BRCA2 mutations in Utah high-risk prostate cancer pedigrees. K. Allen-Brady¹, J.M. Farnham¹, N.J. Camp¹, E.A. Ostrander², L.A. Cannon-Albright¹. 1) Dept Genetic Epidemiology, Univ of Utah, Salt Lake City, UT; 2) National Human Genome Research Institute, Bethesda, MD.
   Germline mutations in the BRCA2 gene have been suggested to account for about 5% of familial prostate cancer; mutations have been reported in 2% of early onset (i.e., 55 years) prostate cancer cases and a founder mutation has been identified in Iceland (999del5). However, the role of BRCA2 in high risk prostate cancer pedigrees remains unclear. We examined the potential involvement of BRCA2 in Utah prostate cancer pedigrees. Using the Utah Population Database, we identified 59 high-risk prostate cancer pedigrees (N = 464 cases and an additional 1,261 unaffected relatives), in which all prostate cases were no more distantly related than two meioses from another case, and the resulting cluster contained at least four prostate cancer cases [see Prostate 2005 65(4):365-74 ]. We genotyped these pedigrees using a panel of 404 fluorescent microsatellite markers spaced ~10 cM apart across the genome. We performed linkage analyses using MCLINK and the Smith et al prostate cancer inheritance model [Science 1996 274: 1371-1374]. We identified five pedigrees with at least nominally significant linkage evidence (LOD score 0.588, p < 0.05) within 10 cM of the BRCA2 gene locus on chromosome 13. The LOD scores ranged between 0.95 (p=0.018) and 1.42 (p=0.005). The number of prostate cancer cases in each of these pedigrees ranged from 5 to 12 and the earliest age at diagnosis ranged from 52 to 60 years. None of the 5 linked pedigrees had a significant excess of breast cancer cases among the descendants of the founder, nor any known male breast cancer cases. There are no special identifying prostate cancer characteristics evident in these pedigrees. We are performing BRCA2 mutation screening in the youngest prostate cancer cases who carry the segregating chromosome 13 haplotype in each pedigree. If BRCA2 germline mutations are found to explain the linkage evidence in these pedigrees, the BRCA2 gene may account for up to 8% (5/59) of Utah high-risk prostate cancer pedigrees.