Kidney cancer. We have identified the tumor suppressor gene for the familial form of kidney cancer associated with von Hippel Lindau disease and have results to suggest that this is also the sporadic RCC tumor suppressor gene. This was accomplished by performing genetic studies in members of kindreds affected with this familial cancer syndrome. Genetic linkage analysis localized the VHL gene to a small region of chromosome 3. The region of the VHL gene was cloned and a genetic and physical map of the region were constructed. By analyzing the cloned DNA from the defined region, two candidate genes were identified, one which was found to be abnormal in the germ line of 28/221 VHL kindreds. Mutational analysis of this conserved gene identified germline mutations in the VHL gene in affected individuals from 3 kindreds resulting in amino acid deletions and/or frameshift changes. Sequence analysis revealed 48% homology with a portion of Trypanosome procyclic surface membrane protein which belongs to a novel class of membrane proteins that are thought to function in signal transduction and intracellular targeting. DNA analyses of cell lines derived from patients with sporadic RCC demonstrated that approximately 90% of cell lines have loss of chromosome 3p heterozygosity. In order to determine whether or not the same gene is associated with both sporadic and familial kidney cancer, mutational analyses of the VHL gene in RCC tumors and cell lines has been performed. A high frequency of mutation of the VHL gene has been detected, suggesting that the same gene may be associated with both sporadic RCC and RCC associated with VHL disease. Prostate carcinoma. A program has been initiated that is designed to identify tumor suppressor genes that are involved in the development and/or progression of prostate cancer. Loss of heterozygosity studies are being performed on matched samples of normal and tumor DNA to map regions of the genome that are frequently lost during tumor development. A region from the short arm of chromosome 8 (8p22) has been shown to be lost frequently in prostate tumors. Candidate cDNAs are being cloned from this region to be evaluated as potential tumor suppressor genes. We are also evaluating the antitumor effect of thymidine kinase or cytosine deaminase gene modified prostate cancer cells followed by treatment ganciclovir or 5FU. 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 new agents for use in therapy of patients with these neoplasms.