A family history of prostate cancer has been shown to be one of the most important determinants of prostate cancer risk. Using segregation analysis, investigators have demonstrated that early-onset prostate cancer in some families may be explained by autosomal dominant inheritance of a rare susceptibility allele. The first putative genetic locus associated with the inherited predisposition to prostate cancer, referred to as HPCl at chromosome 1q24-25, was recently identified through analysis of a set of high-risk prostate cancer families. Analysis of an independent set of families in our laboratory has also revealed evidence of prostate cancer linkage to chromosome 1q markers. Prostate cancer is an exceedingly important health problem for African American men, since the age-adjusted incidence of prostate cancer in African American men is approximately fifty percent greater than in Caucasian American men. The relative risk associated with a family history of prostate cancer is similar between African and Caucasian American men emphasizing the importance of predisposing germline mutations in both ethnic cohorts. African American families, however, have been under-represented in studies of the inherited predisposition to prostate cancer. Furthermore, analysis of six African American families in our laboratory suggests that HPCl may be particularly important in this population. To test the hypothesis that HPCl contributes to prostate cancer predisposition in African American families, the following Specific Aims are proposed: I. Identify African American families with two or more living family members affected with prostate cancer. II. Isolate DNA and genotype all individuals identified at Specific Aim I using a panel of polymorphic markers spanning the HPCl candidate interval. III. Use parametric and non-parametric multipoint analysis to assess for linkage of prostate cancer to markers that map to 1q24-25. IV. Collect all available tumor samples from prostate cancer patients for analysis of loss of heterozygosity (LOH), a characteristic of many tumor suppressor genes, at 1q24-25. If the HPCl gene is cloned within the time frame of this proposal, additional experiments are proposed to characterize potential HPCl mutations and to test for linkage to other potential prostate cancer susceptibility loci in families with prostate cancer that is not due to mutations in the HPCl gene.
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