Abstract PL02-02: The genetic basis of kidney cancer: A metabolic disease.

Much of what is known about the genetic basis of kidney cancer has been learned from the study of inherited forms of kidney cancer, including von Hippel-Lindau (VHL) (clear cell kidney cancer, the VHL gene), hereditary papillary renal carcinoma (type 1 papillary kidney cancer, the MET gene), Birt-Hogg-Dube (BHD) (chromophobe kidney cancer, the FLCN gene), hereditary leiomyomatosis and renal cell carcinoma (HLRCC, the fumarate hydratase gene), and SDH-RCC (the succinate dehydrogenase genes). Study of these disease gene pathways has shown that kidney cancer is fundamentally a metabolic disease. Each of the known kidney cancer genes affects the cell9s ability to sense changes in oxygen, iron, nutrients or ATP. This is most clearly illustrated in fumarate hydratase (FH) and succinate dehydrogenase (SDH) deficient kidney cancer. FH-deficient kidney cancer, an extremely aggressive form of type 2 papillary kidney cancer, is characterized by a metabolic shift to aerobic glycolysis and impaired oxidative phosphorylaton, decreased AMPK, fumarate-induced impairment of dioxygenases (such as prolyl hydroxylase), resulting in increased stability of HIF and DNA and histone methylation, glutamine dependent reductive carboxylation and a fumarate-mediated activation of the Nrf2 pathway. SDH-deficient kidney cancer is characterized by a metabolic shift to aerobic glycolysis, a profound impairment of oxidative phosphorylation and a glutamine-dependent reductive carboxylation pathway for lipid biosynthesis. Clinical trials are currently underway targeting the metabolic basis of FH-deficient kidney cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL02-02. Citation Format: W. Marston Linehan. The genetic basis of kidney cancer: A metabolic disease. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL02-02.