Kidney Cancer. We have identified the tumor suppressor gene for the familial form of kidney cancer associated with von Hippel Lindau disease and have shown that the VHL gene is the kidney cancer tumor suppressor gene. This was accomplished by performing genetic studies in members of kindreds affected with this familial cancer syndrome and performing genetic linkage analysis to localize the gene. Mutational analysis of this conserved gene identified germline mutations in the VHL gene in affected individuals from 85/114 kindreds resulting in amino acid deletions, frameshift and/or other changes. A definite correlation has been identified between the location and type of VHL mutations and the phenotype of the disease; missense mutations were identified in the germline of families in which pheochromocytoma developed. This provides a method for early diagnosis of at-risk or affected individuals. We have demonstrated that the VHL gene is a critical, gene for kidney cancer. Inactivation of the gene by mutation or hypermethylation were detected in a high percentage of clear cell kidney tumors. The discovery of VHL mutations in a majority of localized as well as advanced renal carcinomas indicates that the VHL gene plays a critical role in the origin of both sporadic and hereditary kidney cancer. In characterizing the biochemical function of the VHL gene we have recently shown that the B and C regulatory subunits of the cellular transcription factor Elongin (SIII) are targets of the VHL protein. These findings reveal an important transcriptional regulatory network and suggest that the VHL protein may function as a key regulator of this network, with its ultimate target the RNA polymerase II elongation complex. Prostate carcinoma. A program designed to identify tumor suppressor genes that are involved in the development and/or progression of prostate cancer is underway. 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 as well as prostate intraepithelial neoplasia (PIN). Candidate cDNAs are being cloned from this region to be evaluated as potential tumor suppressor genes. 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.
