At autopsy, ~10-30% of all males over 50 years of age have histologic evidence of prostate cancer, indicating that 11,000,000 U.S. males presently harbor some form of this disease. fortunately, only a small proportion of this total will develop clinically manifest prostate cancer; even so, the 100,000 new cases of prostate cancer diagnosed each year make this disease the most commonly diagnosed caner in men, and the second most common cause of cancer deaths in men (30,000/yr). This cancer poses a particular threat to American back men, whose incidence rates are almost 50% higher than age matched whites. Despite the magnitude of this problem, little is known about the molecular events responsible for either the initiation of this disease or its progression from a latent to a clinically manifest form. Our inability to predict this latter characteristic of prostate cancer has particular relevance in light of recently proposed early detection programs for this disease. Recent studies of other common adult tumors have indicated that multiple genetic alterations including the activation of oncogenes and the inactivation of tumor suppressor genes (TSGs) are critical steps in the pathogenesis of these tumors. The objective of the proposed study is to test the hypothesis that tumor suppressor gene inactivation is associated with the development of hypothesis that tumor suppressor gene inactivation is associated with the development of prostate cancer in humans. To test this hypothesis, TSGs known to be inactivated in other human tumors, as well as other genomic regions harboring potentially novel TSGs inactivated in prostate cancer will be analyzed for alterations (i.e. deletion and/or mutation), using loss of heterozygosity testing and single strand conformational polymorphism analyses. The knowledge gained from such a study is desirable not only to better understand the underlying molecular mechanisms of prostate cancer, but also, eventually, to allow differentiation between prostatic cancers of low and high aggressiveness, based on genetic rather than histological features.
Specific Aims #1. Recent work from this laboratory has identified the long arms of chromosomes 10 and 16 as regions demonstrating frequent loss of heterozygosity in prostate cancer. As a prelude to identifying putative tumor suppressor gene(s) at each of these regions, proposed mapping studies will focus specifically on determining the smallest common region of deletion on chromosomes 10q and 16q. #2 To identify other possible regions harboring inactivated tumor suppressor genes in prostate cancer cells, at least 60 prostatic tumors will be analyzed for loss of heterozygosity using probes for every nonacrocentric chromosomal arm. #3. the role of the p53 gene in prostate cancer will be examined by searching for mutations in this gene by single strand conformational polymorphism analysis in combination with direct sequencing of PCR amplified DNA. The proposed research will provide the basis for the identification and characterization of tumor suppressor genes which become inactivated in this extremely common malignancy.
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