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Common Variation in the BRCA1 Gene and Prostate Cancer Risk

Departments of ¹ Human Genetics, ² Internal Medicine, and ³ Urology, University of Michigan, Ann Arbor, Michigan and Departments of ⁴ Genetics and ⁵ Biostatistics, University of North Carolina, Chapel Hill, North Carolina

Requests for reprints: Julie A. Douglas, Department of Human Genetics, University of Michigan, Room 5912, Buhl Building, Ann Arbor, MI 48109-0618. Phone: 734-615-2616; Fax: 734-763-3784. E-mail: jddoug{at}umich.edu

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 (Gln³⁵⁶Arg) 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 Gln³⁵⁶Arg 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 Gln³⁵⁶Arg 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. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1510–6)