Molecular Genetics Basis of Kidney Cancer In order to identify the genes that cause kidney cancer in order to develop molecular therapeutics for this disease, we have studied the inherited forms of cancer of the kidney. Kidney cancer occurs in both a hereditary and a sporadic (nonhereditary) form. There are five types of inherited kidney cancer: 1) von Hippel Lindau (VHL), the inherited form of clear cell renal carcinoma; 2) Hereditary Papillary Renal Carcinoma (HPRC), hereditary Type 1 kidney cancer, 3) Birt Hogg Dub (BHD), an inherited form of chromophobe renal carcinoma and 4) Hereditary Leiomyomatosis Renal Carcinoma (HLRCC), type 2 papillary renal carcinoma; and 5) Familial Renal Carcinoma (FRC). Individuals with the inherited form of kidney cancer associated with von Hippel Lindau are predisposed to develop tumors in the brain, spine, eyes, pancreas, adrenal gland and inner ear. By studying VHL families we were able to perform genetic linkage analysis to localize and subsequently identify the VHL gene on chromosome 3. We have identified the VHL gene mutation in the germline of 292/292 VHL kindreds and are currently studying genotype/phenotype relationships as well as evaluating minimally invasive forms of therapy for kidney and adrenal tumors in VHL. The VHL gene has been shown to be the gene for the hereditary form of renal carcinoma associated with von Hippel Lindau as well as the common form of sporadic (non-hereditary) kidney cancer (clear cell renal carcinoma). We described HPRC in 1994, found that the c-Met proto-oncogene, on chromosome 7, is the HPRC gene. Defects in the Met gene have been found in the germline of HPRC families and these mutations appear to account for most of the cases of inherited type 1 papillary renal carcinoma. We recently described another new type of inherited kidney cancer associated with Birt Hogg Dub Syndrome. These patients are at risk for the development of chromophobe renal cell carcinoma. We studied BHD kindreds and were able to localize and then identify the BHD gene on chromosome 17. We have described BHD mutations in 51/61 BHD kindreds. We have recently studied another inherited form of kidney cancer called Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC). These individuals are at risk for the development of a very aggressive form of type 2 papillary renal carcinoma. We have recently reported the identification of germline mutations of the fumarate hydratase gene (FH) in the germline of North American HLRCC kindreds and described how altration of the FH gene affects HIF1 and HIF2 levels in the HLRCC-associated kidney tumors. The identification of germline VHL, c-Met, BHD and FH mutations makes possible pre-symptomatic genetic testing for at-risk individuals in VHL, HPRC, BHD and HLRCC families and paves the way for additional studies to understand the pathology of these diseases, and for the design of effective new therapies targeted to the specific defects brought about by mutation of the these disease genes. We have recently demonstrated improved detection of germline mutations in the von Hippel Lindau disease tumor suppressor gene. We can now detect mutations in nearly 100% of families. We have additionally detected a new phenotype associated with complete deletion of the VHL gene. We are intensively studying the somatic events (genomic, cytogenetic) associated with the development of tumors in patients with different types of germline mutations. The ability to detect germline as well as somatic mutations of the VHL, Met, BHD and FH gene may provide substantial opportunity for improvements in the diagnosis of both hereditary as well as sporadic forms of kidney cancer. Finally, we are studying the genetic basis of Familial Renal Carcinoma (FRC). FRC is a term that describes the kidney that runs in families that are not part of previously described hereditary kidney cancer syndromes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
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National Cancer Institute Division of Clinical Sciences
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