While prostate cancer has a strong heritable component, convincing evidence of genetic risk factors as lagged behind that for other epithelial cancers. A number of promising regions have been identified through linkage in familial cases, but few have been convincingly replicated and none can readily explain the dramatic risk in the African-American population. Admixture mapping offers a fresh approach to identify alleles of lower penetrance that are likely operative in sporadic prostate cancer. The concept of admixture mapping was proposed some 17 years ago, and considerable resources of the laboratory of Stephen O'Brien (National Cancer Institute) and others have been devoted to development of this method. The ability to execute such a study has only recently become feasible through the identification of large numbers of SNPs. The African-American population has the necessary attributes to efficiently perform genome wide mapping for prostate cancer genes. The basic idea of admixture mapping is to identify chromosomal segments enriched in African ancestry in prostate cancer cases relative to controls. As the risk of prostate cancer is elevated in individuals of African ancestry, these areas of the genome represent putative candidate regions. Once these regions are identified, a haplotype-based approach can be applied to more finely localize the causal segment. The proposed whole-genome admixture scan will be conducted among African-American men in the Multiethnic Cohort Study, which is a large prospective study of men and women in Los Angeles and Hawaii that was established in 1993 to explore the environmental and genetic determinants of cancer risk. This proposal will bring together researchers from multiple disciplines including genomics, statistics, epidemiology and oncology, and builds on the strong, ongoing collaboration between the University of Southern California, the newly founded Broad Institute which includes the Whitehead Institute/MIT Center for Genome Research and Harvard University, and collaborators at Harvard Medical School. ? ?
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