Prostate cancer is the most common cancer and the second leading cause of cancer deaths among men in the United States. Approximately 334,500 men are diagnosed every year. Despite advances in treatment and increased screening efforts, about 41,800 men each year will go on to die of the disease. This is similar to the number of women that die yearly from breast cancer. Epidemiological data support the hypothesis that strong familial components are involved in the etiology of prostate cancer, particularly in men diagnosed at young age or men with a family history of disease. Mapping and eventual cloning of such genes is likely to provide insight into the molecular mechanisms critical for prostate cancer susceptibility, and provide knowledge about the molecular mechanisms of prostate cancer initiation. This submission proposes to map prostate cancer susceptibility genes by taking advantage of an ongoing effort to collect high risk prostate cancer families that has been undertaken by Seattle investigators. This effort has led to the identification of a large number of high risk prostate cancer families and subsequent collection of DNA samples, epidemiologic and clinical data, and family history information from eligible families. Specifically, the proposal is to 1) Genotype 250 high risk prostate cancer families with 387 microsatellite-based genetic markers that span the human genome at 10cM resolution. 2) Perform linkage and nonparametric analysis to identify regions of the genome likely to contain prostate cancer susceptibility genes using the above genotyping data. This will involve stratifying families by a number of criteria for which they have collected data, such as age of onset, tumor grade and stage, PSA level, and occurrence and incidence of other cancers. 3) Expand the analysis of a prostate cancer susceptibility gene at 1q24-25 from 49 to 250 high risk families. Particular emphasis will be placed on heterogeneity analysis to best determine the subset of families for which this locus is likely to be most significant. Finally, once regions of the genome likely to contain prostate cancer susceptibility genes are localized, they will refine the region of interest by analysis of additional markers and identification of recombinants. These experiments will provide a foundation for subsequent physical mapping efforts and candidate cDNA analysis.
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