EVIDENCE FOR A GENE INVOLVED IN THE ORIGIN OF HUMAN RENAL CELL CARCINOMA* * Adapted from a presentation by Dr. W. Marston Linehan, National Cancer Institute The Malnoti Symposium on Urological Cancer Northwestern University Medical School October 4th, 1990. In the early 1970's Knudson suggested that there may be a recessive oncogene or tumor suppressor gene associated with the initiation of some forms of kidney cancer. In 1979, a familial form of renal cell carcinoma was found to be associated with the relocation of some genetic material from chromosome 3 to chromosome 8. Later, in 1982, Pathak and coworkers reported a second family with renal cell carcinoma in which there was a chromosome 3 to chromosome 11 translocation. These two studies provide evidence that there may be a linkage between a structural change in chromosome 3 in hereditary as well as sporadic renal cell carcinoma. These observations lead to a search for a missing piece of chromosome 3 in sporadic kidney cancer. Genetic DNA analysis techniques suggested the presence of a tumor suppressor gene on chromosome 3 based on tissue from 11 out of 11 patients with renal cell carcinoma. Subsequent studies performed with tumor tissue from other kidney cancer patients found missing genes on chromosome 3 in most patients. Researchers at the National Cancer Institute recently evaluated tissue from 58 patients with advanced kidney cancer. Abnormalities on chromosome 3 were found in 51 of the 58 patients, 88 percent. These abnormalities called "loss of hetero- zygosity" were found in patients with both localized and advanced disease. When NCI analyzed chromosome 3 for patients with a "benign" renal tumor, oncocytoma, no loss of heterozygosity was found. NCI has also analyzed chromosomes 11, 13, and 17 for loss of heterozygosity. It found genetic abnormalities in tissue from some patients with advanced disease; however, it did not identify any missing DNA in patients with early stage disease. This finding suggests that abnormalities on chromosome 11, 13, and 17 may be associated with disease progression. These observations raise the possibility that there is a gene located on chromosome 3 which is involved in kidney cancer. These observations are further supported by observations of patients with von Hippel-Lindau (VHL) disease, a rare hereditary kidney illness. Individuals who inherit the gene for von Hippel-Lindau disease have a predisposition to develop a variety of cancers, including: retinal angiomas, spinal and cerebellar hemangioblastomas, pheochromocytomas, renal and pancre- atic cysts, cystadenomas of the epididymis and renal cell carcinomas. Patients with VHL often get kidney cancer at an early age, in both kidneys and with multiple tumors. Research by Seizinger and his coworkers has shown that the gene for VHL is located on chromosome 3. When NCI analyzed renal cell carcinomas from patients with VHL, all renal cell carcinomas had a loss on chromosome 3. There was also a pattern of loss on chromosome 3 in hereditary renal cell carcinoma. Multiple renal cell tumors in individual patients with VHL showed the same loss on chromosome 3, indicating that the same gene was missing in each tumor. Hereditary renal cell carcinomas examined by NCI for maternal or paternal origin show losses on chromosome 3. These observations indicate that the loss of a "balancing" gene may be a prerequisite for the initia- tion of renal cell carcinoma associated with VHL. More recent research confirms this linkage. The NCI's research indicates that there may be at least one gene located on chromosome 3 which is associated with renal cell carcinoma and strongly suggests that the mechanism of the formation of renal cell carcinoma involves inactivation of both copies of this renal cell carcinoma gene. Current NCI research is aimed at identifying this tumor suppressor gene which is involved in the development of sporadic as well as familial renal cell carcinoma and to provide further understanding of the gene's function in order to develop a more effective means of therapy for kidney cancer. The implications of NCI's research are that once kidney cancer has occurred in a family, the other members of the family have an above average probability of also getting kidney cancer because they may share many of the same genes. All kidney cancer families should be active in the fight against kidney cancer.