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Mutations in the Isocitrate Dehydrogenase Genes IDH1 and IDH2 in Tumors

Schaap, Frank G. PhD*; French, Pim J. PhD; Bovée, Judith V. M. G. MD, PhD*

Advances in Anatomic Pathology: January 2013 - Volume 20 - Issue 1 - p 32–38
doi: 10.1097/PAP.0b013e31827b654d
Review Articles

Heterozygous hotspot mutations in isocitrate dehydrogenases (IDH) IDH1 or IDH2 are frequently observed in specific types of cartilaginous tumors, gliomas, and leukemias. Mutant IDH enzyme loses its normal activity to convert isocitrate into α-ketoglutarate (αKG) and instead acquires the ability to reduce αKG to D-2-hydroxyglutarate. Through direct competition with αKG, accumulation of the oncometabolite D-2-hydroxyglutarate in IDH mutated tumors results in inhibition of αKG-dependent dioxygenases involved in DNA and histone demethylation. Apart from epigenetic alterations, perturbations in the tricarboxylic acid cycle (depletion of intermediates) and activation of the intricately linked hypoxia signaling pathway are apparent in IDH mutated cells. As molecular details are being unraveled, the emerging concept is that IDH mutations result in tumor formation by epigenetic alterations that affect gene expression and result in inhibition of cellular differentiation. Activation of hypoxic stress signaling reprograms cellular energy metabolism and promotes anabolic processes and angiogenesis, thus, providing an advantage to promote neoplastic growth.

*Department of Pathology, Leiden University Medical Center

Department of Neurology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands

Present Address: Frank G. Schaap, Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.

Supported by The Netherlands Organization for Scientific Research (917-76-315).

The authors have no conflicts of interest to disclose.

Reprints: Judith V. M. G. Bovée, MD, PhD, Department of Pathology (L1-Q), Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands (e-mail:

© 2013 Lippincott Williams & Wilkins, Inc.