Clinical Studies of the Molecular Genetic Basis of Kidney Cancer Kidney cancer affects 54,390 Americans each year and over 13,000 die of this disease in the U.S. annually. Our work has shown that kidney cancer is not a single disease;it is made up of a number of different types of cancer, each with a different histology, a different clinical course, responding differently to therapy and each caused by a different gene. Our approach has been to identify the genes that cause kidney cancer in order to provide the foundation targeted therapeutic approaches to this disease. In order to identify the genes that cause kidney cancer 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 a number of different types of inherited kidney cancer including: 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), the inherited form of chromophobe renal carcinoma and 4) Hereditary Leiomyomatosis Renal Carcinoma (HLRCC), type 2 papillary renal carcinoma. In order to develop new methods for treatment of patients with sporadic as well as familial kidney cancer we established an NIH kidney cancer working group involving clinicians and investigators from 29 different laboratories and branch from 9 different NIH Institutes. von Hippel-Lindau: Clear Cell Kidney Cancer-The VHL Gene Individuals affected with von Hippel Lindau (VHL) are at risk for the development of bilateral, multifocal clear cell kidney cancer as well as 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 246/246 VHL kindreds and are currently studying genotype/phenotype relationships as well as evaluating novel minimally invasive forms of therapy for kidney and adrenal tumors in VHL. We have described the surgical management of VHL kidney cancers as well as VHL pheochromocytoma, pancreas tumors, ear tumors and brain and spine tumors. We currently have two clinical trials in progress targeting the VHL gene pathway in patients affected with VHL. Clear Cell Kidney Cancer: The VHL Gene We have shown that the VHL gene is also the gene for the common form of sporadic (non-hereditary) kidney cancer (clear cell renal carcinoma). In a series of studies we have identified mutation/methylation of the VHL gene in up to 92% of tumors from patients with sporadic (non-inherited) clear cell kidney cancer. Study of the VHL gene pathway has provided the foundation for the development of targeted therapeutics for patients with both clear cell kidney cancer as well as von Hippel-Lindau. We currently are conducting a clinical trial of an agent which targets the VHL pathway in patients with advanced clear cell kidney cancer. Hereditary Papillary Renal Cell Carcinoma: Type 1 Papillary Kidney Cancer-The MET Gene In 1994 we described a novel form of inherited kidney cancer, Hereditary Papillary Renal Carcinoma (HPRC) HPRC is an inherited cancer syndrome in which affected individuals are at risk for the formation of multifocal, bilateral type 1 papillary kidney cancer. In order to identify the gene for HPRC we studied families with this rare, inherited cancer syndrome to determine which individuals had the kidney cancers and which did not. Linkage analysis performed in the families to localized the gene to the long arm of chromosome 7. The proto-oncogene, MET, was subsequently identified as the HPRC gene. We have identified activating mutations in the tyrosine kinase domain of the MET gene in the germline of the HPRC families as well as in a subset of tumors from patients with sporadic, non-inherited type 1 papillary kidney cancer. These findings provided the foundation for the development of a targeted therapeutic approach to the treatment of patients affected with HPRC as well as for patients with sporadic, non-hereditary papillary kidney cancer. We are currently conducting a clinical trial with an agent which targets the MET gene pathway in patients with Hereditary Papillary Renal Carcinoma and sporadic papillary kidney cancer. Birt-Hogg-Dub: Chromophobe Kidney Cancer-The BHD gene We recently described another novel type of inherited kidney cancer associated with Birt Hogg Dub (BHD). Birt-Hogg-Dub patients are at risk for the development of bilateral, multifocal chromophobe and hybrid/oncocytic kidney cancer. By studying BHD families and we were able to localize and subsequently identify the BHD gene on chromosome 17. We have detected BHD gene mutations in over 95% of BHD families and are now able to 1) make the clinical diagnose of BHD with a blood test as well as determine which at-risk members of BHD families are affected with BHD. We have defined the kidney cancer phenotype of BHD and have described the surgical management of BHD-associated kidney cancer. Based on our preclinical studies we are planning a clinical trial targeting the BHD pathway in patients with BHD-associated kidney cancer. Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC): Type 2 Papillary Kidney Cancer-The Fumarate Hydratase Gene We have described another inherited form of papillary kidney cancer which is now called Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC). Affected individuals in HLRCC families are at risk for the development of a very aggressive form of type 2 papillary renal carcinoma. We have reported the identification of germline mutations of the fumarate hydratase gene (FH) in the germline of over 90% of North American HLRCC kindreds. We have described the HLRCC kidney cancer phenotype and the method of clinical management of HLRCC-associated kidney cancer. Based on our preclinical studies we are planning a clinical trial targeting the FH pathway in patients with HLRCC-associated kidney cancer. Kidney Cancer Genetic Testing 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. Familial Renal Carcinoma (FRC) 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. Studies in Iceland have suggested that nearly 60% of kidney cancer may be genetic. We suspect that there is a complex genetic pattern to FRC and we are currently evaluating FRC kindreds in order to 1) describe this clinical syndrome and 2) to identify its genetic basis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011028-06
Application #
8763312
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$874,817
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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