Familial renal cell carcinoma: In studies performed to localize the tumor suppressor genes associated with initiation and progression of familial as well as sporadic renal cell carcinoma, patients either affected or at risk for von Hippel-Lindau disease have been evaluated. The results of genetic linkage analysis indicate that the VHL gene is located in a small region of chromosome 3. A prospective clinical trial analyzing the use of presymptomatic detection of VHL disease by DNA polymorphism analysis determined that presymptomatic DNA analysis could accurately predict which at risk patients carry the disease gene for VHL. In situ hybridization, genetic and physical mapping localizes the VHL disease gene to the 3p25.5 locus. Candidate genes, one of which codes for a previously identified member of a family of genes involved in signal transduction has been identified. Full length cDNA cloning and germ line mutational analysis are currently underway in order to identify the familial kidney cancer disease gene. Sporadic renal cell carcinoma: In order to perform analysis of the tumor suppressor genes in initiation and progression of sporadic renal cell carcinoma, over 40 human tumor cell lines have been derived. RFLP analysis, Northern and Western analysis and immunohistochemistry, and polymerase chain reaction-single strand conformation polymorphism abnormalities are being evaluated at tumor suppressor gene loci on chromosomes 17, 13 and 18. Studies are ongoing to identify the sporadic kidney cancer disease gene on chromosome 3 and to evaluate abnormalities at other tumor suppressor gene loci which may be involved in progression of this malignancy. Prostate carcinoma: We are evaluating tumor suppressor gene abnormalities which may be involved in initiation or progression of this malignancy as well as the antitumor effect of a number of antineoplastic agents in human prostate carcinoma.Animal models of metastasis have been developed using human prostate carcinoma cell lines implanted in the prostate of athymic nude mice for this purpose. The role of the metastasis gene nm23 in progression as well as its effect on hormonal regulation of growth of human prostate carcinoma are being determined. The significance of this project lies in the identification of the tumor suppressor genes associated with kidney and prostate cancer as well as in the evaluation and development of antineoplastic agents for use in therapy of patients with advanced forms of these neoplasms.
