Kidney cancer is a lethal disease that affects 39,000 Americans annually and is responsible for nearly 13,000 deaths per year in the United States. Kidney cancer is not a single disease; it is comprised of a number of different kinds of cancers that occur in the kidney. Each of these different types of kidney cancer has a different histologic type, a different clinical course, responds differently to therapy, and is caused by different genes. For the past 25 years, studies have been conducted to identify the genetic basis of kidney cancer with the hope that understanding the kidney cancer gene pathways would provide the basis for the development of targeted therapeutic approaches to treat this malignancy. Studies of families with hereditary forms of kidney cancer have resulted in the identification of several genes and molecular targets specific for kidney cancers with therapeutic approaches that are in various stages of preclinical and clinical evaluation.
Clear Cell Renal Carcinoma: The VHL Gene. The von Hippel-Lindau (VHL) gene, identified in 1993, is a tumor suppressor gene for the inherited (familial) form of clear cell renal carcinoma, von Hippel-Lindau, and for the common type of sporadic (non-familial) clear cell kidney cancer. The product of the VHL gene forms a complex with other proteins that target the hypoxia inducible factors (HIF) for ubiquitin mediated degradation, which in turn regulates transcription of several downstream genes. Understanding the VHL pathway has led to the development of agents such as sunitinib, sorafenib, and bevacizumab. These agents target downstream genes such as vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and transforming growth factor (TGFa) and have shown clinical effects in patients with clear cell renal carcinoma.
Type 1 Papillary Renal Carcinoma: The c-Met Gene. Hereditary Papillary Renal Carcinoma (HPRC) is an inherited cancer syndrome in which affected individuals are at risk for the development of bilateral, multifocal type 1 papillary renal carcinoma. Linkage analysis in the HPRC kindreds led to the identification of the proto-oncogene, c-Met, as the HPRC gene. Intense efforts are underway to target the tyrosine domain of the c-Met gene and other targets in the c-Met pathway as potential treatments for HPRC as well as sporadic type 1 papillary kidney cancer.
Chromophobe/Hybrid Oncocytic Renal Carcinomas: The BHD Gene. Birt Hogg Dubé (BHD) is an inherited can¬cer syndrome in which affected individuals are at risk for the development of cutaneous tumors (fibrofolliculomas), pulmonary cysts, and kidney cancer. Study of the BHD families recently led to the identification of the BHD gene on chromosome 17. The product of the BHD gene has been found to be a part of the AMP-activated protein kinase/serine-threonine kinase/mammalian target of rapamycin (AMPK/LKB1/mTOR) pathway. This has provided the opportunity to target the mTOR pathway as a potential therapy for patients affected with BHD as well as sporadic chromophobe kidney cancer.
Hereditary Leiomyomatosis Renal Cell Carcinoma (Papillary Type 2): The Fumarate Hydratase Gene. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for the development of cutaneous and uterine leiomyomas and a very aggressive type of renal carcino¬ma. The HLRCC gene is the Krebs cycle enzyme, fumarate hydratase (FH). Recent studies have shown that fumarate overaccumulation can stabilize HIF, providing a potential VHL-independent mechanism for dysregulation of HIF degradation and increasing downstream gene transcription in HLRCC kidney cancer. These findings pro¬vide the basis for the development of strategies that involve targeting the vascular endothelial growth factor (VEGF) gene pathway in HLRCC-associated renal cancer.
The genes associated with the development of cancer of the kidney have in common their interaction with pathways that control oxygen and nutrient sensing.
Cover images and narrative courtesy of W. Marston Linehan, M.D., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH.
