Genes With Potential Clinical Relevance in Prostate Cancer Risk
Table 6. Case-Control Studies ofBRCA1andBRCA2and Survival Outcomes continued...
These findings suggest overall survival and prostate cancer–specific survival may be lower in mutation carriers than in controls.
Additional studies involving theBRCAregion
A genome-wide scan for hereditary prostate cancer using 175 families from the University of Michigan Prostate Cancer Genetics Project (UM-PCGP) found evidence of linkage to chromosome 17q markers. The maximum logarithm of the odds (LOD) score in all families was 2.36, and the LOD score increased to 3.27 when only families with four or more confirmed affected men were analyzed. The linkage peak was centered over the BRCA1 gene. In follow-up, these investigators screened the entire BRCA1 gene for mutations using DNA from one individual from each of 93 pedigrees with evidence of prostate cancer linkage to 17q markers. Sixty-five of the individuals screened had wild-type BRCA1 sequence, and only one individual from a family with prostate and ovarian cancers was found to have a truncating mutation (3829delT). The remainder of the individuals harbored one or more germline BRCA1 variants, including 15 missense variants of uncertain clinical significance. The conclusion from these two reports is that there is evidence of a prostate cancer susceptibility gene on chromosome 17q near BRCA1; however, large deleterious inactivating mutations in BRCA1 are not likely to be associated with prostate cancer risk in chromosome 17–linked families.
In another study from the UM-PCGP, common genetic variation in BRCA1 was examined. Conditional logistic regression analysis and family-based association tests were performed in 323 familial prostate cancer families and early-onset prostate cancer families, which included 817 men with and without prostate cancer, to investigate the association of SNPs tagging common haplotype variation in a 200-kilobase (kb) region surrounding and including BRCA1. Three SNPs in BRCA1 (rs1799950, rs3737559, and rs799923) were found to be associated with prostate cancer. The strongest association was observed for SNP rs1799950 (OR, 2.25; 95% CI, 1.21–4.20), which leads to a glutamine-to-arginine substitution at codon 356 (Gln356Arg) of exon 11 of BRCA1. Furthermore, SNP rs1799950 was found to contribute to the linkage signal on chromosome 17q21 originally reported by the UM-PCGP.