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Abstract:
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Hereditary prostate cancer is a heterogeneous complex disease with at least 5 putative susceptibility loci identified to date: HPC1 (1q24-25), PCaP (1q42.2-43), HPCX (Xq27-28), CAPB (1p36), and HPC20 (20q13). Confirmation of linkage in independent datasets is essential to understanding the significance of these findings. Two analyses of high-risk prostate cancer families with 3 or more affected men were conducted using LINKAGE, HOMOG, and GENEHUNTER. First, an analysis of 150 families (2,176 individuals) for linkage to HPC1 was performed. This dataset includes 640 affected men with an average age at prostate cancer diagnosis of 66.8 years (range 39--94). Linkage to multiple 1q24-25 markers was strongly rejected for the sample as a whole. Assuming heterogeneity, however, the estimated proportion of families linked in the entire dataset was 2.6%, using multipoint analysis. Families were stratified by race, mean age at diagnosis, and number of affected men; no significant evidence for linkage was observed. These results indicate that the overall portion of hereditary prostate cancer families whose disease is due to inherited variation in HPC1 may be less than 34 percent, as originally estimated. Second, clinical data from the medical records of 505 affected men was incorporated into analysis of multiple markers at HPC1, PCaP, HPCX, and CAPB in 149 families. Overall, maximum 2-point lods were: 0.43 (theta = 0.24) at HPC1 (D1S1660), 0.57 (theta = 0.26) at PCaP (D1S2785), 0.16 (theta = 0.34) at HPCX (DXS984), and 0.86 (theta = 0.18) at CAPB (D1S407). Distributions of prostate cancer grade and stage and median age at diagnosis were used to stratify families, in addition to race and lod scores at other loci. Analysis of 16 white families with at least one high-grade case and with minimal evidence for linkage to other loci produced a peak NPL score at of 2.03 (p = 0.03) at HPC1 (D1S2818). A maximum NPL of 1.83 (p = 0.04) was seen at CAPB (D1S407) for 37 white families with at least one high-grade cancer suggesting that CAPB may be involved with high-grade prostate cancer. Considering clinical data as well as evidence for linkage to other loci may prove useful in understanding multiple loci responsible for hereditary prostate cancer. |