IDH1andIDH2Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives
- 14 October 2012
- journal article
- review article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 18 (20), 5562-5571
- https://doi.org/10.1158/1078-0432.ccr-12-1773
Abstract
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 α-ketoglutarate (α-KG), and gain of a new function, the production of 2-hydroxyglutarate (2-HG). 2-HG is structurally similar to α-KG, and acts as an α-KG antagonist to competitively inhibit multiple α-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. ©2012 AACR.Keywords
This publication has 93 references indexed in Scilit:
- Progress in understanding 2‐hydroxyglutaric aciduriasJournal of Inherited Metabolic Disease, 2012
- Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopyJournal of Neuro-Oncology, 2011
- Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancersThe Journal of Pathology, 2011
- Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent DioxygenasesCancer Cell, 2011
- IDH1 mutation identified in one human melanoma metastasis, but not correlated with metastases to the brainBiochemical and Biophysical Research Communications, 2010
- Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of GliomaCancer Cell, 2010
- The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-HydroxyglutarateCancer Cell, 2010
- Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancerBiochemical and Biophysical Research Communications, 2010
- Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1Cancer Cell, 2010
- l‐2‐Hydroxyglutaric aciduria, a defect of metabolite repairJournal of Inherited Metabolic Disease, 2007