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 occurrences. 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 continued to developed and applied high-throughput fluorescent methods to enable genotyping of now thousands of individuals from affected families at high density, followed by high marker resolution analysis. Allele identification is accomplished in a semi-automated fashion with genome surveys was completed with both parametric and non-parametric methods of analysis employed. Results provided evidence of the first locus for hereditary prostate cancer (termed HPC1), and there have now been four independent groups who have identified variants in this gene in disequilibrium in a given population. Also, we continue to look for a gene within a previously second locus 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. A broad large scale (>300 families) genome-wide scan is underway, as are continued efforts in physical mapping to HPCX and other candidate loci. Further study is necessary and results will be reported in the future.
