293 cells using a p53-responsive luciferase reporter. M1628T had the same transcriptional activity as wild-type BRCA1 but V1804D and the empty vector control showed a 60% reduction. This indicates that V1804D is deleterious but M1628T is not.

    View details for DOI 10.1016/j.cancergencyto.2004.01.020

    View details for Web of Science ID 000224115800014

    View details for PubMedID 15350310

  • Role of Ethnicity in Risk for Hepatocellular Carcinoma in Patients With Chronic Hepatitis C and Cirrhosis CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Nguyen, M. H., Whittemore, A. S., Garcia, R. T., Tawfeek, S. A., Ning, J., Lam, S., Wright, T. L., Keeffe, E. B. 2004; 2 (9): 820-824

    Abstract

    In the United States, hepatocellular carcinoma (HCC) is more common among Asians and African Americans than Caucasians, with chronic hepatitis C virus (HCV) infection accounting for up to half of the patients. Our study examined ethnicity as a potential risk factor for HCC among patients with chronic hepatitis C.We conducted a case-control study of 464 patients with chronic hepatitis C and cirrhosis (207 cancer patients and 257 controls) using medical records and pathology records at 4 medical centers. We estimated odds ratios with 95% confidence intervals by using conditional logistic regression on case-control sets, matched within study centers and study period on sex and age groups (< or =45, 46-55, 56-65, >65 yr). To control for potential confounding caused by severity of cirrhosis and residual confounding caused by age, we also included Child-Turcotte-Pugh (CTP) scores and age (continuous variable) in all regression analyses.Compared with Caucasians, the cancer risk was increased significantly among Asians (adjusted odds ratio, 4.3; 95% confidence interval, 2.1-9.0 for men, and 4.6; 1.2-18.5 for women) and somewhat increased among African-American men (adjusted odds ratio, 2.4; 95% confidence interval, 0.9-6.3).This study suggests that, among patients with chronic hepatitis C and cirrhosis, liver cancer risk is increased 4-fold in Asians and may be doubled in African-American men, compared with Caucasians. These results need confirmation in larger studies from racially diverse populations, but, if confirmed, these results point to high-risk populations that should be targeted for screening and preventive efforts.

    View details for DOI 10.1053/S1542-3565(04)00353-2

    View details for Web of Science ID 000208072100013

    View details for PubMedID 15354283

  • Risk of early-onset prostate cancer in relation to germ line polymorphisms of the vitamin D receptor CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Oakley-Girvan, I., Feldman, D., Eccleshall, T. R., Gallagher, R. P., Wu, A. H., Kolonel, L. N., Halpern, J., Balise, R. R., West, D. W., Paffenbarger, R. S., Whittemore, A. S. 2004; 13 (8): 1325-1330

    Abstract

    Vitamin D inhibits prostate cancer cell growth, angiogenesis, and metastasis. These actions are mediated by the vitamin D receptor. We examined associations between prostate cancer risk and five polymorphisms in the VDR gene: four single nucleotide polymorphisms (FokI, BsmI, ApaI, and TaqI restriction sites) and the polyadenylic acid microsatellite. Specifically, we genotyped population-based samples of young African Americans (113 cases and 121 controls) and Whites (232 cases and 171 controls) and members of 98 predominantly White families with multiple cases of prostate cancer. Among Whites, there was no evidence for association between prostate cancer risk and alleles at any of the five polymorphic sites regardless of how the men were ascertained. Moreover, estimated five-locus haplotype frequencies were similar in White cases and controls. Among African Americans, prostate cancer risk was associated with homozygosity for the F allele at the FokI site (odds ratio 1.9, 95% confidence interval 1.0-3.3). In addition, estimated haplotype frequencies differed significantly (P < 0.01) between African American cases and controls. These findings need replication in other studies of African Americans. Homozygosity for the F allele at the FokI site is more prevalent in the African American population than in U.S. Whites. If the FokI association noted here were causal, this difference could account for some of the disease burden among African Americans and some of the excess risk in African Americans compared with Whites.

    View details for Web of Science ID 000223155500010

    View details for PubMedID 15298953

  • A family-based genetic association study of variants in estrogen-metabolism genes COMT and CYP1B1 and breast cancer risk BREAST CANCER RESEARCH AND TREATMENT Ahsan, H., Chen, Y., Whittemore, A. S., Kibriya, M. G., Gurvich, I., Senie, R. T., Santella, R. M. 2004; 85 (2): 121-131

    Abstract

    In this paper, we report findings from a family-based association study examining the association between polymorphisms in two key estrogen-metabolism genes CYP1B1 (codon 432 G --> C and codon 453 A --> G variants) and COMT (codon 158 G --> A variant) and female breast cancer. We conducted the study among 280 nuclear families containing one or more daughters with breast cancer with a total of 1124 family members (702 with available constitutional DNA and questionnaire data and 421 without). These nuclear families were selected from breast cancer families participating in the Metropolitan New York Registry (MNYR) - one of the six centers of NCI's Breast Cooperative Family Registry. We used likelihood-based statistical methods to examine the allelic associations. We found none of the variant alleles of the CYP1B1 and COMT genes to be associated with breast cancer in these families. This was consistent with results from matched case-control analyses using all available sib-ships in these families. However, we found that parental carrier status of the CYP1B1 codon 453 variant G allele and the COMT codon 158 variant A allele was associated with breast cancer risk in daughters (independent of the daughters' own genotype). In conclusion, findings from this family-based study indicate that a woman's own CYP1B1 or COMT genotypes are not associated with her breast cancer risk. Although the study found that parental carrier status of certain CYP1B1 or COMT genotypes might be associated with daughter's breast cancer risk, the biological basis as well as independent confirmation of this finding need to be investigated in future larger family-based studies before making meaningful inferences.

    View details for Web of Science ID 000221057400003

    View details for PubMedID 15111770

  • Increasing colorectal cancer incidence rates in Japan INTERNATIONAL JOURNAL OF CANCER Yiu, H. Y., Whittemore, A. S., Shibata, A. 2004; 109 (5): 777-781

    Abstract

    We examined trends of colorectal cancer incidence rates among Japanese (Miyagi Prefecture) and United States (US) whites (State of Connecticut) between 1959 and 1992. Age-standardized rates in Japan have increased dramatically and are now similar to US white rates. For both colon and rectum, age-specific rates in Japanese men born after 1930 exceed those in US whites, and the Japanese excess increases with year of birth. Similar patterns are evident for women. The current trends suggest that colorectal cancer will become a major source of morbidity and mortality in Japan, as these young Japanese age and their risks increase.

    View details for DOI 10.1002/ijc.20030

    View details for Web of Science ID 000220524000022

    View details for PubMedID 14999789

  • The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer BREAST CANCER RESEARCH John, E. M., Hopper, J. L., Beck, J. C., Knight, J. A., Neuhausen, S. L., Senie, R. T., Ziogas, A., Andrulis, I. L., Anton-Culver, H., Boyd, N., Buys, S. S., Daly, M. B., O'Malley, F. P., Santella, R. M., Southey, M. C., Venne, V. L., Venter, D. J., West, D. W., Whittemore, A. S., Seminara, D. 2004; 6 (4): R375-R389

    Abstract

    The etiology of familial breast cancer is complex and involves genetic and environmental factors such as hormonal and lifestyle factors. Understanding familial aggregation is a key to understanding the causes of breast cancer and to facilitating the development of effective prevention and therapy. To address urgent research questions and to expedite the translation of research results to the clinical setting, the National Cancer Institute (USA) supported in 1995 the establishment of a novel research infrastructure, the Breast Cancer Family Registry, a collaboration of six academic and research institutions and their medical affiliates in the USA, Canada, and Australia.The sites have developed core family history and epidemiology questionnaires, data dictionaries, and common protocols for biospecimen collection and processing and pathology review. An Informatics Center has been established to collate, manage, and distribute core data.As of September 2003, 9116 population-based and 2834 clinic-based families have been enrolled, including 2346 families from minority populations. Epidemiology questionnaire data are available for 6779 affected probands (with a personal history of breast cancer), 4116 unaffected probands, and 16,526 relatives with or without a personal history of breast or ovarian cancer. The biospecimen repository contains blood or mouthwash samples for 6316 affected probands, 2966 unaffected probands, and 10,763 relatives, and tumor tissue samples for 4293 individuals.This resource is available to internal and external researchers for collaborative, interdisciplinary, and translational studies of the genetic epidemiology of breast cancer. Detailed information can be found at the URL http://www.cfr.epi.uci.edu/.

    View details for DOI 10.1186/bcr801

    View details for Web of Science ID 000222828200022

    View details for PubMedID 15217505

  • Histopathology, FIGO stage, and BRCA mutation status of ovarian cancers from the Gilda Radner Familial Ovarian Cancer Registry INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Werness, B. A., Ramus, S. J., DiCioccio, R. A., Whittemore, A. S., Garlinghouse-Jones, K., Oakley-Girvan, I., Tsukada, Y., Harrington, P., Gayther, S. A., Ponder, B. A., Piver, M. S. 2004; 23 (1): 29-34

    Abstract

    Studies of the histopathology of ovarian cancer arising in patients with germline mutations in BRCA1 or BRCA2 have shown inconsistent findings. We analyzed the large number of tumors from women enrolled in the Gilda Radner Familial Ovarian Cancer Registry for correlations between histopathology and BRCA mutation status. Histopathology slides and reports were reviewed for histology, grade, and stage for cancers of the ovary or peritoneum in 220 women from 126 Gilda Radner Familial Ovarian Cancer Registry families. At least one affected member of each family was analyzed for mutations in the BRCA1 and BRCA2 genes, and tumors from mutation-positive families were compared with those from mutation-negative families. Of 70 patients from 38 BRCA1-positive families, 69 had epithelial ovarian carcinoma and one had a dysgerminoma. Fifteen of 16 patients from nine BRCA2-positive families had epithelial ovarian cancer, and one had a primary peritoneal cancer. Of 134 patients from 79 BRCA-negative families, 118 had epithelial ovarian carcinoma, 11 had ovarian borderline tumors, three had nonepithelial tumors, and two had primary peritoneal carcinoma. There were fewer grade 1 (p < 0.001) and stage I (p = 0.005) cancers in patients from BRCA-positive families than in patients from BRCA-negative families. Neither mucinous nor borderline tumors were found in the BRCA-positive families. In conclusion, ovarian cancers arising in women from BRCA-positive families are more likely to be high-grade and have extraovarian spread than tumors arising in women from BRCA-negative families. Borderline and mucinous tumors do not appear to be part of the phenotype of families with germline mutations in the BRCA genes.

    View details for DOI 10.1097/01.pgp.0000101083.35393.cd

    View details for Web of Science ID 000187434700006

    View details for PubMedID 14668547

  • Where are the prostate cancer genes? A summary of eight genome wide searches PROSTATE Easton, D. F., Schaid, D. J., Whittemore, A. S., Isaacs, W. J. 2003; 57 (4): 261-269

    Abstract

    There is strong evidence for genetic susceptibility to prostate cancer, but most of the genes underlying this susceptibility remain to be identified.We reviewed the results of eight genome-wide linkage searches based on 1,293 families with multiple cases of prostate cancer.Across these studies, 11 linkage peaks with LOD scores in excess of 2 were identified. However, no chromosomal region was reported as significant at this level by more than one study and only one corresponded to a peak previously suggested by another group.These results indicate that prostate cancer is genetically complex, and that combined analyses of large family sets will be required to evaluate reliably the linkage evidence.

    View details for DOI 10.1002/pros.10300

    View details for Web of Science ID 000186871700002

    View details for PubMedID 14601022

  • Logistic regression of family data from retrospective study designs GENETIC EPIDEMIOLOGY Whittemore, A. S., Halpern, J. 2003; 25 (3): 177-189

    Abstract

    We wish to study the effects of genetic and environmental factors on disease risk, using data from families ascertained because they contain multiple cases of the disease. To do so, we must account for the way participants were ascertained, and for within-family correlations in both disease occurrences and covariates. We model the joint probability distribution of the covariates of ascertained family members, given family disease occurrence and pedigree structure. We describe two such covariate models: the random effects model and the marginal model. Both models assume a logistic form for the distribution of one person's covariates that involves a vector beta of regression parameters. The components of beta in the two models have different interpretations, and they differ in magnitude when the covariates are correlated within families. We describe ascertainment assumptions needed to estimate consistently the parameters beta(RE) in the random effects model and the parameters beta(M) in the marginal model. Under the ascertainment assumptions for the random effects model, we show that conditional logistic regression (CLR) of matched family data gives a consistent estimate beta(RE) for beta(RE) and a consistent estimate for the covariance matrix of beta(RE). Under the ascertainment assumptions for the marginal model, we show that unconditional logistic regression (ULR) gives a consistent estimate for beta(M), and we give a consistent estimator for its covariance matrix. The random effects/CLR approach is simple to use and to interpret, but it can use data only from families containing both affected and unaffected members. The marginal/ULR approach uses data from all individuals, but its variance estimates require special computations. A C program to compute these variance estimates is available at http://www.stanford.edu/dept/HRP/epidemiology. We illustrate these pros and cons by application to data on the effects of parity on ovarian cancer risk in mother/daughter pairs, and use simulations to study the performance of the estimates.

    View details for DOI 10.1002/gepi.10267

    View details for Web of Science ID 000186053600001

    View details for PubMedID 14557986

  • Stage at diagnosis and survival in a multiethnic cohort of prostate cancer patients AMERICAN JOURNAL OF PUBLIC HEALTH Oakley-Girvan, I., Kolonel, L. N., Gallagher, R. P., Wu, A. H., Felberg, A., Whittemore, A. S. 2003; 93 (10): 1753-1759

    Abstract

    We evaluated the effects of socioeconomic status and comorbidity on stage of disease and survival among 1509 population-based prostate cancer patients.We applied logistic regression and Cox proportional hazards regression to data from Whites, African Americans, and Asian Americans who were diagnosed from 1987 to 1991.Patients with existing comorbid conditions were less likely than those without these conditions to be diagnosed with advanced cancer. Compared with Whites, African Americans (odds ratio [OR] = 1.5; 95% confidence interval [CI] = 1.1, 2.2) and foreign-born Asian Americans (OR = 1.6; 95% CI = 1.0, 2.4) were more likely to be diagnosed with advanced cancer. Among men with localized disease, prostate cancer death rates were higher for African Americans than for Whites (death rate ratio = 2.3; 95% CI = 1.2, 4.7).These findings support the need for further investigation of factors that affect access to and use of health care among African Americans and Asian Americans.

    View details for Web of Science ID 000185881100031

    View details for PubMedID 14534233

  • Genetic association tests for family data with missing parental genotypes: A comparison GENETIC EPIDEMIOLOGY Whittemore, A. S., Halpern, J. 2003; 25 (1): 80-91

    Abstract

    We consider three tests for genetic association in data from nuclear families (the Family-Based Association Test (FBAT) test proposed by Rabinowitz and Laird ([2000] Hum. Hered. 50:211-223), a second test proposed by Rabinowitz ([2002] J. Am. Stat. Assoc. 97:742-758), and the Family Genotype Analysis Program (FGAP) nonfounder or partial score test proposed by Clayton ([1999] Am. J. Hum. Genet. 65:1170-1177) and Whittemore and Tu ([2000] Am. J. Hum. Genet. 66:1329-1340)). We show that each test statistic arises from the efficient score of the family data as the solution to a set of constraints on its null expectation. Moreover, the FBAT and Rabinowitz tests (but not the FGAP test) are locally the most powerful among all tests satisfying their constraints. We used simulations to examine how the three tests perform in situations when their assumptions are violated and the number of families is not huge. We found that the FBAT test tended to have less power than the other two tests, particularly when applied to families in whom all offspring were affected. The Rabinowitz and FGAP tests performed similarly, although the latter tended to extract more information from families containing one typed parent. While none of the tests showed good power to detect rare, recessively acting genes, the Rabinowitz test with a sample variance estimate performed particularly poorly in this case. However, the Rabinowitz test with a model-based variance had power comparable to that of the FGAP test, and more accurate type I error rates. We conclude that for the situations we considered, the Rabinowitz test with model-based variance has good power without forfeiting robustness against misspecification of parental genotype probabilities. However, its utility is limited by the lack of a simple algorithm to apply it to families with varying structures and phenotypes.

    View details for DOI 10.1002/gepi.10247

    View details for Web of Science ID 000183909000008

    View details for PubMedID 12813729

  • Optimal designs for estimating penetrance of rare mutations of a disease-susceptibility gene GENETIC EPIDEMIOLOGY Gong, G., Whittemore, A. S. 2003; 24 (3): 173-180

    Abstract

    Many clinical decisions require accurate estimates of disease risks associated with mutations of known disease-susceptibility genes. Such risk estimation is difficult when the mutations are rare. We used computer simulations to compare the performance of estimates obtained from two types of designs based on family data. In the first (clinic-based designs), families are ascertained because they meet certain criteria concerning multiple disease occurrences among family members. In the second (population-based designs), families are sampled through a population-based registry of affected individuals called probands, with oversampling of probands whose families are more likely to segregate mutations. We generated family structures, genotypes, and phenotypes using models that reflect the frequencies and penetrances of mutations of the BRCA1/2 genes. We studied the effects of risk heterogeneity due to unmeasured, shared risk factors by including risk variation due to unmeasured genotypes of another gene. The simulations were chosen to mimic the ascertainment and selection processes commonly used in the two types of designs. We found that penetrance estimates from both designs are nearly unbiased in the absence of unmeasured shared risk factors, but are biased upward in the presence of such factors. The bias increases with increasing variation in risks across genotypes of the second gene. However, it is small compared to the standard error of the estimates. Standard errors from population-based designs are roughly twice those from clinic-based designs with the same number of families. Using the root-mean-square error as a measure of performance, we found that in all instances, the clinic-based designs gave more accurate estimates than did the population-based designs with the same numbers of families. Rough variance calculations suggest that clinic-based designs give more accurate estimates because they include more identified mutation carriers.

    View details for DOI 10.1002/gepi.10219

    View details for Web of Science ID 000182077700002

    View details for PubMedID 12652521

  • BRCA1/2 mutation status influences somatic genetic progression in inherited and sporadic epithelial ovarian cancer cases CANCER RESEARCH Ramus, S. J., Pharoah, P. D., Harrington, P., Pye, C., Werness, B., Bobrow, L., Ayhan, A., Wells, D., Fishman, A., Gore, M., DiCioccio, R. A., Piver, M. S., Whittemore, A. S., Ponder, B. A., Gayther, S. A. 2003; 63 (2): 417-423

    Abstract

    Metaphase comparative genomic hybridization was used to analyze the spectrum of genetic alterations in 141 epithelial ovarian cancers from BRCA1 and BRCA2 mutation carriers, individuals with familial non-BRCA1/2 epithelial ovarian cancer, and women with nonfamilial epithelial ovarian cancer. Multiple genetic alterations were identified in almost all tumors. The high frequency with which some alterations were identified suggests the location of genes that are commonly altered during ovarian tumor development. In multiple chromosome regions, there were significant differences in alteration frequency between the four tumor types suggesting that BRCA1/2 mutation status and a family history of ovarian cancer influences the somatic genetic pathway of ovarian cancer progression. These findings were supported by hierarchical cluster analysis, which identified genetic events that tend to occur together during tumorigenesis and several alterations that were specific to tumors of a particular type. In addition, some genetic alterations were strongly associated with differences in tumor differentiation and disease stage. Taken together, these data provide molecular genetic evidence to support previous findings from histopathological studies, which suggest that clinical features of ovarian and breast tumors differ with respect to BRCA1/2 mutation status and/or cancer family history.

    View details for Web of Science ID 000180697500026

    View details for PubMedID 12543797

  • Breast cancer in Marin County BREAST CANCER RESEARCH Whittemore, A. S. 2003; 5 (5): 232-234

    Abstract

    Two articles previously published in Breast Cancer Research illustrate the high rates of breast cancer in Marin County, a wealthy, urban county immediately northwest of the city of San Francisco. I herein comment on these articles, and on the political/psychological/scientific dilemma presented by regions with high cancer rates, such as Marin County. I discuss possible causes for such cancer 'clusters', and conclude with some thoughts about the future.

    View details for DOI 10.1186/bcr633

    View details for Web of Science ID 000184841000004

    View details for PubMedID 12927030

  • Re: On the use of familial aggregation in population-based case probands for calculating penetrance JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Gong, G. 2003; 95 (1): 76-77

    View details for Web of Science ID 000180079200019

    View details for PubMedID 12509408

  • Observational studies and Randomized trials of hormone replacement therapy: What can we learn from them? EPIDEMIOLOGY Whittemore, A. S., McGuire, V. 2003; 14 (1): 8-10

    View details for Web of Science ID 000180166300004

    View details for PubMedID 12500037

  • Analysis of the human progesterone receptor gene polymorphism PROGINS in Austrian ovarian cancer patients INTERNATIONAL JOURNAL OF CANCER Whittemore, A. S., McGuire, V. 2002; 101 (2): 202-202

    View details for DOI 10.1002/ijc.10571

    View details for Web of Science ID 000177622600015

    View details for PubMedID 12210000

  • Comparison of techniques for the successful detection of BRCA1 mutations in fixed paraffin-embedded tissue CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Bernstein, J. L., Thompson, W. D., Casey, G., DiCioccio, R. A., Whittemore, A. S., Diep, A. T., Thakore, S. S., Vaziri, S., Xue, S. Y., Haile, R. W. 2002; 11 (9): 809-814

    Abstract

    Genomic DNA isolated from archived paraffin-embedded tissues (PETs) has important applicability in genetic epidemiological studies. To determine the accuracy of the sequence data, using DNA derived from PET among patients with known mutations characterized from blood, we conducted a blinded factorial experiment to simultaneously examine the influence of mutation type, age of the PET, PCR product type, and Taq DNA polymerase on BRCA1 gene mutation detection. The probability of detecting sequencing artifacts was also investigated. We found that: (a) gene detection was most accurate for newer PET; (b) high fidelity Taq with shorter PCR amplicon length yielded the highest mutation detection success rate and lowest artifact rate; and (c) base substitutions were more often correctly identified than frameshift mutations or wild-type sequences. We concluded that DNA derived from PET that archived for less than 18 years can be used successfully for detecting BRCA1 gene mutations if quality control is strictly maintained.

    View details for Web of Science ID 000177967900003

    View details for PubMedID 12223423

  • Segregation analysis of prostate cancer in 1719 white, African-American and Asian-American families in the United States and Canada CANCER CAUSES & CONTROL Gong, G., Oakley-Girvan, I., Wu, A. H., Kolonel, L. N., John, E. M., West, D. W., Felberg, A., Gallagher, R. P., Whittemore, A. S. 2002; 13 (5): 471-482

    Abstract

    Some data suggest that brothers of prostate cancer patients have higher disease risk than their fathers, supporting an X-linked or recessive mode of inheritance. However, higher observed frequencies in brothers than fathers may merely reflect the strong temporal changes in US incidence rates.(a) to evaluate the fit of X-linked, recessive, and dominant modes of inheritance to prostate cancer incidence, specific for calendar year, age, and race, in population-based samples of US and Canadian families; and (b) to evaluate a simple multifactorial model for familial aggregation of prostate cancer due to shared low-penetrance variants of many genes or shared lifestyle factors.The data consist of reported prostate cancer incidence in first-degree relatives of 1,719 white, African-American, and Asian-American men with and without prostate cancer at ages <70 years. Model parameters were estimated by maximizing a pseudo-likelihood function of the data, and goodness of model fit was assessed by evaluating discrepancies between observed and expected numbers of pairs of relatives with prostate cancer.After adjusting for temporal trends in prostate cancer incidence rates we found that the X-linked model fit poorly. underpredicting the observed number of affected father-son pairs. This also was true of the recessive model, although the evidence for poor fit did not achieve statistical significance. In contrast, the dominant model provided adequate fit to the data. In this model the race-specific penetrance estimates for carriers of deleterious genotypes were similar among African-Americans and whites, but lower among Asian-Americans: risk by age 80 years for carriers born in 1900 was estimated as 75.3% for African-Americans and whites, and 44.4% for Asian-Americans. None of the Mendelian models fit the data better than did the simple multifactorial model.The good fit of the multifactorial model suggests that multiple genes, each having low penetrance, may be responsible for most inherited prostate cancer susceptibility, and that the contribution of rare highly penetrant mutations is small.

    View details for Web of Science ID 000175947900010

    View details for PubMedID 12146852

  • Race, epithelial ovarian cancer survival, and membership in a large health maintenance organization EPIDEMIOLOGY McGuire, V., Herrinton, L., Whittemore, A. S. 2002; 13 (2): 231-234

    Abstract

    African-American ovarian cancer patients present with more advanced disease and have poorer survival than do white patients.To determine whether these differences occur among African-American and white patients who have equal access to medical care, we analyzed ovarian cancer patient characteristics separately for 1,587 members of the Kaiser Permanente Medical Plan of Northern California and 5,757 non-members.The distributions of disease stage at diagnosis were similar among African-American and white patients, both in the Kaiser plan and elsewhere. However, ovarian cancer death rates, adjusted for disease stage and age at diagnosis and for histology, were higher for African-American patients compared with white patients, regardless of Kaiser membership status. The death rate ratios for African-Americans compared with whites were 1.32 (95% CI = 1.02-1.70) for Kaiser members and 1.20 (95% CI = 1.04-1.40) for Kaiser non-members.Further research within an equal-access care system is needed to evaluate other important factors such as specialty of surgeon, extent of residual tumor after surgery, chemotherapy treatment, and postoperative management to determine whether these factors are contributing to the differences in survival between African-American and white ovarian cancer patients.

    View details for Web of Science ID 000174037800021

    View details for PubMedID 11880767

  • Survival among US women with invasive epithelial ovarian cancer GYNECOLOGIC ONCOLOGY McGuire, V., Jesser, C. A., Whittemore, A. S. 2002; 84 (3): 399-403

    Abstract

    Invasive epithelial ovarian cancer is a highly fatal disease, diagnosed at advanced stages when survival is poor. Relatively little is known about the variation in survival across U.S. women of different race/ethnicities. To investigate this issue, we evaluated pathological characteristics and death rates due to invasive epithelial ovarian cancer in a population-based sample of patients from six racial/ethnic groups.The analysis included 38,012 women diagnosed with primary invasive epithelial ovarian cancer between 1973 and 1997 in the Surveillance, Epidemiology and End Results Program of the National Cancer Institute.Filipina patients were younger at diagnosis, more likely to have localized disease, and had more mucinous cancers than whites. African-Americans were more likely than whites to be diagnosed at older ages, with distant disease and with undifferentiated/unclassified cancers. After adjusting for age at diagnosis, stage of disease at diagnosis, and cancer histology, we found that, compared to whites, death rates were significantly elevated among African-Americans and significantly reduced among Hispanics and Filipina. We also found that death rates declined significantly with time since diagnosis among women with advanced disease.The declining death rates in women with advanced disease suggest the presence of considerable prognostic heterogeneity among these women, which could reflect differences in quality of care. This issue, as well as the survival disadvantage for African-American women and survival advantages for Hispanic and Filipina women, needs investigation.

    View details for DOI 10.1006/gyno.2001.6536

    View details for Web of Science ID 000174372100010

    View details for PubMedID 11855877

  • Carbohydrates and colorectal cancer risk among Chinese in North America CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Borugian, M. J., Sheps, S. B., Whittemore, A. S., Wu, A. H., Potter, J. D., Gallagher, R. P. 2002; 11 (2): 187-193

    Abstract

    Previous studies have analyzed total carbohydrate as a dietary risk factor for colorectal cancer (CRC) but obtained conflicting results, perhaps attributable in part to the embedded potential confounder, fiber. The aim of this study was to analyze the nonfiber ("effective") carbohydrate component (eCarb) separately and to test the hypothesis that effective carbohydrate consumption is directly related to CRC risk. The data (473 cases and 1192 controls) were from a large, multicenter, case-control study of Chinese residing in North America. Multivariate logistic regression was used to perform a secondary analysis controlling for age; sex; consumption of fat, fiber, calcium, and total kilocalories; body mass (Quetelet's) index; family history; education; and years in North America. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate risk among subgroups by sex and cancer site. A statistically significant positive association was observed between eCarb consumption and risk of CRC in both men (OR, 1.7 comparing highest with lowest tertile of eCarb consumption; 95% CI, 1.1-2.7) and women (OR, 2.7; 95% CI, 1.5-4.8). As expected, the ORs for total carbohydrate were somewhat lower than those for effective carbohydrate, but the differences were not large. A sex difference in risk by colorectal subsite was observed, with risk concentrated in the right colon for women (OR, 6.5; 95% CI, 2.4-18.4) and in the rectum for men (OR, 2.4; 95% CI, 1.2-4.8). These data indicate that increased eCarb and total carbohydrate consumption are both associated with increased risk of CRC in both sexes, and that among women, relative risk appears greatest for the right colon, whereas among men, relative risk appears greatest for the rectum.

    View details for Web of Science ID 000174233100005

    View details for PubMedID 11867506

  • Tests for genetic association using family data GENETIC EPIDEMIOLOGY Shih, M. C., Whittemore, A. S. 2002; 22 (2): 128-145

    Abstract

    We use likelihood-based score statistics to test for association between a disease and a diallelic polymorphism, based on data from arbitrary types of nuclear families. The Nonfounder statistic extends the transmission disequilibrium test (TDT) to accommodate affected and unaffected offspring, missing parental genotypes, phenotypes more general than qualitative traits, such as censored survival data and quantitative traits, and residual correlation of phenotypes within families. The Founder statistic compares observed or inferred parental genotypes to those expected in the general population. Here the genotypes of affected parents and those with many affected offspring are weighted more heavily than unaffected parents and those with few affected offspring. We illustrate the tests by applying them to data on a polymorphism of the SRD5A2 gene in nuclear families with multiple cases of prostate cancer. We also use simulations to compare the power of these family-based statistics to that of the score statistic based on Cox's partial likelihood for censored survival data, and find that the family-based statistics have considerably more power when there are many untyped parents. The software program FGAP for computing test statistics is available at http://www.stanford.edu/dept/HRP/epidemiology/FGAP.

    View details for Web of Science ID 000173390200003

    View details for PubMedID 11788959

  • Comparison of DNA- and RNA-based methods for detection of truncating BRCA1 mutations HUMAN MUTATION Andrulis, I. L., Anton-Culver, H., Beck, J., Bove, B., Boyd, J., Buys, S., Godwin, A. K., Hopper, J. L., Li, F., Neuhausen, S. L., Ozcelik, H., Peel, D., Santella, R. M., Southey, M. C., van Orsouw, N. J., Venter, D. J., Vijg, J., Whittemore, A. S. 2002; 20 (1): 65-73

    Abstract

    A number of methods are used for mutational analysis of BRCA1, a large multi-exon gene. A comparison was made of five methods to detect mutations generating premature stop codons that are predicted to result in synthesis of a truncated protein in BRCA1. These included four DNA-based methods: two-dimensional gene scanning (TDGS), denaturing high performance liquid chromatography (DHPLC), enzymatic mutation detection (EMD), and single strand conformation polymorphism analysis (SSCP) and an RNA/DNA-based protein truncation test (PTT) with and without complementary 5' sequencing. DNA and RNA samples isolated from 21 coded lymphoblastoid cell line samples were tested. These specimens had previously been analyzed by direct automated DNA sequencing, considered to be the optimum method for mutation detection. The set of 21 cell lines included 14 samples with 13 unique frameshift or nonsense mutations, three samples with two unique splice site mutations, and four samples without deleterious mutations. The present study focused on the detection of protein-truncating mutations, those that have been reported most often to be disease-causing alterations that segregate with cancer in families. PTT with complementary 5' sequencing correctly identified all 15 deleterious mutations. Not surprisingly, the DNA-based techniques did not detect a deletion of exon 22. EMD and DHPLC identified all of the mutations with the exception of the exon 22 deletion. Two mutations were initially missed by TDGS, but could be detected after slight changes in the test design, and five truncating mutations were missed by SSCP. It will continue to be important to use complementary methods for mutational analysis.

    View details for DOI 10.1002/humu.10097

    View details for Web of Science ID 000176744500008

    View details for PubMedID 12112659

  • Iodine and thyroid cancer risk among women in a multiethnic population: The Bay Area thyroid cancer study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Horn-Ross, P. L., Morris, J. S., Lee, M., West, D. W., Whittemore, A. S., McDougall, I. R., Nowels, K., Stewart, S. L., Spate, V. L., Shiau, A. C., Krone, M. R. 2001; 10 (9): 979-985

    Abstract

    Research on the relationship between iodine exposure and thyroid cancer risk is limited, and the findings are inconclusive. In most studies, fish/shellfish consumption has been used as a proxy measure of iodine exposure. The present study extends this research by quantifying dietary iodine exposure as well as incorporating a biomarker of long-term (1 year) exposure, i.e., from toenail clippings. This study is conducted in a multiethnic population with a wide variation in thyroid cancer incidence rates and substantial diversity in exposure. Women, ages 20-74, residing in the San Francisco Bay Area and diagnosed with thyroid cancer between 1995 and 1998 (1992-1998 for Asian women) were compared with women selected from the general population via random digit dialing. Interviews were conducted in six languages with 608 cases and 558 controls. The established risk factors for thyroid cancer were found to increase risk in this population: radiation to the head/neck [odds ratio (OR), 2.3; 95% confidence interval (CI), 0.97-5.5]; history of goiter/nodules (OR, 3.7; 95% CI, 2.5-5.6); and a family history of proliferative thyroid disease (OR, 2.5; 95% CI, 1.6-3.8). Contrary to our hypothesis, increased dietary iodine, most likely related to the use of multivitamin pills, was associated with a reduced risk of papillary thyroid cancer. This risk reduction was observed in "low-risk" women (i.e., women without any of the three established risk factors noted above; OR, 0.53; 95% CI, 0.33-0.85) but not in "high-risk" women, among whom a slight elevation in risk was seen (OR, 1.4; 95% CI, 0.56-3.4). However, no association with risk was observed in either group when the biomarker of exposure was evaluated. In addition, no ethnic differences in risk were observed. The authors conclude that iodine exposure appears to have, at most, a weak effect on the risk of papillary thyroid cancer.

    View details for Web of Science ID 000170899000011

    View details for PubMedID 11535551

  • Re: Prostate cancer incidence and mortality in the United States and the United Kingdom JOURNAL OF THE NATIONAL CANCER INSTITUTE Shibata, A., Whittemore, A. S. 2001; 93 (14): 1109-1110

    View details for Web of Science ID 000169829000017

    View details for PubMedID 11459874

  • Problems in the definition, interpretation, and evaluation of genetic heterogeneity AMERICAN JOURNAL OF HUMAN GENETICS Whittemore, A. S., Halpern, J. 2001; 68 (2): 457-465

    Abstract

    Suppose that we wish to classify families with multiple cases of disease into one of three categories: those that segregate mutations of a gene of interest, those which segregate mutations of other genes, and those whose disease is due to nonhereditary factors or chance. Among families in the first two categories (the hereditary families), we wish to estimate the proportion, p, of families that segregate mutations of the gene of interest. Although this proportion is a commonly accepted concept, it is well defined only with an unambiguous definition of "family." Even then, extraneous factors such as family sizes and structures can cause p to vary across different populations and, within a population, to be estimated differently by different studies. Restrictive assumptions about the disease are needed, in order to avoid this undesirable variation. The assumptions require that mutations of all disease-causing genes (i) have no effect on family size, (ii) have very low frequencies, and (iii) have penetrances that satisfy certain constraints. Despite the unverifiability of these assumptions, linkage studies often invoke them to estimate p, using the admixture likelihood introduced by Smith and discussed by Ott. We argue against this common practice, because (1) it also requires the stronger assumption of equal penetrances for all etiologically relevant genes; (2) even if all assumptions are met, estimates of p are sensitive to misspecification of the unknown phenocopy rate; (3) even if all the necessary assumptions are met and the phenocopy rate is correctly specified, estimates of p that are obtained by linkage programs such as HOMOG and GENEHUNTER are based on the wrong likelihood and therefore are biased in the presence of phenocopies. We show how to correct these estimates; but, nevertheless, we do not recommend the use of parametric heterogeneity models in linkage analysis, even merely as a tool for increasing the statistical power to detect linkage. This is because the assumptions required by these models cannot be verified, and their violation could actually decrease power. Instead, we suggest that estimation of p be postponed until the relevant genes have been identified. Then their frequencies and penetrances can be estimated on the basis of population-based samples and can be used to obtain more-robust estimates of p for specific populations.

    View details for Web of Science ID 000166524800015

    View details for PubMedID 11170893

  • Allele-sharing among affected relatives: non-parametric methods for identifying genes STATISTICAL METHODS IN MEDICAL RESEARCH Shih, M. C., Whittemore, A. S. 2001; 10 (1): 27-55

    Abstract

    Non-parametric linkage analysis examines similarities among affected relatives in alleles of one or more genetic markers (pieces of DNA at known locations on a chromosome). The objective is to evaluate departures from the null hypothesis that the markers are not near a disease gene. Under the null hypothesis, Mendel's laws give the probabilities that a set of relatives exhibits a particular allele-sharing pattern, and the null hypothesis is rejected if the extent of allele sharing among affected relatives exceeds Mendelian expectation. Because the rationale for allele-sharing methods is intuitively plausible and easily grasped, geneticists have used these methods for more than 30 years, well before the advent of the large sets of polymorphic markers that have made linkage analysis so fruitful today. Here we describe methods for assessing whether the extent of marker allele sharing among affected relatives exceeds Mendelian expectation. We first quantify the notion of allele sharing and the probabilities of allele sharing in various sets of relatives. Then we describe allele sharing methods for affected sibs and more general sets of relatives. We also discuss related issues of test size and power. We conclude with a brief discussion of areas in need of further research.

    View details for Web of Science ID 000168123300003

    View details for PubMedID 11329690

  • Survival in epithelial ovarian cancer patients with prior breast cancer AMERICAN JOURNAL OF EPIDEMIOLOGY McGuire, V., Whittemore, A. S., Norris, R., Oakley-Girvan, I. 2000; 152 (6): 528-532

    Abstract

    Ovarian cancer patients who carry germ-line BRCA1 mutations may have improved survival compared with ovarian cancer patients without these mutations. To evaluate this hypothesis, the authors compared survival in ovarian cancer patients who had a history of prior breast cancer with that of patients without such a history. Specifically, they used data from the population-based US Surveillance, Epidemiology, and End Results (SEER) Program to assess time to death from ovarian cancer among ovarian cancer patients with and without a prior breast cancer. All 25,637 White women diagnosed with invasive epithelial ovarian cancer in SEER registries between 1973 and 1995 were included. Of these, 824 women had had a prior breast cancer diagnosis. The ovarian cancer death rate among women with prior breast cancer was significantly lower than that of women with ovarian cancer only, adjusted for age and stage at ovarian cancer diagnosis. The survival advantage was most pronounced among older women and among those whose ovarian cancers were more advanced at the time of diagnosis. These results lend indirect support to prior findings of improved ovarian cancer survival in BRCA1 mutation carriers.

    View details for Web of Science ID 000089252100004

    View details for PubMedID 10997542

  • Prostate cancer risk in relation to anthropometry and physical activity: The National Health and Nutrition Examination Survey I epidemiological follow-up study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Clarke, G., Whittemore, A. S. 2000; 9 (9): 875-881

    Abstract

    We studied the relationship of prostate cancer to anthropometry and self-reported physical activity among 5377 African-American and Caucasian participants in the National Health and Nutrition Examination Survey I cohort. The cohort was first examined between 1971 and 1975 and then followed prospectively through the Epidemiologic Follow-up Study in 1982-1984, 1986, 1987, and 1992. Men who reported low levels of nonrecreational physical activity had increased risk of prostate cancer compared with very active men. These findings were unchanged after adjustment for potential confounders and were stronger for African-Americans (relative risk, 3.7; 95% confidence interval, 1.7-8.4) than for Caucasians (relative risk, 1.7; confidence interval, 0.8-2.3). Lower levels of recreational activity were weakly associated with increased prostate cancer risk among African-Americans but not among Caucasians. Prostate cancer risk was unrelated to a variety of anthropometric variables. These results suggest that inactive men are at increased risk of prostate cancer.

    View details for Web of Science ID 000089392600003

    View details for PubMedID 11008903

  • Detection of disease genes by use of family data. II. Application to nuclear families AMERICAN JOURNAL OF HUMAN GENETICS Tu, I. P., Balise, R. R., Whittemore, A. S. 2000; 66 (4): 1341-1350

    Abstract

    Two likelihood-based score statistics are used to detect association between a disease and a single diallelic polymorphism, on the basis of data from arbitrary types of nuclear families. The first statistic, the nonfounder statistic, extends the transmission/disequilibrium test to accommodate affected and unaffected offspring and missing parental genotypes. The second statistic, the founder statistic, compares observed or inferred parental genotypes with those of some reference population. In this comparison, the genotypes of affected parents or of those with many affected offspring are weighted more heavily than are the genotypes of unaffected parents or of those with few affected offspring. Genotypes of single unrelated cases and controls can be included in this analysis. We illustrate the two statistics by applying them to data on a polymorphism of the SDR5A2 gene in nuclear families with multiple cases of prostate cancer. We also use simulations to compare the power of the nonfounder statistic with that of the score statistic, on the basis of the conditional logistic regression of offspring genotypes.

    View details for Web of Science ID 000088373400016

    View details for PubMedID 10739759

  • Detection of disease genes by use of family data. I. Likelihood-based theory AMERICAN JOURNAL OF HUMAN GENETICS Whittemore, A. S., Tu, I. P. 2000; 66 (4): 1328-1340

    Abstract

    We present a class of likelihood-based score statistics that accommodate genotypes of both unrelated individuals and families, thereby combining the advantages of case-control and family-based designs. The likelihood extends the one proposed by Schaid and colleagues (Schaid and Sommer 1993, 1994; Schaid 1996; Schaid and Li 1997) to arbitrary family structures with arbitrary patterns of missing data and to dense sets of multiple markers. The score statistic comprises two component test statistics. The first component statistic, the nonfounder statistic, evaluates disequilibrium in the transmission of marker alleles from parents to offspring. This statistic, when applied to nuclear families, generalizes the transmission/disequilibrium test to arbitrary numbers of affected and unaffected siblings, with or without typed parents. The second component statistic, the founder statistic, compares observed or inferred marker genotypes in the family founders with those of controls or those of some reference population. The founder statistic generalizes the statistics commonly used for case-control data. The strengths of the approach include both the ability to assess, by comparison of nonfounder and founder statistics, the potential bias resulting from population stratification and the ability to accommodate arbitrary family structures, thus eliminating the need for many different ad hoc tests. A limitation of the approach is the potential power loss and/or bias resulting from inappropriate assumptions on the distribution of founder genotypes. The systematic likelihood-based framework provided here should be useful in the evaluation of both the relative merits of case-control and various family-based designs and the relative merits of different tests applied to the same design. It should also be useful for genotype-disease association studies done with the use of a dense set of multiple markers.

    View details for Web of Science ID 000088373400015

    View details for PubMedID 10739758

  • Declining ovarian cancer rates in US women in relation to parity and oral contraceptive use EPIDEMIOLOGY Gnagy, S., Ming, E. E., Devesa, S. S., Hartge, P., Whittemore, A. S. 2000; 11 (2): 102-105

    Abstract

    Ovarian cancer incidence and mortality rates have declined among U.S. women age 35-59 years during the period 1970-1995. Epidemiologic studies have shown that ovarian cancer risk decreases with increasing parity and increasing duration of oral contraceptive use. During this period, parity has declined while oral contraceptive use has increased. We compared temporal trends in observed ovarian cancer incidence rates with rates predicted by changes in parity and duration of oral contraceptive use to determine whether the changes in these characteristics could explain the declining rates in younger women. In addition, we wished to examine whether oral contraceptive use continues to be protective to postmenopausal women. To predict changes in rates between 1970 and 1995, we assumed that increases in parity and duration of oral contraceptive use induce proportional decreases in incidence rates. We found that the rates predicted by these assumptions agreed well with observed rates in young women (age 30-49) but were substantially lower than observed rates in older women (age 50-64). The data indicate that the relative decrease in incidence rates due to the protective effect of oral contraceptive use declines with age.

    View details for Web of Science ID 000085472700004

    View details for PubMedID 11021604

  • Differences in socioeconomic status and survival among white and black men with prostate cancer AMERICAN JOURNAL OF EPIDEMIOLOGY Robbins, A. S., Whittemore, A. S., Thom, D. H. 2000; 151 (4): 409-416

    Abstract

    After diagnosis with prostate cancer, Black men in the United States have poorer survival than White men, even after controlling for differences in cancer stage. The extent to which these racial survival differences are due to biologic versus non-biologic factors is unclear, and it has been hypothesized that differences associated with socioeconomic status (SES) might account for much of the observed survival difference. The authors examined this hypothesis in a cohort study, using cancer registry and US Census data for White and Black men with incident prostate cancer (n = 23,334) who resided in 1,005 census tracts in the San Francisco Bay Area during 1973-1993. Separate analyses were conducted using two endpoints: death from prostate cancer and death from other causes. For each endpoint, death rate ratios (Blacks vs. Whites) were computed for men diagnosed at ages <65 years and at ages > or =65 years. These data suggest that differences associated with SES do not explain why Black men die from prostate cancer at a higher rate when compared with White men with this condition. However, among men with prostate cancer, SES-associated differences appear to explain almost all of the racial difference in risk of death from other causes.

    View details for Web of Science ID 000085474800010

    View details for PubMedID 10695600

  • Correction Statistics in medicine Whittemore, A. S. 2000; 19 (9): 1251

    View details for PubMedID 10797520

  • Estimating genetic influence on disease from population-based case-control data: Application to cancers of the breast and ovary STATISTICS IN MEDICINE Gong, G., Whittemore, A. S. 1999; 18 (23): 3321-3336

    Abstract

    We describe genetic mixture models and goodness-of-fit statistics for evaluating the joint effects of genetic and environmental factors on the risk of chronic diseases. We focus particularly on situations wherein the gene(s) of interest play roles in several diseases, and death due to one disease can censor the occurrence of others. We use the methods to investigate the risks of cancers of the breast and ovary associated with germline mutations of BRCA1, using data pooled from three population-based U.S. case-control studies of ovarian cancer. We evaluate the goodness-of-fit of the genetic models by comparing the predicted numbers of diseased mother-daughter and sister-sister pairs to the numbers observed. We also use simulations to examine the performance of estimates obtained from such complex mixture models, and the contribution of control families to the precision of parameter estimates.

    View details for Web of Science ID 000084077400014

    View details for PubMedID 10602154

  • The Eighth AACR American Cancer Society Award lecture on cancer epidemiology and prevention. Genetically tailored preventive strategies: an effective plan for the twenty-first century? American Association for Cancer Research. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Whittemore, A. S. 1999; 8 (8): 649-658

    Abstract

    A preventive strategy of considerable appeal would offer specific lifestyle changes and preventive interventions to people at increased cancer risk because of inherited susceptibility. The hope for such a strategy stems in part from the variation in risk among carriers of cancer-predisposing mutations. For example, despite the high risks of cancers of the breast and ovary among BRCA1 and BRCA2 mutation carriers, some 30% of these women are estimated to reach age 70 years without developing either cancer. We need to know what protects these women, compared with carriers who do develop these malignancies. Apart from chance, possible explanations include variation in type of mutation, in genotypes at other loci, or in potentially modifiable lifestyle characteristics. This article reviews our present knowledge about risks for cancers of the colorectum, female breast, and ovary in carriers of highly penetrant germ-line mutations of susceptibility genes. The paper also reviews our present knowledge about options for reducing these risks through changes in lifestyle, chemopreventive agents, and prophylactic surgery. It concludes with a discussion of what we need to know to offer those with inherited susceptibility safe, effective options for preventing these cancers and to provide a framework for deciding among the options.

    View details for PubMedID 10744124

  • Power of association and linkage tests when the disease alleles are unobserved AMERICAN JOURNAL OF HUMAN GENETICS Tu, I. P., Whittemore, A. S. 1999; 64 (2): 641-649

    Abstract

    Genomewide association studies have been advocated as a promising alternative to genomewide linkage scans for detection of small-effect genes in complex diseases. Comparisons of power and sample size between the two strategies have shown considerable advantages for the association studies. These comparisons assume that the set of markers includes the exact disease-related polymorphism. A concern, however, is that the power of an association study decreases when this is not the case, because of discrepant allele frequencies and less-than-maximum disequilibrium between the disease-related polymorphism and its nearest marker. Here, we quantify this concern by comparing the sample sizes needed by the two strategies when the markers exclude the disease-related polymorphism. For affected sib pairs and their parents, we found that incomplete disequilibrium and differing allele frequencies can have substantial negative impact on the power of association studies, resulting, in some circumstances, in little gain and even in loss of power, compared with linkage analysis. We provide some guidelines for choosing between strategies, for the detection of genes for complex diseases.

    View details for Web of Science ID 000078740600035

    View details for PubMedID 9973303

  • Multipoint linkage analysis - A cautionary note HUMAN HEREDITY Halpern, J., Whittemore, A. S. 1999; 49 (4): 194-196

    Abstract

    Multipoint linkage analysis is commonly used to evaluate linkage of a disease to multiple markers in a small region. Multipoint analysis is particularly powerful when the IBD relations of family members at the trait locus are ambiguous. The increased power arises because, unlike single-marker analyses, multipoint analysis uses haplotype information from several markers to infer the IBD relations. We wish to temper this advantage with a cautionary note: multipoint analysis is sensitive to power loss due to misspecification of intermarker distances. Such misspecification is especially problematic when dealing with closely spaced markers. We present computer simulations comparing the power of single-point and multipoint analyses, both when IBD relations are ambiguous, and when the intermarker distances are misspecified. We conclude that when evaluating markers in a small region to confirm or refute previous findings, a situation in which p values of modest statistical significance are important, single marker analyses may provide more reliable measures of the strength of support for linkage than multipoint statistics.

    View details for Web of Science ID 000081857700004

    View details for PubMedID 10436380

  • Study design in genetic epidemiology: theoretical and practical considerations. Journal of the National Cancer Institute. Monographs Whittemore, A. S., Nelson, L. M. 1999: 61-69

    Abstract

    Recent advances in molecular genetics have created new opportunities and challenges for genetic epidemiologists. Here we review some of the issues that arise when designing a study involving the genetic epidemiology of chronic diseases of late onset, such as cancer. We discuss two considerations that influence the choice of design. The first consideration is the study's goals. We describe the goals of identifying new susceptibility genes for a disease, of estimating important characteristics of known genes, and of learning how to prevent the disease in the genetically susceptible. We indicate how these goals affect the choice of design and present some guidelines for choosing designs that effectively address them. The second consideration is the set of practical constraints to successfully conducting the research. These contraints include problems of potential selection bias, reduced response rates, problems particular to family registries, problems particular to the cultures of various ethnic groups, and ethical issues. We indicate how these constraints affect the choice of design and discuss ways to deal with them.

    View details for PubMedID 10854488

  • Prostate cancer incidence and mortality in the United States and the United Kingdom JOURNAL OF THE NATIONAL CANCER INSTITUTE Shibata, A., Ma, J., Whittemore, A. S. 1998; 90 (16): 1230-1231

    View details for Web of Science ID 000075476700014

    View details for PubMedID 9719085

  • Race, prostate cancer survival, and membership in a large health maintenance organization JOURNAL OF THE NATIONAL CANCER INSTITUTE Robbins, A. S., Whittemore, A. S., Van Den Eeden, S. K. 1998; 90 (13): 986-990

    Abstract

    Population-based cancer registry data have shown that black men with prostate cancer have poorer stage-specific survival than white men, while studies in equal-access health care systems have not found racial differences in stage-specific survival. This study was designed to test the hypothesis that black men and white men with prostate cancer have equal stage-specific survival in equal-access health care systems.We conducted a cohort study using cancer registry data from all incident cases of prostate cancer occurring in a five-county San Francisco Bay Area region. Incident cases occurred among members (5263 cases, from January 1973 through June 1995) and nonmembers (16,019 cases, from January 1973 through December 1992) of the Kaiser Permanente Medical Care Program, a large health maintenance organization. Death rate ratios (DRRs, black men versus white men) for Kaiser members and nonmembers were computed for all stages combined (adjusting for age and stage) and for each stage (adjusting for age).Among Kaiser members, adjusted DRRs comparing black men with white men were as follows: all stages combined, 1.28 (95% confidence interval [CI] = 1.14-1.44); local stage, 1.23 (95% CI = 1.01-1.51); regional stage, 1.30 (95% CI = 0.97-1.75); and distant stage, 1.27 (95% CI = 1.07-1.50). Corresponding DRRs for nonmembers were as follows: all stages combined, 1.22 (95% CI = 1.14-1.30); local stage, 1.24 (95% CI = 1.09-1.41); regional stage, 1.48 (95% CI = 1.29-1.68); and distant stage, 1.01 (95% CI = 0.91-1.12).These results show poorer prostate cancer survival for black men compared with white men in an equal-access medical care setting. The findings are most consistent with the hypothesis of increased tumor virulence in blacks.

    View details for Web of Science ID 000074508800010

    View details for PubMedID 9665146

  • Simple, robust linkage tests for affected sibs AMERICAN JOURNAL OF HUMAN GENETICS Whittemore, A. S., Tu, I. P. 1998; 62 (5): 1228-1242

    Abstract

    Parametric-linkage analysis applied to large pedigrees with many affected individuals has helped in the identification of highly penetrant genes; but, for diseases lacking a clear Mendelian inheritance pattern or caused by several genes of low to moderate penetrance, a more robust strategy is nonparametric analysis applied to small sets of affected relatives, such as affected sib pairs. Here we show that the robustness of affected-sib-pair tests is related to the shape of the constraint set for the sibs' identity-by-descent (IBD) probabilities. We also derive a set of constraints for the IBD probabilities of affected sib triples and use common features of the shapes of the two constrain sets to introduce new nonparametric tests (called "minmax" tests) that are more robust than those in current use. Asymptotic-power computations support the robustness of the proposed minmax tests.

    View details for Web of Science ID 000073487000027

    View details for PubMedID 9599188

  • Serum levels of prostate-specific antigen among Japanese-American and native Japanese men JOURNAL OF THE NATIONAL CANCER INSTITUTE Shibata, A., Whittemore, A. S., Imai, K., Kolonel, L. N., Wu, A. H., John, E. H., Stamey, T. A., Paffenbarger, R. S. 1997; 89 (22): 1716-1720

    Abstract

    Fourfold to sixfold higher prostate cancer rates in Japanese-American men in the United States compared with Japanese men in Japan have been cited to support a role for environmental risk factors in the etiology of the disease. To examine the hypothesis that part or all of the elevated prostate cancer rates in Japanese-American men may reflect more intensive prostate cancer screening in the United States than in Japan, we compared prostate-specific antigen (PSA) levels in community-based samples of serum from men without prostate cancer.Japanese-American men aged 40-85 years and native Japanese men aged 40-89 years with no history of prostate cancer provided sera, respectively, in the United States from March 1990 through March 1992 (n = 237) or in Japan from January 1992 through December 1993 (n = 3522). Age-specific PSA levels were used to estimate the prevalences of undetected prostate cancer in the two populations.Age-specific mean PSA levels were significantly lower in Japanese-Americans than in native Japanese (two-sided P<.001). The prevalence of an elevated PSA level increased with age in both populations and exceeded 5% among men aged 60 years or more. Combined with data on prevalence of detected prostate cancer in the two populations, our data suggest that some 10.0% of Japanese-Americans aged 75 years have prostate cancer, with 31% of that fraction remaining undiagnosed. The corresponding estimates in Japan are a total cancer prevalence of 5.4%, of which 81% has not been detected clinically.The total cancer prevalence ratio 10.0/5.4 = 1.9 (95% confidence interval = 1.5-2.3) in Japanese-American men compared with Japanese men in Japan suggests an increased risk for Japanese-American men, but of less magnitude than the fourfold to sixfold increase indicated by the incidence data.

    View details for Web of Science ID A1997YG50300016

    View details for PubMedID 9390541

  • Genetic predisposition to prostate cancer: Possible explanations for ethnic differences in risk PROSTATE Shibata, A., Whittemore, A. S. 1997; 32 (1): 65-72

    Abstract

    It seems unlikely that the large ethnic differences in prostate cancer risk can be explained completely by ethnic differences in diet or other lifestyle characteristics. Instead, the differences may be due to ethnic variation in endogenous factors, such as androgen metabolism or inherited susceptibility.We have reviewed the literature for evidence and support of ethnic variation in genetic susceptibility to prostate cancer as a reason for the ethnic differences in rates.We distinguish two types of ethnic variation: 1) variation in the prevalence of certain alleles of specific genes that confer modestly increased risk. Such variation might be reflected in ethnic differences in serum levels of androgens, their metabolites, or indicators of metabolism in the prostate; 2) variation in the prevalence of rare germline mutations conferring substantially increased risk. Such variation would be reflected in ethnic differences in familial aggregation of prostate cancer. We discuss the evidence in support of each of these two possibilities.Ethnic variation in polymorphic alleles of genes associated with modest fluctuations in risk could explain a large proportion of the ethnic difference in cancer risk. In contrast, rare mutations associated with substantially increased risk are likely to account for a smaller fraction of these differences.

    View details for Web of Science ID A1997XG77400009

    View details for PubMedID 9207959

  • Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: Results from three US population-based case-control studies of ovarian cancer AMERICAN JOURNAL OF HUMAN GENETICS Whittemore, A. S., Gong, G., ITNYRE, J. 1997; 60 (3): 496-504

    Abstract

    We investigate the familial risks of cancers of the breast and ovary, using data pooled from three population-based case-control studies of ovarian cancer that were conducted in the United States. We base estimates of the frequency of mutations of BRCA1 (and possibly other genes) on the reported occurrence of breast cancer and ovarian cancer in the mothers and sisters of 922 women with incident ovarian cancer (cases) and in 922 women with no history of ovarian cancer (controls). Segregation analysis and goodness-of-fit testing of genetic models suggest that rare mutations (frequency .0014; 95% confidence interval .0002-.011) account for all the observed aggregation of breast cancer and ovarian cancer in these families. The estimated risk of breast cancer by age 80 years is 73.5% in mutation carriers and 6.8% in noncarriers. The corresponding estimates for ovarian cancer are 27.8% in carriers and 1.8% in noncarriers. For cancer risk in carriers, these estimates are lower than those obtained from families selected for high cancer prevalence. The estimated proportion of all U.S. cancer diagnoses, by age 80 years, that are due to germ-line BRCA1 mutations is 3.0% for breast cancer and 4.4% for ovarian cancer. Aggregation of breast cancer and ovarian cancer was less evident in the families of 169 cases with borderline ovarian cancers than in the families of cases with invasive cancers. Familial aggregation did not differ by the ethnicity of the probands, although the number of non-White and Hispanic cases (N = 99) was sparse.

    View details for Web of Science ID A1997WK40300005

    View details for PubMedID 9042908

  • Genome scanning for linkage: An overview AMERICAN JOURNAL OF HUMAN GENETICS Whittemore, A. S. 1996; 59 (3): 704-716

    Abstract

    Several different methods for linkage analysis are shown to arise from a single likelihood function L for the observed allele-sharing data at multiple markers in a chromosomal region. These include classical parametric lod score methods, nonparametric or "model-free" affected pedigree-member (APM) methods, and the Gaussian process method. Setting the methods in the context of the likelihood function L clarifies their underlying assumptions. A test statistic derived from L, the efficient score statistic, is introduced. It is asymptotically equivalent to the lod score, but it can be easier to compute when the penetrances and frequencies of alleles of the trait gene are not known. APM test statistics and the Gaussian lod score are shown to be special cases of efficient score statistics. This unified framework facilitates exploration of a range of models for the effects of a putative trait-predisposing gene, and it facilitates sensitivity analyses to examine the consequences of model misspecification.

    View details for Web of Science ID A1996VN62500025

    View details for PubMedID 8751872

  • VASECTOMY AND PROSTATE-CANCER - RESULTS FROM A MULTIETHNIC CASE-CONTROL STUDY JOURNAL OF THE NATIONAL CANCER INSTITUTE John, E. M., Whittemore, A. S., Wu, A. H., Kolonel, L. N., Hislop, T. G., Howe, G. R., West, D. W., Hankin, J., Dreon, D. M., Teh, C. Z., Burch, J. D., PAFFENBARGER, S. 1995; 87 (9): 662-669

    Abstract

    Vasectomy, a widely used form of contraception, has been associated in some studies with increased prostate cancer risk.We assessed this association on the basis of data collected in a large multiethnic case-control study of prostate cancer that was conducted in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Toronto and Vancouver).In home interviews conducted with newly diagnosed prostate cancer case patients and population control subjects, we obtained information on the participants' medical history, including a history of vasectomy and the age at which the procedure was performed, as well as other potential risk factors. Blood samples were collected from control subjects only and were assayed for concentration of sex hormones and sex hormone-binding globulin.The present analysis was based on 1642 prostate cancer patients and 1636 control subjects. A history of vasectomy was not significantly associated with prostate cancer risk among all racial/ethnic groups combined (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 0.83-1.3), whites (OR = 0.94; 95% CI = 0.69-1.3), blacks (OR = 1.0; 95% CI = 0.59-1.8), or Chinese-Americans (OR = 0.96; 95% CI = 0.42-2.2). Among Japanese-Americans, the OR was 1.8 (95% CI = 0.97-3.4), but the statistically nonsignificant elevation in risk was limited to more educated men and those with localized cancers. ORs did not vary significantly by age at vasectomy or years since vasectomy. We found a lower serum concentration of sex hormone-binding globulin and a higher ratio of dihydrotestosterone to testosterone among vasectomized control subjects than among nonvasectomized control subjects.The findings of this study do not support previous reports of increased prostate cancer risk associated with vasectomy. However, the altered endocrine profiles of vasectomized control subjects seen in this cross-sectional comparison warrant further evaluation in longitudinal studies.

    View details for Web of Science ID A1995QV01400013

    View details for PubMedID 7538594

  • PROSTATE-CANCER IN RELATION TO DIET, PHYSICAL-ACTIVITY, AND BODY-SIZE IN BLACKS, WHITES, AND ASIANS IN THE UNITED-STATES AND CANADA JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Kolonel, L. N., Wu, A. H., John, E. M., Gallagher, R. P., Howe, G. R., Burch, J. D., Hankin, J., Dreon, D. M., West, D. W., Teh, C. Z., Paffenbarger, R. S. 1995; 87 (9): 652-661

    Abstract

    International and interethnic differences in prostate cancer incidence suggest an environmental, potentially modifiable etiology for the disease.We conducted a population-based case-control study of prostate cancer among blacks (very high risk), whites (high risk), and Asian-Americans (low risk) in Los Angeles, San Francisco, Hawaii, Vancouver, and Toronto. Our aim was to evaluate the roles of diet, physical activity patterns, body size, and migration characteristics on risk in these ethnic groups and to assess how much of the interethnic differences in risk might be attributed to interethnic differences in such lifestyle characteristics.We used a common protocol and questionnaire to administer personal interviews to 1655 black, white, Chinese-American, and Japanese-American case patients diagnosed during 1987-1991 with histologically confirmed prostate carcinoma and to 1645 population-based control subjects matched to case patients by age, ethnicity, and region of residence. Sera collected from 1127 control subjects were analyzed for levels of prostate-specific antigen (PSA) to permit comparison of case patients with control subjects lacking serological evidence of prostate disease. Odds ratios were estimated using conditional logistic regression. We estimated the proportion of prostate cancer attributable to certain risk factors and the proportion of interethnic risk differences attributable to interethnic differences in risk-factor prevalence.A positive statistically significant association of prostate cancer risk and total fat intake was found for all ethnic groups combined. This association was attributable to energy from saturated fats; after adjusting for saturated fat, risk was associated only weakly with monounsaturated fat and was unrelated to protein, carbohydrate, polyunsaturated fat, and total food energy. Saturated fat intake was associated with higher risks for Asian-Americans than for blacks and whites. In all ethnic groups combined, the risk tended to be higher when only case patients with advanced disease were compared with control subjects with normal PSA levels. Among foreign-born Asian-Americans, risk increased independently with years of residence in North America and with saturated fat intake. Crude estimates suggest that differences in saturated fat intake account for about 10% of black-white differences and about 15% of white-Asian-American differences in prostate cancer incidence. Risk was not consistently associated with intake of any micronutrients, body mass, or physical activity patterns.These data support a causal role in prostate cancer for saturated fat intake but suggest that other factors are largely responsible for interethnic differences in risk.

    View details for Web of Science ID A1995QV01400012

    View details for PubMedID 7752270

  • CHRONIC OBSTRUCTIVE PULMONARY-DISEASE IN LIFELONG NONSMOKERS - RESULTS FROM NHANES AMERICAN JOURNAL OF PUBLIC HEALTH Whittemore, A. S., Perlin, S. A., DICICCIO, Y. 1995; 85 (5): 702-706

    Abstract

    The prevalence of chronic obstructive pulmonary disease was evaluated in 12,980 lifelong nonsmoking adults who participated in one of three National US Health and Nutrition Examination Surveys. Also evaluated were the relationships between chronic obstructive pulmonary disease and age, sex, ethnicity, education, income, and certain environmental and occupational factors. Overall, 4% of men and 5% of women reported physician-diagnosed chronic obstructive pulmonary disease. Prevalence increased with age and with decreasing household income, was higher in Whites than in non-Whites, and was particularly high in Hispanic women. Further research is needed to explain the excess risk for chronic obstructive pulmonary disease in economically disadvantaged nonsmokers, and to assess the role of environmental tobacco smoke in nonsmokers' risk for the disease.

    View details for Web of Science ID A1995QW83900018

    View details for PubMedID 7733432

  • FAMILY HISTORY AND PROSTATE-CANCER RISK IN BLACK, WHITE, AND ASIAN MEN IN THE UNITED-STATES AND CANADA AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S., Wu, A. H., Kolonel, L. N., John, E. M., Gallagher, R. P., Howe, G. R., West, D. W., Teh, C. Z., Stamey, T. 1995; 141 (8): 732-740

    Abstract

    Increased risk of prostate cancer in men with a family history of the disease has been observed consistently in epidemiologic studies. However, most studies have been confined to white men; little is known about familial aggregation of prostate cancer in populations with unusually high incidence, such as African Americans, or in populations with low incidence, such as Asian-Americans. The authors report results from a population-based case-control study of prostate cancer among blacks, whites, and Asian-Americans in the United States and Canada. Controls were matched to cases on age (5-year groups), ethnicity (black, white, Chinese-American, Japanese-American), and region of residence (Los Angeles, San Francisco, Hawaii, Vancouver, Toronto). In the combined group of participants, 5% of controls and 13% of cases reported a father, brother, or son with prostate cancer. These prevalences were somewhat lower among Asian-Americans than among blacks or whites. A positive family history was associated with a statistically significant two- to threefold increase in risk in each of the three ethnic groups. The overall odds ratio associated with such a family history, adjusted for age and ethnicity, was 2.5 (95% confidence interval 1.9-3.3). This odds ratio varied by neither ethnicity nor age of the participants. Sera from 1,087 controls were used to examine the relations between family history and serum concentrations of androgens and prostate-specific antigen. The concentrations of sex hormone-binding globulin were slightly higher in men with than without a positive family history. Prostate-specific antigen concentrations were unrelated to family history.

    View details for Web of Science ID A1995QR99500006

    View details for PubMedID 7535977

  • PROSTATE-SPECIFIC ANTIGEN AS PREDICTOR OF PROSTATE-CANCER IN BLACK-MEN AND WHITE MEN JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Lele, C., Friedman, G. D., Stamey, T., Vogelman, J. H., Orentreich, N. 1995; 87 (5): 354-360

    Abstract

    The increasing incidence of prostate cancer creates complex issues in health care management and cost containment. There is a need to evaluate serial measurements of prostate-specific antigen (PSA) as a marker for long-term risk of clinically important prostate cancer (stages B through D).We used a nested case-control design within a retrospective cohort study to evaluate serial PSA concentrations in relation to subsequent prostate cancer diagnoses.Participants included 40 black and 96 white men with subsequent diagnoses of prostate cancer and 84 black and 100 white men without such diagnoses (control subjects) in a multiphasic health screening program conducted by the Kaiser Permanente Medical Care Program of Northern California. Serial serum samples were collected 1.5-23 years before prostate cancer diagnosis.Median serum PSA concentrations, specific for age and subsequent cancer status, were similar in blacks and whites. Concentrations in control subjects increased exponentially with age, with a doubling time of 24.9 years. Concentrations in men with stage A cancer were similar to those in control subjects. Until about 13 years before diagnosis, PSA in men with subsequent cancer stages B through D increased exponentially with age, with a doubling time similar to that of control subjects. Thereafter, the PSA concentrations increased exponentially, with a doubling time of 4.3 years. Rapid increase in PSA concentration started about 1.5 years earlier for men with stage D cancer than for men with stage B or C cancer. The single PSA measurement drawn closest to diagnosis was a more sensitive marker of stages B through D cancer within the next 7 years than was any index of change that also took account of earlier PSA readings.These data suggest that 1) age-specific PSA concentrations are similar in black men and white men and 2) current PSA concentration, specific for age, outperforms changes in past concentrations in identifying the man who will develop stage B, C, or D cancer within 7 years, albeit at the cost of a slightly higher rate of false-positive results. This interpretation needs confirmation in other data containing many serial PSA measurements within a few years of diagnosis.

    View details for Web of Science ID A1995QH57000008

    View details for PubMedID 7531773

  • SEGREGATION ANALYSIS OF CASE-CONTROL DATA USING GENERALIZED ESTIMATING EQUATIONS BIOMETRICS Whittemore, A. S., Gong, G. 1994; 50 (4): 1073-1087

    Abstract

    Generalized estimating equations (GEEs) (Liang and Zeger, 1986, Biometrika 73, 13-22) are used to fit genetic models to binary disease data for families of subjects in case-control studies. The GEEs include model specification of both the disease probabilities and the two-way (and possibly three-way) correlation coefficients of the family disease data. These quantities are modelled as nonlinear functions of unobserved genotypes, observed environmental covariates, and the unknown parameters; the functions reflect the method used to ascertain the family data. Goodness of fit is tested by allowing more flexible forms for the correlation coefficients, regressing them against covariates specific to the relevant pair (or triple) of family members. The approach is applied to family data obtained from simulated and real case-control studies. This semiparametric approach is less dependent on unverifiable assumptions and more computationally tractable than other methods for segregation analysis.

    View details for Web of Science ID A1994QP05000015

    View details for PubMedID 7786989

  • USE OF BIOLOGICAL MARKERS IN RISK ASSESSMENT RISK ANALYSIS McMillan, A., Whittemore, A. S., Silvers, A., DICICCIO, Y. 1994; 14 (5): 807-813

    Abstract

    Measurements of intermediate end points in the carcinogenic process may reduce uncertainty in human risk assessment from bioassay data, by identifying sources of interspecies variation and dose nonlinearity. This paper describes desirable properties of such markers: persistence, predictive power, temporal relevance, and consistency across dose rate and species. We illustrate these properties by evaluating markers for squamous cell nasal carcinoma in rodents exposed to formaldehyde. We also discuss design issues for bioassays that evaluate markers and tumors simultaneously at necropsy.

    View details for Web of Science ID A1994PT37000013

    View details for PubMedID 7800865

  • COMPARISON OF DIETARY HABITS, PHYSICAL-ACTIVITY AND BODY-SIZE AMONG CHINESE IN NORTH-AMERICA AND CHINA INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Lee, M. M., WUWILLIAMS, A., Whittemore, A. S., Zheng, S., Gallagher, R., Teh, C. Z., Zhou, L., Wang, X. H., Chen, K., Ling, C. D., JIAO, D. A., Jung, D., Paffenbarger, R. S. 1994; 23 (5): 984-990

    Abstract

    Chinese in North America have higher rates of many chronic diseases than do Chinese in Asia. However, there is a lack of data among comparisons of the environmental and lifestyle factors for Chinese in China and Chinese residing in North America.We examined self-reported dietary nutrient intakes, physical activity patterns and body mass index of 2488 healthy Chinese men and women residing in North America (US and Canada) and in the People's Republic of China.On average, Chinese in China consumed more calories (males 2904 kcal in China, versus 2201 kcal in North America; females 2317 Kcal in China, versus 1795 Kcal in North America and more carbohydrate, but less fat (males 72.2 g in China versus 84.5 g in North America, females 56.6 g in China versus 70.8 g in North America), protein, vitamin A, beta-carotene and vitamin C than did Chinese in North America. Per cent calories from fat was 35% for Chinese in North America and 22% for Chinese in China. In contrast, the per cent of calories from carbohydrates was 62-68% in China and 48% in North America. Chinese in China reported spending more time in vigorous activity, sleeping and walking but less hours in sitting than Chinese in North America. Chinese in China weighted less and were leaner than North American Chinese.These differences in nutrient intakes, physical activity and body size of Chinese living on two different continents suggest possible explanations for observed differences in chronic disease rates in the two populations.

    View details for Web of Science ID A1994PT30300014

    View details for PubMedID 7860179

  • PROBABILITY OF GENE IDENTITY BY DESCENT - COMPUTATION AND APPLICATIONS BIOMETRICS Whittemore, A. S., Halpern, J. 1994; 50 (1): 109-117

    Abstract

    Two genes at a given locus are identical by descent (IBD) if both have been inherited from a common ancestor. We present an algorithm for computing the probabilities of all IBD relationships among the genes of pedigree members. We show how to use these probabilities to calculate the probability of any combination of genotypes or phenotypes for the pedigree members. Applications to linkage analysis and genetic counseling are illustrated with examples. The algorithm also can be used to calculate the generalized kinship coefficients proposed by others.

    View details for Web of Science ID A1994NH26500010

    View details for PubMedID 8086594

  • A CLASS OF TESTS FOR LINKAGE USING AFFECTED PEDIGREE MEMBERS BIOMETRICS Whittemore, A. S., Halpern, J. 1994; 50 (1): 118-127

    Abstract

    We describe a class of nonparametric tests for linkage between a marker and a gene assumed to exist and to govern susceptibility to a disease. The tests are formed by assigning a score to each possible pattern of marker allele sharing (identity-by-descent) among affected pedigree members, and then averaging the scores over all patterns compatible with the observed marker genotype and genealogical relationship of the affected members. Different score functions give different tests. One function, which examines marker allele similarity across pairs of affected pedigree members, gives a test similar to that of Fimmers et al. (1989, in Multipoint Mapping and Linkage Based on Affected Pedigree Members: Genetic Analysis Workshop, R. C. Elston, M. A. Spence, S. E. Hodge, and J. W. MacCluer (eds), 123-128; City: Alan R. Liss). A second function examines allele similarity across arbitrary subsets, not just pairs, of affected members. The resulting test can be more powerful than the one based solely on pairs of affected members. The approach has several advantages: it does not require knowledge of the mode of disease inheritance; it does not require unambiguous determination of identity-by-descent at the marker; it does not suffer from variability due to chance allele similarity among affected members who are unrelated, such as spouses; it allows marker genotypes of unaffected members to contribute information on allele sharing among the affected; it permits calculation of exact P-values. Computational requirements limit the tests to many pedigrees with few (< 16) affected members.

    View details for Web of Science ID A1994NH26500011

    View details for PubMedID 8086596

  • Epidemiology and primary prevention of cancers of the breast, endometrium, and ovary. A brief overview. Annals of epidemiology Kelsey, J. L., Whittemore, A. S. 1994; 4 (2): 89-95

    Abstract

    Cancers of the breast, endometrium, and ovary account for 41% of incident cancers among women. Many risk factors for breast cancer have been identified, but most are associated with only modest elevations in risk. Also, of all the risk factors identified, few are likely to be affected by intervention programs. The pathogenesis of breast cancer is not well understood, but estrogen and possibly estrogen plus progesterone are likely to be etiologically involved. For endometrial cancer, a major etiologic pathway is exposure to estrogen without cyclic exposure to progesterone. Most of the established risk factors for endometrial cancer appear to affect risk at least in part through this pathway. Only a few risk factors for ovarian cancer have been identified. The two most commonly suggested etiologic mechanisms for ovarian cancer are (a) that suppression of ovulation reduces risk and (b) that suppression of pituitary gonadotropins reduces risk. Each hypothesis is consistent with some, but not all, of the data. Prospects for the primary prevention of these cancers are discouraging at present because few of the risk factors identified to date are readily subject to modification, especially for breast cancer, and the underlying etiologies of these cancers are not well understood, particularly for breast and ovarian cancers.

    View details for PubMedID 8205289

  • Prostate cancer. Cancer surveys Whittemore, A. S. 1994; 19-20: 309-322

    Abstract

    Trends in prostate cancer incidence and mortality are examined for men in England, Italy, Japan, Sweden and the USA. Incidence rose during the period 1968-1972 to 1983-1987 in all these populations. A substantial portion of this increase may be due to increased detection rates. However, mortality also has risen during this period in most of the populations. Although some of the increased mortality may be due to changes in death certification, the possibility of real increases in incidence of aggressive disease cannot be excluded. Large international and interethnic differences are evident for both incidence and mortality, in all time periods. Interpretation of the differences in incidence is complicated by international and interethnic differences in detection rates. The differences in mortality are unlikely to be due entirely to differences in death certification. The temporal rise in incidence demonstrated by all these populations suggests worldwide increases in health care costs for prostate cancer. Since a large part of the increased incidence seems to be due to increased detection rates of localized disease that would otherwise have remained asymptomatic, the increased costs may not be associated with concomitant reductions in morbidity and mortality.

    View details for PubMedID 7895221

  • FERTILITY DRUGS AND RISK OF OVARIAN-CANCER HUMAN REPRODUCTION Whittemore, A. S. 1993; 8 (7): 999-1000

    View details for Web of Science ID A1993LK72800006

    View details for PubMedID 8408508

  • CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - COLLABORATIVE ANALYSIS OF 7 UNITED-STATES CASE-CONTROL STUDIES - EPITHELIAL OVARIAN-CANCER IN BLACK-WOMEN JOURNAL OF THE NATIONAL CANCER INSTITUTE John, E. M., Whittemore, A. S., Harris, R., ITNYRE, J. 1993; 85 (2): 142-147

    Abstract

    Previous epidemiologic studies of ovarian cancer have focused chiefly on White women, who have a higher incidence of ovarian cancer than Black women. No study has previously examined risk factors for ovarian cancer among Black women.This study was designed to evaluate the risk of epithelial ovarian cancer in Black women in relation to reproductive characteristics such as pregnancy, oral contraceptive use, and breast-feeding, and to determine whether differences in reproductive factors between Black and White women account for differences in ovarian cancer incidence.Combining interview data from seven case-control studies, we compared reproductive characteristics of 110 Black case subjects with a diagnosis of epithelial ovarian cancer between 1971 and 1986 with characteristics of 251 Black population control subjects and 114 Black hospital control subjects. We also compared the prevalence of reproductive factors in 246 Black population control subjects and 4378 White population control subjects and estimated the fraction of Black-White differences in ovarian cancer incidence attributable to racial differences in prevalence of these characteristics.Decreased risks of epithelial ovarian cancer in Black women were associated with parity of four or higher (odds ratio [OR] = 0.53; 95% confidence interval [CI] = 0.25-1.1), breast-feeding for 6 months or longer (OR = 0.85; 95% CI = 0.36-2.0), and use of oral contraceptives for 6 years or longer (OR = 0.62; 95% CI = 0.24-1.6). A greater proportion of Black women (48%) than White women (27%) reported four or more term pregnancies, and Black women (62%) were more likely than White women (53%) to have breast-fed their children. Oral contraceptive use was more common among White women (59%) than Black women (51%).Differences in the prevalence of other factors related to ovarian cancer risk or differences in genetic susceptibility must explain most of the Black-White differences in incidence of ovarian cancer.

    View details for Web of Science ID A1993KG46800012

    View details for PubMedID 8418303

  • USE OF NHANES DATA TO ASSIGN NUTRIENT DENSITIES TO FOOD GROUPS IN A MULTIETHNIC DIET HISTORY QUESTIONNAIRE NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL Dreon, D. M., John, E. M., DICICCIO, Y., Whittemore, A. S. 1993; 20 (3): 223-230

    Abstract

    In epidemiological studies of diet and chronic disease, a brief yet comprehensive diet history questionnaire must aggregate some foods into food groups. A nutrient density is assigned to each food group by averaging the densities of its constituent foods. A person's intake of a given nutrient is then estimated by multiplying the reported consumption of each food group by its average nutrient density and summing over food groups. These calculations could introduce bias in multiethnic studies, if the average nutrient densities assigned to food groups are inappropriate for some ethnic populations. This issue is examined here for intakes of total fat, saturated fat, and vitamin A for U.S. blacks and whites. We used 24-hour diet recall data from the Second National Health and Nutrition Examination Survey (NHANES II) to assess black-white differences in relative frequency of consumption of foods within food groups of a diet history questionnaire. We also calculated ethnic-specific average nutrient densities for each food group by weighting the densities of its foods in proportion to their frequency of consumption by black and white NHANES II participants. We found black-white differences in the frequency of consumption of foods within 14 food groups. However, blacks and whites had different average total fat densities for only 1 of the 14 food groups, no difference in saturated fat densities for any food group, and different vitamin A densities for 2 food groups. Among blacks and whites, there is no advantage to calculating ethnic-specific average nutrient densities for food groups comprised of foods with similar densities.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993MK02900004

    View details for PubMedID 8108272

  • CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - COLLABORATIVE ANALYSIS OF 12 UNITED-STATES CASE-CONTROL STUDIES .3. EPITHELIAL TUMORS OF LOW MALIGNANT POTENTIAL IN WHITE WOMEN AMERICAN JOURNAL OF EPIDEMIOLOGY Harris, R., Whittemore, A. S., ITNYRE, J. 1992; 136 (10): 1204-1211

    Abstract

    Epithelial ovarian neoplasms of low malignant potential, also called borderline ovarian tumors, have various features of malignancy, but they do not invade the ovarian stroma. Women with these tumors usually are younger when diagnosed and have better prognoses than do women with invasive tumors. There have been few epidemiologic studies of borderline tumors, and it is unclear whether there are etiologic differences between the two types of tumor behavior. Combined data from nine case-control studies, conducted from 1974 to 1986 and representing 327 white women with tumors of low malignant potential and 4,144 white controls, were used to evaluate the relation between these tumors and personal characteristics related to invasive ovarian cancer. The risk profile for tumors of low malignant potential was found to be similar to that for invasive tumors, with two exceptions: Compared with that of invasive tumors, risk of borderline tumors was less clearly reduced among women who had used oral contraceptives and more clearly elevated among women with a history of infertility.

    View details for Web of Science ID A1992KG47200003

    View details for PubMedID 1476142

  • CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - COLLABORATIVE ANALYSIS OF 12 UNITED-STATES CASE-CONTROL STUDIES .1. METHODS AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S., Harris, R., ITNYRE, J., Halpern, J. 1992; 136 (10): 1175-1183

    Abstract

    Data from 12 US case-control studies of ovarian cancer, conducted during the period 1956-1986 and representing some 3,000 cases and 10,000 controls, were pooled and reanalyzed. Separate analyses were conducted for four subgroups of the pooled data: invasive epithelial ovarian cancers in white women; epithelial ovarian cancers of low malignant potential in white women, epithelial ovarian cancers in black women, and nonepithelial ovarian cancers. This paper gives a brief description of the participating studies and describes the methods used in the collaborative analysis.

    View details for Web of Science ID A1992KG47200001

    View details for PubMedID 1476140

  • CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - COLLABORATIVE ANALYSIS OF 12 UNITED-STATES CASE-CONTROL STUDIES .2. INVASIVE EPITHELIAL OVARIAN CANCERS IN WHITE WOMEN AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S., Harris, R., ITNYRE, J. 1992; 136 (10): 1184-1203

    Abstract

    Data collected from 2,197 white ovarian cancer patients and 8,893 white controls in 12 US case-control studies conducted in the period 1956-1986 were used to evaluate the relation of invasive epithelial ovarian cancer to reproductive and menstrual characteristics, exogenous estrogen use, and prior pelvic surgeries. Clear trends of decreasing risk were evident with increasing number of pregnancies (regardless of outcome) and increasing duration of breast feeding and oral contraceptive use. Ovarian dysfunction leading to both infertility and malignancy is an unlikely explanation for these trends for several reasons: 1) The trends were evident even among the highly parous; 2) risk among nulliparous women did not vary by marital status or gravidity; and 3) risk among ever-married women showed little relation to length of longest pregnancy attempt or history of clinically diagnosed infertility. Risk was increased among women who had used fertility drugs and among women with long total duration of premenopausal sexual activity without birth control; these associations were particularly strong among the nulligravid. No consistent trends in risk were seen with age at menarche, age at menopause, or duration of estrogen replacement therapy. A history of tubal ligation or of hysterectomy with ovarian conservation was associated with reduced ovarian cancer risk. These observations suggest that pregnancy, breast feeding, and oral contraceptive use induce biological changes that protect against ovarian malignancy, that, at most, a small fraction of the excess ovarian cancer risk among nulliparous women is due to infertility, and that any increased risk associated with infertility may be due to the use of fertility drugs.

    View details for Web of Science ID A1992KG47200002

    View details for PubMedID 1476141

  • CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - COLLABORATIVE ANALYSIS OF 12 UNITED-STATES CASE-CONTROL STUDIES .4. THE PATHOGENESIS OF EPITHELIAL OVARIAN-CANCER AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S., Harris, R., ITNYRE, J. 1992; 136 (10): 1212-1220

    Abstract

    Two hypotheses have been proposed to explain the reduced risk of epithelial ovarian cancer associated with pregnancy and oral contraceptive use. The first states that some sequelae of ovulation increase the likelihood of malignancy and that pregnancies and oral contraceptives protect by suppressing ovulation. The second hypothesis states that circulating levels of pituitary gonadotropins increase the risk of malignancy and that pregnancies and oral contraceptives protect by suppressing secretion of these hormones. The authors evaluate the two hypotheses in light of combined data from 12 United States case-control studies of epithelial ovarian cancer in white women conducted from 1956 to 1986. While a number of observations support both hypotheses, there are exceptions. Differential risk reduction associated with pregnancy and oral contraceptive use (pregnancy being the more effective in young women and the less effective in older women) conflicts with the first "ovulation" hypothesis, while reduced risk associated with breast feeding and absence of altered risk associated with estrogen replacement therapy conflicts with the second "gonadotropin" hypothesis. Several findings would not have been predicted by either hypothesis, e.g., only weak trends relate cancer risk to age at menarche, and, among older women, no clear trends relate risk to age at menopause. Odds ratio attenuation due to errors in reporting personal characteristics may be responsible for some of these inconsistencies. Multidisciplinary research is needed to clarify the etiologic roles of ovulation and gonadotropin stimulation, both of which may enhance carcinogenesis in the ovarian epithelium.

    View details for Web of Science ID A1992KG47200004

    View details for PubMedID 1476143

  • CUTANEOUS MELANOMA AT LAWRENCE-LIVERMORE-NATIONAL-LABORATORY - COMPARISON WITH RATES IN 2 SAN-FRANCISCO BAY AREA COUNTIES CANCER CAUSES & CONTROL Gong, G., Whittemore, A. S., West, D., Moore, D. H. 1992; 3 (3): 191-197

    Abstract

    During the period 1974 through 1985, employees at Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States) were diagnosed with cutaneous malignant melanoma at approximately three times the rate of the surrounding community. We investigated two explanations for this excess: the first explanation examined was that the recorded incidence of the neighboring community underestimates actual incidence. We estimated the amount of excess attributable to underreporting by using data from a survey conducted among San Francisco Bay Area clinicians and pathologists to determine previously unrecorded occurrences. We found that underreporting has negligible impact on melanoma incidence. The second explanation examined was that heightened medical awareness of the disease among LLNL employees and their physicians has led to greater detection. We found that LLNL melanomas are thinner than those from the surrounding community and that no excess was observed if we limited our attention to thicker, more invasive melanomas.

    View details for Web of Science ID A1992HU58700001

    View details for PubMedID 1610965

  • LOW-GRADE, LATENT PROSTATE-CANCER VOLUME - PREDICTOR OF CLINICAL CANCER INCIDENCE JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Keller, J. B., Betensky, R. 1991; 83 (17): 1231-1235

    Abstract

    We hypothesize that each cell in low-grade (Gleason grade 1-3) prostate cancer tissue is at risk of transformation into a cell which produces a high-grade (Gleason grade 4-5) clinical cancer after a short period of growth. As a consequence, the volume of low-grade, latent cancer tissue in the prostate glands of men at any age determines their incidence rate for high-grade, clinical cancer a few years later. Autopsy and incidence data for both white men and black men support this conclusion, with a tumor growth period of about 7 years. The transformation rate is similar for black men and for white men, about 0.024 high-grade cancers per year per cm3 of low-grade, latent cancer volume. Our hypothesis explains the infrequent occurrence of clinical cancer despite the high prevalence of latent cancer, the steep rise of clinical cancer incidence with age despite the slow rise of latent cancer prevalence with age, and the disparities in clinical cancer incidence among some populations despite their similar latent cancer prevalence. This hypothesis suggests that low-grade cancer volume is a critical determinant of clinical cancer risk.

    View details for Web of Science ID A1991GD15200012

    View details for PubMedID 1870149

  • FAMILY DATA DETERMINE ALL PARAMETERS IN MENDELIAN INCOMPLETE PENETRANCE MODELS ANNALS OF HUMAN GENETICS Whittemore, A. S., Keller, J. B., Ward, M. J. 1991; 55: 175-177

    Abstract

    We show that data on the frequency of occurrence of an hereditary trait in family members can be used to determine all four parameters in a Mendelian genetic model with incomplete penetrance. Thus previous statements in the literature that such data can determine only three combinations of the parameters are incorrect.

    View details for Web of Science ID A1991FV08800009

    View details for PubMedID 1952809

  • URINARY CADMIUM AND BLOOD-PRESSURE - RESULTS FROM THE NHANES-II SURVEY ENVIRONMENTAL HEALTH PERSPECTIVES Whittemore, A. S., DICICCIO, Y., Provenzano, G. 1991; 91: 133-140

    Abstract

    Relationships between urinary cadmium levels and blood pressure were examined in a sample of 951 adult men and women who participated in the Second National Health and Nutritional Examination Survey (NHANES II). Among all participants, positive relationships were seen between urinary cadmium levels and both systolic and diastolic blood pressure (p less than 0.05 and p less than 0.01, respectively), after adjusting for age, sex, race, relative body weight, smoking status, and hypertensive medication use. However, analyses for subgroups determined by sex and smoking status were inconsistent. Among current smokers, urinary cadmium levels were significantly positively associated with both systolic and diastolic blood pressure for women, and with diastolic blood pressure for men. Yet among former smokers and lifelong nonsmokers of both sexes, urinary cadmium was not significantly associated with either systolic or diastolic blood pressure. Evidence that some hypertensive medications increase urinary cadmium excretion suggests that the positive associations seen among current smokers may reflect high urinary cadmium levels among hypertensives induced by hypertensive treatment. After treated hypertensives were removed from the analysis, regression coefficients relating blood pressure to cadmium dropped by a factor of two and lost statistical significance. We conclude that the present data provide little support for a causal association between systemic cadmium and hypertension at nonoccupational exposure levels. Further, conflicting results of previous studies may reflect failure to control adequately for age, smoking status, and hypertensive treatment.

    View details for Web of Science ID A1991FD60400014

    View details for PubMedID 2040243

  • THE IMPORTANCE OF MODELS IN THE ASSESSMENT OF SYNERGY JOURNAL OF CLINICAL EPIDEMIOLOGY Hlatky, M. A., Whittemore, A. S. 1991; 44 (12): 1287-1288

    View details for Web of Science ID A1991GY65900002

    View details for PubMedID 1753259

  • DIET, PHYSICAL-ACTIVITY, AND COLORECTAL-CANCER AMONG CHINESE IN NORTH-AMERICA AND CHINA JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., WUWILLIAMS, A. H., Lee, M., Zheng, S., Gallagher, R. P., JIAO, D. A., Zhou, L., Wang, X. H., Chen, K., Jung, D., Teh, C. Z., Ling, C. D., Xu, J. Y., Paffenbarger, R. S., Henderson, B. E. 1990; 82 (11): 915-926

    Abstract

    In a population-based case-control study of colorectal cancer among Chinese men and women in western North America and the People's Republic of China, a common protocol was used to assess past life-style characteristics of 905 cases diagnosed during 1981-1986 and 2,488 controls. Risks for cancers of both the colon and rectum increased with increased food energy from fat, protein, carbohydrate, and all energy sources combined, for both sexes and on both continents. Yet, in multivariate analysis, colorectal cancer risk was significantly associated only with saturated fat; no relationships were seen with other dietary sources of energy. Colon cancer risk was elevated among men employed in sedentary occupations. On both continents and in both sexes, risks for cancers of both the colon and rectum increased with increasing time spent sitting. Further, the association between colorectal cancer risk and saturated fat was stronger among the sedentary than among the active. Risk among sedentary Chinese Americans of either sex increased more than fourfold from the lowest to the highest category of saturated fat intake. Among migrants to North America, risk increased with increasing years lived in North America. These observations suggest (a) that colorectal cancer risk increases with duration of exposure to a sedentary life-style and a diet rich in saturated fat; (b) that higher incidence among Chinese-American men relative to women is due to longer duration of these habits among men, who have lived longer in North America; and (c) that higher risk among Chinese Americans of both sexes relative to risk among the general population in China is due to differences in such habits. Attributable risk calculations suggest that, if these associations are causal, saturated fat intakes exceeding 10 g/day, particularly in combination with physical inactivity, could account for 60% of colorectal cancer incidence among Chinese-American men and 40% among Chinese-American women.

    View details for Web of Science ID A1990DG12800012

    View details for PubMedID 2342126

  • MYCOSIS-FUNGOIDES IN RELATION TO ENVIRONMENTAL EXPOSURES AND IMMUNE-RESPONSE - A CASE-CONTROL STUDY JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Holly, E. A., Lee, I. M., Abel, E. A., ADAMS, R. M., Nickoloff, B. J., Bley, L., Peters, J. M., Gibney, C. 1989; 81 (20): 1560-1567

    Abstract

    Mycosis fungoides is a cutaneous T-cell lymphoma of unknown etiology, thought to be a rare sequela of chronic antigenic stimulation that may occur, for example, with exposure to contact allergens. To explore this possibility, we interviewed 174 patients with mycosis fungoides and 294 randomly selected control subjects in the San Francisco, Los Angeles, and Seattle areas concerning their lifetime histories of employment, chemical exposures, allergy, atopy, and certain medical conditions. Patients reported higher prevalence of cancers other than the non-Hodgkin's lymphomas and skin cancers (relative risk = 3.3, P less than .001) and were more likely than controls to burn when exposed to the sun (for nonblacks, relative risk = 1.7, P = .01). The latter difference may reflect a manifestation rather than a precursor of the disease. We found no consistent or biologically plausible differences between patients and controls with respect to types of jobs held, or to occupational or vocational exposures to chemicals. These findings do not support the hypothesis that persistent antigenic stimulation by contact allergens is etiologically important in the pathogenesis of mycosis fungoides.

    View details for Web of Science ID A1989AU61300013

    View details for PubMedID 2795681

  • COLORECTAL-CANCER INCIDENCE AMONG CHINESE IN NORTH-AMERICA AND THE PEOPLES-REPUBLIC-OF-CHINA - VARIATION WITH SEX, AGE AND ANATOMICAL SITE INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Whittemore, A. S. 1989; 18 (3): 563-568

    Abstract

    Age-specific incidence rates for cancers of the colon and rectum are presented for Chinese in the western United States and Canada (high risk area), and in Shanghai, the People's Republic of China (low risk area). These rates are compared to those among North American whites. Among Chinese, rate differences between high and low risk areas are greater for colon cancer than rectal cancer, are greater for men than women, and increase with age. The most striking finding is the high colon cancer incidence among older Chinese-American men, compared to Chinese-American women. Colon cancer rates among elderly Chinese-American men equal those of whites, which are seven times the corresponding rates in China. By contrast, colon cancer rates among older Chinese-American women are intermediate between those of whites and those in China, and are only three to four times the rates in China. Rectal cancer rate differences for Chinese men also exceed those for Chinese women. However, they are less dramatic than for colon cancer, with elderly Chinese-American men having roughly double the rates in China, and with women exhibiting little variation between continents or ethnic groups. Male:female (M:F) rate ratios increase with age for both continents, both ethnic groups, and both colon and rectum. The colon cancer M:F ratios among Chinese-Americans exceed the others, reaching two in the older age groups. These observations suggest sex-specific aetiological exposures, or sex-specific susceptibilities to common exposures, among Chinese-Americans.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1989CA15200011

    View details for PubMedID 2807658

  • EPITHELIAL OVARIAN-CANCER AND THE ABILITY TO CONCEIVE CANCER RESEARCH Whittemore, A. S., Wu, M. L., Paffenbarger, R. S., SARLES, D. L., Kampert, J. B., Grosser, S., Jung, D. L., Ballon, S., Hendrickson, M., MOHLEBOETANI, J. 1989; 49 (14): 4047-4052

    Abstract

    Relationships between ovarian cancer and ability to conceive were explored in a case-control study of 188 women with histologically confirmed epithelial ovarian cancer and 539 control women in the San Francisco Bay Area. Control women consisted of two groups: those hospitalized without cancer, matched to cases by age, race, and hospital of diagnosis (n = 280); and those selected from the general population by random digital dialing, matched to cases by age, race, and telephone prefix (n = 259). Ovarian cancer risk among nulliparous (but not parous) women was positively associated with a history of unsuccessful attempts to conceive, of physician-diagnosed infertility, and of doubts about ability to conceive. Among all women, risk increased with increasing years of unprotected intercourse (P value for trend = 0.02). Risk among women having 10 or more yr of unprotected intercourse was 1.8 relative to that among women having less than 2 such yr (P = 0.01). This association was independent of parity, oral contraceptive use, and estimated years of ovulation, each associated with ovarian cancer. Further, duration of unprotected intercourse combined multiplicatively with each of these latter characteristics in increasing ovarian cancer risk. For example, while cancer risk exhibited a 2-fold range from lowest to highest years of unprotected intercourse and a 4-fold range from lowest to highest years of ovulation, risk among women in the highest joint category of these characteristics was 8 times that of women in the lowest category. We believe that some abnormality of ovulation that reduces the likelihood of conception plays a role in epithelial ovarian cancer.

    View details for Web of Science ID A1989AE49800059

    View details for PubMedID 2736545

  • CANCER RISK ASSESSMENT AND PREVENTION - WHERE DO WE STAND ENVIRONMENTAL HEALTH PERSPECTIVES Whittemore, A. S. 1989; 81: 95-101

    Abstract

    This paper reviews selected aspects of progress and setbacks in cancer risk assessment and prevention during the four decades since the founding in 1947 of the Institute of Environmental Medicine at the New York University Medical Center. The period has been marked by substantial gains in quantifying the risks posed by exposures to known human carcinogens such as tobacco and ionizing radiation. By contrast, the search for sensitive and specific laboratory screens for human carcinogens has met setbacks, and epidemiological data still are needed to monitor the adverse effects of environmental exposures. The determination of acceptable levels of exposure to potential human carcinogens remains a formidable task, one for which no scientific framework yet exists. Future challenges in cancer risk assessment include the validation and use of biological markers of exposure and effective monitoring of risk among exposed populations. Future challenges in cancer prevention include the elimination of tobacco consumption and the acquisition of knowledge needed to prevent nutritionally and hormonally related cancers such as cancers of the bowel, prostate, and breast.

    View details for Web of Science ID A1989AA49000019

    View details for PubMedID 2667993

  • PERSONAL AND ENVIRONMENTAL CHARACTERISTICS RELATED TO EPITHELIAL OVARIAN-CANCER - .1. REPRODUCTIVE AND MENSTRUAL EVENTS AND ORAL-CONTRACEPTIVE USE AMERICAN JOURNAL OF EPIDEMIOLOGY Wu, M. L., Whittemore, A. S., Paffenbarger, R. S., SARLES, D. L., Kampert, J. B., Grosser, S., Jung, D. L., Ballon, S., Hendrickson, M., MOHLEBOETANI, J. 1988; 128 (6): 1216-1227

    Abstract

    In two case-control studies conducted in the six-county San Francisco Bay Area, 111 women diagnosed with epithelial ovarian carcinoma in 1974-1977 and 188 women diagnosed in 1983-1985 were interviewed concerning their menstrual, sexual, and reproductive histories. For comparison, interviews were conducted with 752 control women admitted to the same hospitals within six months of the cases; for cases diagnosed in the later period, interviews were also conducted with an additional 259 population-based controls selected by random digit dialing. Controls were matched to cases by age and race. Qualitative and quantitative findings were similar for the two studies. In the combined data, cases were more likely than their matched controls to have been nulliparous, to have undergone menarche at an early age, and to have refrained from using oral contraceptives. Menopause occurred slightly later for cases than for controls, but the differences were not statistically significant. Neither age at first term pregnancy (20 or more weeks gestation) nor number of term pregnancies was predictive of ovarian cancer risk. The protection afforded by oral contraceptive use was independent of parity, and it increased with increasing duration of use. There were no trends in risk with time since last oral contraceptive use or with time since first use, after adjustment for duration of use. These observations suggest that oral contraceptive use decreases risk for ovarian cancer, rather than merely indicates fertility, which may itself decrease risk of developing the disease. The authors combined reproductive characteristics and oral contraceptive use to estimate a woman's total duration of ovulation, which was positively associated with ovarian cancer risk (p less than 0.001 for trend). These observations support the concept that the greater the duration of ovulation or accompanying endocrinologic phenomena, the greater a woman's risk for ovarian cancer.

    View details for Web of Science ID A1988R305200004

    View details for PubMedID 3195563

  • PERSONAL AND ENVIRONMENTAL CHARACTERISTICS RELATED TO EPITHELIAL OVARIAN-CANCER .2. EXPOSURES TO TALCUM POWDER, TOBACCO, ALCOHOL, AND COFFEE AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S., Wu, M. L., Paffenbarger, R. S., SARLES, D. L., Kampert, J. B., Grosser, S., Jung, D. L., Ballon, S., Hendrickson, M. 1988; 128 (6): 1228-1240

    Abstract

    Vaginal exposures to talc and other particulates may play an etiologic role in epithelial ovarian cancer. Surgical sterilization may protect against ovarian cancer by blocking entry of such particulates into the peritoneal cavity. The authors assessed histories of talcum powder use, tubal sterilization, and hysterectomy with ovarian conservation in 188 women in the San Francisco Bay Area with epithelial ovarian cancers diagnosed in 1983-1985 and in 539 control women. To investigate the roles of blood-borne environmental exposures on ovarian cancer risk, they assessed lifetime consumption of coffee, tobacco, and alcohol in these women. Of the 539 controls, 280 were hospitalized women without overt cancer, and 259 were chosen from the general population by random digit telephone dialing. Ninety-seven (52%) of the cancer patients habitually used talcum powder on the perineum, compared with 247 (46%) of the controls. Adjusted for parity, the relative risk (RR) = 1.40, p = 0.06. There were no statistically significant trends with increasing frequency or duration of talc use, and patients did not differ from controls in use of talc on sanitary pads and/or contraceptive diaphragms. Fewer ovarian cancer patients (7%) than controls (13%) reported prior fallopian tube ligation (RR, adjusted for parity, = 0.56, p = 0.06), and fewer patients (20%) than controls (28%) reported prior hysterectomy (RR = 0.66, p = 0.05). The protective effect of hysterectomy was confined to those who underwent this surgery 10 or more years prior to interview and to those who had not undergone prior tubal sterilization. Consumption of cigarettes and alcohol did not differ between cases and controls. By contrast, 11 (6%) cases never regularly consumed coffee, compared with 31 (11%) hospital controls and 26 (10%) population controls (RR, adjusted for smoking, = 2.2, p = 0.03, for the comparison using all controls). Overall, ovarian cancer risk among women who had drunk coffee for more than 40 years was 3.4 times that of women who had never regularly consumed coffee (p less than 0.01). However, the data exhibited no clear trends in risk with increasing consumption. Although risk ratios relating duration of coffee drinking to ovarian cancer were unaffected by adjustment for several characteristics, further study is needed to exclude potential confounding by other unmeasured characteristics.

    View details for Web of Science ID A1988R305200005

    View details for PubMedID 3195564

  • ERRORS IN REPORTED DIETARY INTAKES .2. LONG-TERM RECALL AMERICAN JOURNAL OF EPIDEMIOLOGY Wu, M. L., Whittemore, A. S., Jung, D. L. 1988; 128 (5): 1137-1145

    Abstract

    Inconsistent results among case-control studies of diet and cancer may reflect discrepancies between dietary reports based on current habits and actual intakes from the time of cancer initiation in the distant past. To examine the validity of reported past and current diet as measures of past diet, the authors queried 873 men and women in three northern California communities about their diet 11 years earlier in 1972 and about their current diet in 1983. They used the same dietary history questionnaire that had been administered to the subjects in 1972. Retrospectively recalled and currently reported nutrient intakes and measures of body size were compared with original reports obtained in 1972. Mean values of recalled nutrient intakes agreed with mean values of intakes reported in 1972. The agreement held for each sex, community, and nutrient examined. By contrast, mean values of current intakes were smaller than those reported in 1972. Correlation coefficients showed closer agreement between recalled and original intakes than between current and original intakes. Nevertheless, recalled intakes correlated more closely with current intakes than with original ones. Analysis of variance was used to partition the variation in recalled and original intakes into components due to interpersonal variation in true intakes, errors in recall, and residual reporting error. Interpersonal variation accounted for only 20-40% of the variation in dietary intakes, with most of the balance due to reporting error. For comparison, interpersonal variation accounted for 70-85% of the variance of recalled and original reports of body size. These results suggest that inconsistencies among case-control studies of diet may be due to large random measurement errors in individual dietary intakes. The apparent validity and reproducibility of mean dietary measures, averaged over large populations, suggests the need for new designs for studies of diet and disease.

    View details for Web of Science ID A1988Q806700018

    View details for PubMedID 3189287

  • COMBINED EFFECT OF CHILDBEARING, MENSTRUAL EVENTS, AND BODY SIZE ON AGE-SPECIFIC BREAST-CANCER RISK AMERICAN JOURNAL OF EPIDEMIOLOGY Kampert, J. B., Whittemore, A. S., Paffenbarger, R. S. 1988; 128 (5): 962-979

    Abstract

    Pike et al. (Nature 1983;303:767-70) and Moolgavkar et al. (JNCI 1980;65:59-69) proposed quantitative theories for the effect on age-specific breast cancer risk of ages at menarche, first childbirth, and menopause. Here the incidence rate functions predicted by these theories are fit to data for 1,884 women of all ages with breast cancer and 3,432 matched controls admitted to San Francisco Bay area hospitals in 1970-1977. A third function describing age-specific breast cancer risk based on the timing of childbearing and menstrual events is presented, and its fit to the data is compared with that of the functions of Pike et al. and Moolgavkar et al. None of the three fully accounted for the protective effects of early age at first childbirth in premenopausal women or of early age at menopause in parous postmenopausal women. To account for the effects of total parity and body mass (Quetelet) index on risk of breast cancer occurrence, the authors developed a fourth incidence rate function by extending the third. Goodness of fit to the data of the fourth function is demonstrated. Age-specific relative risks of breast cancer according to childbearing, menstrual events, and body size are estimated from the fourth function. The main qualitative findings are that 1) the protective effects of late menarche and of early first full-term pregnancy are greater in premenopausal than in postmenopausal women; 2) first full-term pregnancy initially boosts the level of risk, but incidence rates increase with age more slowly thereafter; 3) among the parous, multiparity is protective both in premenopausal and postmenopausal women, regardless of age at first full-term pregnancy; 4) both nulliparous and lean women are more protected by early menopause than are parous and overweight women; 5) increased body mass index is protective before, but detrimental after, menopause; and 6) postmenopausal incidence rates increase with age more rapidly among overweight than among lean women.

    View details for Web of Science ID A1988Q806700002

    View details for PubMedID 3189296

  • BODY SIZE, REPRODUCTIVE FACTORS, AND BREAST-CANCER SURVIVAL PREVENTIVE MEDICINE MOHLEBOETANI, J. C., Grosser, S., Whittemore, A. S., Malec, M., Kampert, J. B., Paffenbarger, R. S. 1988; 17 (5): 634-642

    Abstract

    Mortality rates among 838 white female breast cancer patients were examined for relationships to personal characteristics assessed at time of diagnosis. These included weight and body mass index, oral contraceptive use, and prior menstrual and reproductive events. Multivariate analyses were used to determine the importance of these characteristics in predicting death rates specific for age and extent of disease at time of diagnosis. Weight was associated with poor prognosis among premenopausal patients, but not among postmenopausal patients. Premenopausal women weighing more than 140 lbs at diagnosis had death rates 1.7 times those of lighter women (P = 0.04). This effect was not explained by differences in the distribution of disease stage between the two groups. Body mass index was positively associated with mortality in both premenopausal and postmenopausal patients. In the entire group, the death rate ratio was 1.4 (P = 0.02) for obese (body mass index greater than 30.4 X 10(-3) lbs/in.2) vs lean women. Among premenopausal patients, parous women had higher mortality rates than nulliparous women (death rate ratio = 2.0, P = 0.06). Although the data were sparse, death rates were higher for women having a full-term pregnancy within 2 years of diagnosis than for premenopausal women with earlier pregnancies. Oral contraceptive use, age at menarche, age at first full term birth, and age at menopause were unrelated to mortality.

    View details for Web of Science ID A1988Q962700008

    View details for PubMedID 3237661

  • EFFECT OF CIGARETTE-SMOKING IN EPIDEMIOLOGICAL-STUDIES OF LUNG-CANCER STATISTICS IN MEDICINE Whittemore, A. S. 1988; 7 (1-2): 223-238

    Abstract

    This paper describes a method for adjusting the analysis of occupational/environmental lung cancer risks for the effects of cigarette smoking in cohort and case-control studies. The method uses a function that relates an individual's death rate to his age and cigarette smoking history. Two such functions are examined. The first depends on total packs of cigarettes smoked and age. The second, based on the multistage theory of carcinogenesis, depends on age, age at start of smoking, and subsequent smoking rates. The lung cancer rates predicted by these two functions are compared to those observed in cohort studies of male British physicians and U.S. veterans, and in a case-control study of non-Hispanic white men in New Mexico. Neither of the cohort data sets distinguished the fit of the two functions. The New Mexico data were fit better by the second function, though both functions overpredicted death rates among ex-smokers. Each function explained substantially more variation in the New Mexico data than did any of several logistic regression models involving categorical variables for age and smoking.

    View details for Web of Science ID A1988M095800021

    View details for PubMedID 3353605

  • Methods for analyzing occupational cohort data with application to lung cancer in U.S. uranium miners. Journal of chronic diseases Halpern, J., Whittemore, A. S. 1987; 40: 79S-88S

    Abstract

    We used two methods to examine how lung cancer death rates vary with cumulative exposures to radiation and tobacco among U.S. uranium miners. We assumed that exposures act proportionately on age-specific death rates among nonsmokers who are unexposed to uranium. The two methods produced similar results when death rate ratios were taken to be the product of radiation and tobacco effects. The estimates were discrepant when death rate ratios were taken to be the sum of radiation and tobacco effects. Both methods indicated better fit for the multiplicative model, as judged by the maximized loglikelihood values. Death rates estimated in this way for white males in the absence of mining and smoking increased only weakly with age. This weak relation suggests that our models of death rates fit poorly. It may be that cumulative exposures are inappropriate measures of the effects of radiation and tobacco on lung cancer death rates.

    View details for PubMedID 3667869

  • METHODS OLD AND NEW FOR ANALYZING OCCUPATIONAL COHORT DATA AMERICAN JOURNAL OF INDUSTRIAL MEDICINE Whittemore, A. S. 1987; 12 (3): 233-248

    Abstract

    The person-years approach to analyzing mortality data from occupational cohorts was introduced in the midtwentieth century. It cross-classifies all observed deaths and observation times into cells, computes the number of expected deaths for each cell based on referenced mortality rates, and then examines the ratio of total number of observed deaths to total number of expected deaths (the standardized mortality ratio). The maximum likelihood method of statistical inference was developed in the early twentieth century. However, only recently has it been applied to the analysis of occupational cohort data. When so applied, it provides estimates of measures of association between exposures and disease by maximizing the probability of the observed data. This paper shows how recent developments in the use of this tool justify and extend the person-years approach. In particular, problems with the standardized mortality ratio cited in the literature are shown to result from reliance on assumptions that are inappropriate for the data at hand. Methods for testing these assumptions are described. The discussion is illustrated with examples from occupational cohort studies of lung cancer.

    View details for Web of Science ID A1987J748300001

    View details for PubMedID 3674019

  • ERRORS IN REPORTED DIETARY INTAKES .1. SHORT-TERM RECALL AMERICAN JOURNAL OF EPIDEMIOLOGY Wu, M. L., Whittemore, A. S., Jung, D. L. 1986; 124 (5): 826-835

    Abstract

    Measures for quantifying reproducibility and between-subject variability of nutrient intake data are applied to intakes reported in two interviews (1-3 months apart) by 44 male and 17 female healthy white subjects aged 45-75 years. Intakes were assessed by three methods: a dietary history that included consumption frequency and serving size for 71 food items (dietary history method); a combination of individual consumption frequencies with sex-specific mean serving sizes (frequency method); an extrapolation from frequencies and serving sizes of all foods reported for a "typical day" in the specified time period (typical day method). Intake variation within subjects, between subjects, and between methods was assessed by analysis of variance for each sex and for each of the nutrients: total calories, protein, fat, vitamin A, and protein and fat as percentage of total calories. Dietary history-assessed intakes exceeded those assessed by the other two methods. The dietary history versus frequency excess was greater than the dietary history versus typical day excess for calories, fat, and protein, while the reverse was true for vitamin A and fat as percentage of total calories. The typical day method was unreliable for vitamin A because it occasionally produced extremely high, unreproducible intakes. The intraclass correlation coefficient was used to measure a method's ability to distinguish interpersonal variation from within-person error. The frequency method produced less within-person error than did the dietary history method for all nutrients. For absolute intakes, the frequency method produced less interpersonal variation than did the dietary history method, while for relative intakes, the reverse was true. Females reported intakes with less within-person error than did males, and the interpersonal spread of their intakes was smaller. Consequences of these findings for the power and sensitivity of studies on the role of dietary factors in the etiology of chronic disease are explored.

    View details for Web of Science ID A1986E498300014

    View details for PubMedID 3766514

Conference Proceedings


  • Serum steroid hormones in young manhood and the risk of subsequent prostate cancer Tsai, C. J., Cohn, B. A., Cirillo, P. M., Feldman, D., Whittemore, A. S. OXFORD UNIV PRESS INC. 2005: S16-S16
  • Comparison of methods for detection of mutations in the BRCA1 gene. Bove, B. A., Ozcelik, H., Neuhausen, S., Boyd, J., Southey, M., Santella, R., Venter, D., Beck, J., Li, F., Buys, S., Andrulis, I. L., Godwin, A. K., Whittemore, A. CELL PRESS. 2001: 440-440
  • Multi-stage sampling in genetic epidemiology Whittemore, A. S., Halpern, J. JOHN WILEY & SONS LTD. 1997: 153-167

    Abstract

    When data are expensive to collect, it can be cost-efficient to sample in two or more stages. In the first stage a simple random sample is drawn and then stratified according to some easily measured attribute. In each subsequent stage a random subset of previously selected units is sampled for more detailed observation, with a unit's sampling probability determined by its attributes as observed in the previous stages. These designs are useful in many medical studies; here we use them in genetic epidemiology. Two genetic studies illustrate the strengths and limitations of the approach. The first study evaluates nuclear and mitochondrial DNA in U.S. blacks. The goal is to estimate the relative contributions of white male genes and white female genes to the gene pool of African-Americans. This example shows that the Horvitz-Thompson estimators proposed for multi-stage designs can be inefficient, particularly when used with unnecessary stratification. The second example is a multi-stage study of familial prostate cancer. The goal is to gather pedigrees, blood samples and archived tissue for segregation and linkage analysis of familial prostate cancer data by first obtaining crude family data from prostate cancer cases and cancer-free controls. This second example shows the gains in efficiency from multi-stage sampling when the individual likelihood or quasilikelihood scores vary substantially across strata.

    View details for Web of Science ID A1997WA62500011

    View details for PubMedID 9004389

  • CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - IMPLICATIONS FOR PREVENTION AND DETECTION Whittemore, A. S. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1994: S15-S19

    Abstract

    Approximately 20,000 women are diagnosed with ovarian cancer in the United States each year, and some 12,000 women die because of it. Epithelial ovarian cancer, the most common histopathologic type, is uncommon before age 40 years, after which incidence rates increase steeply until age 70-79 years and then decrease somewhat. In the United States, the lifetime risk from birth to age 85 years is about 1.5%. There is general agreement that residence in North America or northern Europe, nulliparity, and having a mother or sister with ovarian cancer are associated with an elevated risk, and that increasing number of pregnancies (whether or not full term), increasing length of oral contraceptive use, and increasing duration of lactation are protective. A history of breast or endometrial cancer appears to be associated with a slight elevation in risk. Apart from oral contraceptive use, none of these characteristics can be modified easily to reduce ovarian cancer risk. However, long-term oral contraceptive use before the menopause could prevent as much as half of all ovarian cancer. At present, the subgroup of the population at highest risk consists of women with a mother or sister with the disease; the lifetime ovarian cancer risk in these women is about 9%. A small fraction of them have families with multiple cases of ovarian cancer and early-onset breast cancer, due largely or entirely to mutated alleles of the gene BRCA1. These women, who have a lifetime risk of breast or ovarian cancer of 85-100%, need aggressive screening and possibly prophylactic surgery.

    View details for Web of Science ID A1994QF35200003

    View details for PubMedID 7835800

  • LOCALIZED PROSTATE-CANCER - RELATIONSHIP OF TUMOR VOLUME TO CLINICAL-SIGNIFICANCE FOR TREATMENT OF PROSTATE-CANCER Stamey, T. A., Freiha, F. S., McNeal, J. E., REDWINE, E. A., Whittemore, A. S., Schmid, H. P. WILEY-LISS. 1993: 933-938

    Abstract

    Using the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute and American total mortality rates, the authors calculated the probability at birth of having a diagnosis of prostate cancer within a man's life to be 8.8% and then subtracted the incidence of microscopic Stage A cancers too small to ever be clinically significant. This gave a final probability of 8%.Prostates were examined after 139 consecutive unselected cystoprostatectomies from patients with bladder cancers in whom it was unknown whether they had prostate cancer. Prostate cancer was found in 55 patients (40%); the volume of the largest cancer in each specimen was determined using histologic morphometry. The authors identified the 8% of these 139 cytoprostatectomy specimens with the largest volume of prostate cancer.The largest 11 of the 55 cancers represented 7.9% of the total 139 samples. These cancers ranged in volume from 0.5-6.1 ml, representing only 20% of all patients with prostate cancer.If the strong evidence is accepted that cancer progression is proportional to cancer volume, it was concluded that prostate cancers larger than 0.5 ml appear to correspond to the 8% of men who will be diagnosed with a clinically significant carcinoma, as derived previously. Conversely, those 80% of prostate cancers smaller than 0.5 ml probably are not likely to reach a clinically significant size in view of the long doubling time of this cancer.

    View details for Web of Science ID A1993KM67400007

    View details for PubMedID 7679045

  • PERSONAL CHARACTERISTICS RELATING TO RISK OF INVASIVE EPITHELIAL OVARIAN-CANCER IN OLDER WOMEN IN THE UNITED-STATES Whittemore, A. S. WILEY-LISS. 1993: 558-565

    Abstract

    The ovarian cancer incidence rate is higher for women over 55 years of age than for younger women, but it increases less rapidly with age after age 55 years than before. This slower rate of increase suggests that the postmenopausal ovary may be less exposed or less susceptible than the functioning one to endogenous or exogenous carcinogens. For example, it is not exposed to mitotic stimuli at follicle rupture, which may increase the likelihood of malignancy.Findings from a collaborative analysis of 12 U.S. case-control studies are used to examine associations between invasive epithelial ovarian cancer and certain reproductive and hormonal characteristics, and to determine if those associations change as women age.Ovarian cancer risk reductions were associated with pregnancy (regardless of outcome), lactation, and oral contraceptive use. The percentage risk reduction associated with pregnancy was smaller for older women than younger women, although the absolute magnitude of the risk reduction increased with age. In contrast, the percentage risk reduction associated with oral contraceptive use was greater for older women. The total duration of ovulation was strongly associated with increased risk in women under 55 years of age, but not in older women.The greater protection to older women associated with oral contraceptive use suggests that the early high-potency contraceptive formulations used by these women may have been more protective than recent ones. The sparsity of strong risk factors in older women emphasizes the need for sensitive and specific markers for early detection of ovarian malignancy in this age group.

    View details for Web of Science ID A1993KH50600009

    View details for PubMedID 8420677

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