""""""""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 hereditaary 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 in sights into the role of this cancer gene. In addition, this finding provides new avenues for studies of 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 tuor suppresor 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 diagnosis of both hereditary as well as sporadic forms of kidney cancer.""""""""

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
Project #
Application #
Study Section
Special Emphasis Panel (UOB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Clinical Sciences
United States
Zip Code
Sourbier, Carole; Ricketts, Christopher J; Matsumoto, Shingo et al. (2014) Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer. Cancer Cell 26:840-850
Atkins, Michael B; Bukowski, Ronald M; Escudier, Bernard J et al. (2009) Innovations and challenges in renal cancer: summary statement from the Third Cambridge Conference. Cancer 115:2247-51
Linguraru, Marius George; Wang, Shijun; Shah, Furhawn et al. (2009) Computer-aided renal cancer quantification and classification from contrast-enhanced CT via histograms of curvature-related features. Conf Proc IEEE Eng Med Biol Soc 2009:6679-82
Linehan, W Marston (2009) Genetic basis of bilateral renal cancer: implications for evaluation and management. J Clin Oncol 27:3731-3
Beroukhim, Rameen; Brunet, Jean-Philippe; Di Napoli, Arianna et al. (2009) Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res 69:4674-81
Sudarshan, Sunil; Sourbier, Carole; Kong, Hye-Sik et al. (2009) Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol 29:4080-90
Boris, Ronald; Proano, Miguel; Linehan, W Marston et al. (2009) Initial experience with robot assisted partial nephrectomy for multiple renal masses. J Urol 182:1280-6
Giubellino, Alessio; Linehan, W Marston; Bottaro, Donald P (2009) Targeting the Met signaling pathway in renal cancer. Expert Rev Anticancer Ther 9:785-93
Rosner, Inger; Bratslavsky, Gennady; Pinto, Peter A et al. (2009) The clinical implications of the genetics of renal cell carcinoma. Urol Oncol 27:131-6
Linehan, W Marston; Pinto, Peter A; Bratslavsky, Gennady et al. (2009) Hereditary kidney cancer: unique opportunity for disease-based therapy. Cancer 115:2252-61

Showing the most recent 10 out of 113 publications