Prostate cancer is the leading cause and the second leading cause of cancer in deaths in American men. Little is known about the molecular events in prostate carcinogenesis. The identification of populations of man at increased risk for the development of prostate cancer have suggested new molecular targets for study. For example, the coincident familial relationship between breast and prostate cancer has been recognized in several large population studies. Recent recognition of families with early-onset breast or breast/ovarian cancer has led to the identification of two new genetic loci involved in carcinogenesis, BRCA1 on chromosome 17q and BRCA2 on chromosome 13q. In kindreds with familial breast or breast/ovarian cancer due to defects in BRCA1, an excess risk of prostate cancer has been identified. There is also preliminary data to support the increased risk of prostate cancer in BRCA2-linked families. Studies of small numbers of patients with sporadic prostate cancer have confirmed the presence of loss of heterozygosity (LOH) involving 13q and 17q, further supporting the potential involvement of these or perhaps other tumor suppressors in prostate carcinogenesis. We propose to perform LOH analysis of prostate tumors using a panel of mapped short tandem repeat polymorphisms (STRPs) on chromosomes 17q and 13q, encompassing the BRCA1 and BRCA2 genes respectively. The frequency of LOH involving BRCA1 and BRCA2 will be compared between men with sporadic prostate cancer and men in breast or breast/ovarian cancer families. Mutation analysis of BRCA1 using single strand conformation polymorphism (SSCP) gels will also be performed on tumors demonstrating LOH with intragenic or closely linked markers flanking the recently cloned BRCA1. Taken together, these studies will elucidate the potential roles of the tumor suppressors BRCA1 and BRCA2, as well as other putative antioncogenes on chromosomes 17q and 13q, in the development of prostate cancer. The studies outlined in this grant application will be performed in a 1000 square foot molecular biology laboratory shared with Sofia Merajever, M.D., Ph.D., who will be a collaborator for this work. The laboratory of Jill Macoska, Ph.D., a contributor to the SPORE and my mentor for this project, is located down the hall. Additional members of the Divisions of Molecular Medicine nd Genetics, Hematology/Oncology and Urology as well as the University of Michigan Cancer Center will provide both technical academic support for this proposal.
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