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Genetic Basis of Cancer of the Kidney

Disease-Specific Approaches to Therapy

¹ Urologic Oncology Branch, ² Laboratory of Immunobiology, ³ Laboratory of Pathology and ⁴ Molecular Imaging Program, and ⁵ Center for Cancer Research and Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; and ⁶ Basic Research Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute Frederick, Frederick, Maryland

Studies during the past two decades have shown that kidney cancer is not a single disease; it is made up of a number of different types of cancer that occur in this organ. Clear cell renal carcinoma is characterized by mutation of the VHL gene. The VHL gene product forms a heterotrimeric complex with elongin C, elongin B, and Cul-2 to target hypoxia-inducible factors 1 and 2 for ubiquitin-mediated degradation. VHL–/– clear cell renal carcinoma overexpresses epidermal growth factor receptor and transforming growth factor . Both hypoxia-inducible factor 1 and the epidermal growth factor receptor are potential therapeutic targets in clear cell renal carcinoma. Studies of the hereditary form of renal cell carcinoma (RCC) associated with hereditary papillary renal carcinoma (HPRC) determined that the c-Met proto-oncogene on chromosome 7 is the gene for HPRC and for a number of sporadic papillary RCCs. The HPRC c-Met mutations are activating mutations in the tyrosine kinase domain of the gene. The gene for a new form of hereditary RCC (Birt Hogg Dubé syndrome) associated with cutaneous tumors, lung cysts, and colon polyps or cancer has recently been identified. Studies are currently under way to determine what type of gene BHD is and how damage to this gene leads to kidney cancer. Individuals affected with hereditary leiomyomatosis renal cell carcinoma are at risk for the development of cutaneous leiomyomas, uterine leiomyomas (fibroids), and type 2 papillary RCC. The HLRC gene has been found to be the Krebs cycle enzyme, fumarate hydratase. Studies are under way to understand the downstream pathway of this cancer gene.

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