IDH1 and IDH2 Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives

Genes encoding for isocitrate dehydrogenases 1 and 2, IDH1 and IDH2, are frequently mutated in multiple types of human cancer. Mutations targeting IDH1 and IDH2 result in simultaneous loss of their normal catalytic activity, the production of alpha-ketoglutarate (alpha-KG), and gain of a new function, the production of 2-hydroxyglutarate (2-HG). 2-HG is structurally similar to alpha-KG, and acts as an alpha-KG antagonist to competitively inhibit multiple alpha-KG-dependent dioxygenases, including both lysine histone demethylases and the ten-eleven translocation family of DNA hydroxylases. Abnormal histone and DNA methylation are emerging as a common feature of tumors with IDH1 and IDH2 mutations and may cause altered stem cell differentiation and eventual tumorigenesis. Therapeutically, unique features of IDH1 and IDH2 mutations make them good biomarkers and potential drug targets. Clin Cancer Res; 18(20); 5562-71. (C) 2012 AACR.