Molecular Genetics of Kidney Cancer Kidney cancer occurs in both a hereditary and a sporadic (nonhereditary) form. There are at least three known types of hereditary kidney cancer: von Hippel Lindau (VHL), Hereditary Papillary Renal Carcinoma (HPRC) and Hereditary Renal Carcinoma (HRC). We reported the initial description of HPRC in 1994, and have recently determined that the Met proto-oncogene, located 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 papillary renal carcinoma. The Met gene codes for a cell surface receptor for a systemically circulating growth factor, hepatocyte growth factor (HGF). The germline mutations identified in the HPRC kindreds are located in the tyrosine kinase domain of the MET gene and are predicted to activate this receptor. This work is the first to identify a germline mutation of this gene and confirms its importance as a cancer gene. We have recently demonstrated trisomy 7 to be harboring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas, and are effect of tyrosine kinase mutations in the gene in association with development of kidney and other tumors. Associations between germline mutation of the Met gene and the appearance of other cancers, such as colon cancer, melanoma and stomach cancer are under investigation. The identification of germline Met mutations makes possible pre-symptomatic genetic testing for at-risk individuals in HPRC families and paves the way for additional studies to learn the pathology of HPRC, and for the design of effective new therapies targeted to the specific defects brought about by mutation of the Met gene. Individuals with the inherited form of kidney cancer associated with von Hippel Lindau are also predisposed to develop tumors in the brain, spine, eyes, pancreas, adrenal gland and inner ear. 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). NCI scientists are studying intensively how damage (mutation) to the VHL gene leads to the manifestations in VHL and sporadic renal carcinoma patients. Recently, it is has been shown that the VHL protein complex binds to the CUL-2 protein, a protein from a recently identified multigene cullin family. The finding that the VHL tumor suppressor gene protein associates with CUL-2 suggests interaction of VHL with the cell cycle, which provides significant insights into the role of this cancer gene. In addition, this finding provides new avenues for studies in the development of new therapies for both kidney cancer as well as von Hippel Lindau disease. We have recently demonstrated improved detection of germine 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 and the Met gene also provides substantial opportunity for improvements in the diagnosis of both hereditary as well as sporadic forms of kidney cancer.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006659-20
Application #
6756284
Study Section
(UOB)
Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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