Common variation in the BRCA1 gene and prostate cancer risk.
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.
Douglas
Julie A
JA
Department of Human Genetics, University of Michigan, Room 5912, Buhl Building, Ann Arbor, MI 48109-0618, USA. jddoug@umich.edu
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
D019313:BRCA1 Protein / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000453:epidemiology* / Q000235:genetics; D018570:Risk Assessment; D014481:United States / Q000453:epidemiology
D019313:BRCA1 Protein; D017430:Prostate-Specific Antigen