Dataset Information

Common variation in the BRCA1 gene and prostate cancer risk.

ABSTRACT: Rare inactivating mutations in the BRCA1 gene seem to play a limited role in prostate cancer. To our knowledge, however, no study has comprehensively assessed the role of other BRCA1 sequence variations (e.g., missense mutations) in prostate cancer. In a study of 817 men with and without prostate cancer from 323 familial and early-onset prostate cancer families, we used family-based association tests and conditional logistic regression to investigate the association between prostate cancer and single nucleotide polymorphisms (SNPs) tagging common haplotype variation in a 200-kb region surrounding (and including) the BRCA1 gene. We also used the Genotype-Identity-by-Descent Sharing Test to determine whether our most strongly associated SNP could account for prostate cancer linkage to chromosome 17q21 in a sample of 154 families from our previous genome-wide linkage study. The strongest evidence for prostate cancer association was for a glutamine-to-arginine substitution at codon 356 (Gln(356)Arg) in exon 11 of the BRCA1 gene. The minor (Arg) allele was preferentially transmitted to affected men (P = 0.005 for a dominant model), with an estimated odds ratio of 2.25 (95% confidence interval, 1.21-4.20). Notably, BRCA1 Gln(356)Arg is not in strong linkage disequilibrium with other BRCA1 coding SNPs or any known HapMap SNP on chromosome 17. In addition, Genotype-Identity-by-Descent Sharing Test results suggest that Gln(356)Arg accounts (in part) for our prior evidence of prostate cancer linkage to chromosome 17q21 (P = 0.022). Thus, we have identified a common, nonsynonymous substitution in the BRCA1 gene that is associated with and linked to prostate cancer.

SUBMITTER: Douglas JA

PROVIDER: S-EPMC3082399 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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Common variation in the BRCA1 gene and prostate cancer risk.

Douglas Julie A JA Levin Albert M AM Zuhlke Kimberly A KA Ray Anna M AM Johnson Gregory R GR Lange Ethan M EM Wood David P DP Cooney Kathleen A KA

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20070621 7

Rare inactivating mutations in the BRCA1 gene seem to play a limited role in prostate cancer. To our knowledge, however, no study has comprehensively assessed the role of other BRCA1 sequence variations (e.g., missense mutations) in prostate cancer. In a study of 817 men with and without prostate cancer from 323 familial and early-onset prostate cancer families, we used family-based association tests and conditional logistic regression to investigate the association between prostate cancer and s ...[more]

PMID: 17585057

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Project description:Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17beta-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Delta5-androsterone-3beta,17beta-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.

Dataset Information

Common variation in the BRCA1 gene and prostate cancer risk.

Publications

Common variation in the BRCA1 gene and prostate cancer risk.

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