PATHOGENESIS OF HUMAN PROSTATE CARCINOMAS

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Prostate cancer has become the most frequently diagnosed malignancy of men in the United States. This cancer exhibits a diverse spectrum of clinical behaviors from prolonged dormancy to rapid growth and metastatic phenotypes. The steps through which prostate epithelial cells progress to malignancy remain to be defined. We propose to examine the development of prostate cancer by using novel technologies including selective ultraviolet radiation fractionation (SURF) and DNA fingerprinting which should identify some of the genetic differences between the indolent form of the disease and more aggressive phenotypes of the tumor. In preliminary experiments, we have identified the p53 tumor suppressor gene locus as a target for mutation in several prostate cancer specimens and demonstrated the applicability of DNA fingerprinting in detecting variations in the prostate tumor DNA compared to the constitutive DNA pattern. We also present evidence that SURF followed by PCR is appropriate for the analysis of specific mutations in histologic subsets of prostatic tumor cells in archival fixed tissue sections. This proposal is designed to further develop the research through (1) determination of the frequency and nature of p53 gene mutations and comparison of the topography of these genetic lesions (genotype) to the phenotype of the prostate tumor cells from a bank of 400 prostatectomy specimens well-defined by histologic grade, pathologic stage and DNA ploidy; (2) analysis and identification of somatic changes in prostate cancers by oligonucleotide-based DNA fingerprinting of normal and tumor DNAs of individuals with prostate cancer; (3) based on DNA fingerprinting leads, characterization of new prostate cancer associated gene loci for identification of critical genes affected by the mutation; and (4) examination of different mutant forms of p53, which have been identified to occur commonly in prostate cancers, for potential gain of function, in the context of prostatic epithelial cell cultures. These interconnected studies, in combination, should lead to new insights into the pathogenesis of human prostatic cancer.