RECESSIVE MUTATIONS IN THE GENESIS OF PROSTATE CANCER

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Recent studies have defined several of the multiple genetic changes underlying the genesis of common adult neoplasms such as colon, breast, and lung carcinoma. Mutations affecting two classes of genes, oncogenes and tumor suppressor genes, are considered most fundamental. Whereas oncogenes are hyperfunctional forms of endogenous genes that promote cellular proliferation, tumor suppressor genes normally function to negatively regulate cell division in response to external growth or differentiation signals. Inactivation of both suppressor alleles is necessary for an oncogenic effect; typically a recessive mutation of one allele is followed by the loss of the other wild-type allele. Two suppressor genes, Rb on chromosome 13q14 and p53 on chromosome 17p13, have been most intensely studied. Each is mutated in a substantial fraction of common epithelial neoplasms as well as unusual tumors such as retinoblastoma, bone or soft- tissue sarcomas, leukemias, and brain tumors, and exogenous copies of wild- type Rb or p53 genes are able to suppress the neoplastic phenotype of human tumor cells bearing the appropriate mutated endogenous alleles. These results strongly suggest that mutations of these genes are significant in the genesis of many types of cancer. Despite its major health impact as the most common cancer in men, prostate carcinoma is relatively poorly understood at the genetic level. It is hypothesized that, as with other neoplasms, mutations of tumor suppressor genes contribute to the genesis of prostate carcinoma, although the identities, mutational frequencies and functional roles of such genes may differ for each cancer type. This hypothesis will be tested in three Aims. First, mutations and/or allelic losses of Rb,4p53 and other potential suppressor loci will be investigated in a large series of frozen and archival prostate tumors using immunohistochemistry and molecular genetic analyses. Significant correlation of such alterations with major clinicopathological indices such as tumor stage will give insight into specific oncogenic roles for these genes. Second, cellular mechanisms of tumor suppression will be explored in a model system, including a comparison of the activities of Rb and p53 and their possible synergy in suppressing the tumorigenic phenotype. Third, chromosomal regions that are frequently affected by allelic loss in prostate cancer will be examined by complementary structural and functional approaches for direct evidence that they harbor novel suppressor loci involved in prostatic oncogenesis. These studies will provide a molecular genetic framework for understanding the development and progression of prostate cancer, and may lead to novel diagnostic or therapeutic approaches to prostate cancer management.