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 or association 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 survey 10 centiMorgan density, followed by high resolution analysis. Allele identification was accomplished in a semi- automated fashion. A genome survey was completed with both parametic and nonparametric methods of analysis employed, an the results provided evidence of the first locus for hereditary prostate cancer (termed HPC1). We have subsequently published information on the second loci for a susceptibility gene in human prostate cancer on the X-chromosome (termed HPC-X). Supplemental pedigrees are now also being genotyped in the higher density survey to increase power to refine linkage for these and other candidate loci. We are also collecting extended pedigrees with prostate cancer in Finland, Iceland and Sweden as confirmatory populations. Physical mapping to identify the HPC1 and HPCX genes are a primary function on this program.
