Brain Tumor Pathology

, Volume 29, Issue 3, pp 131–139

Molecular pathogenesis of IDH mutations in gliomas

Review Article


The isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are mutated in 50–80% of astrocytomas, oligodendrogliomas or oligoastrocytomas of grades II and III, and secondary glioblastomas; they are, however, seldom mutated in primary glioblastomas and never in other types of glioma. Gliomas with IDH1/2 mutations always harbor either TP53 mutations or total 1p/19q loss. This suggests these two types of tumor may arise from common progenitor cells that have IDH1/2 mutations, subsequently evolving into each tumor type with the acquisition of TP53 mutations or total 1p/19q loss. Survival is significantly longer for patients with IDH-mutated gliomas than for those with IDH-wild type tumors. This observation indicates that IDH status defines biologically different subgroups among gliomas. The molecular pathogenesis of IDH1/2 mutations in the development of gliomas is unclear. The mutated IDH1/2 enzyme generates d-2-hydroxyglutarate. Several theories have been proposed, including: increased angiogenesis because of accumulation of HIF-1α; a glioma CpG island methylator phenotype (G-CIMP) induced by inhibition of TET2; and increased vulnerability to oxidative stress because of depletion of antioxidants. Elucidating the pathogenesis of IDH mutations will aid better understanding of the molecular mechanisms of gliomagenesis and may lead to the development of novel molecular classification and therapy.


IDH1 Astrocytoma Oligodendroglioma G-CIMP d-2-Hydroxyglutarate 



Isocitrate dehydrogenase


Central nervous system


World Health Organization


Acute myeloid leukemia


CpG island




Diffuse astrocytoma grade II


Anaplastic astrocytoma WHO grade III


Primary glioblastoma WHO grade IV


Secondary glioblastoma WHO grade IV


Oligodendroglioma WHO grade II


Anaplastic oligodendroglioma WHO grade III


Oligoastrocytoma WHO grade II


Anaplastic oligoastrocytoma WHO grade III




Hypoxia-inducible factor 1-alpha


Vascular endothelial growth factor


Prolyl hydroxylase


Glioma CpG island methylator phenotype






Hydroxyglutaric aciduria


Hydroxyglutarate dehydrogenase




Glutathione disulfide


Reactive oxygen species


Nicotinamide adenine dinucleotide phosphate


Nicotinamide adenine dinucleotide phosphate (reduced form)


Glucose 6-phosphate dehydrogenase


Formalin-fixed paraffin-embedded


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Copyright information

© The Japan Society of Brain Tumor Pathology 2012

Authors and Affiliations

  1. 1.Division of Brain Tumor Translational ResearchNational Cancer Center Research InstituteTokyoJapan

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