Familial clustering of early-onset prostate cancer best fits a model of autosomal dominant inheritance of a rare, high-risk allele, predisposing 9% of all prostate cancer occurrence. Prostate cancer is inherited in a Mendelian fashion in these families, providing an opportunity to apply linkage analysis to this complex disease. We have developed and applied high-throughput fluorescent methods to enable genotyping of hundreds of individuals from affected families at a 10 centiMorgan density. Allele identification was accomplished in a semi-automated fashion. The genome survey was completed both parametic and nonparametric methods of analysis were employed, an the results provided evidence of the first locus for hereditary prostate cancer (termed HPC1). Supplemental U.S. pedigrees are now also being genotyped in the higher density survey to increase power to refine linkage. We are also collecting extended pedigrees with prostate cancer in Finland and Sweden as confirmatory populations. Physical mapping of the HPC1 region is now underway.
