Brain Tumor Pathology

, Volume 29, Issue 3, pp 131–139

Molecular pathogenesis of IDH mutations in gliomas

Review Article

DOI: 10.1007/s10014-012-0090-4

Cite this article as:
Ichimura, K. Brain Tumor Pathol (2012) 29: 131. doi:10.1007/s10014-012-0090-4

Abstract

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.

Keywords

IDH1AstrocytomaOligodendrogliomaG-CIMPd-2-Hydroxyglutarate

Abbreviations

IDH

Isocitrate dehydrogenase

CNS

Central nervous system

WHO

World Health Organization

AML

Acute myeloid leukemia

CGI

CpG island

TMZ

Temozolomide

A

Diffuse astrocytoma grade II

AA

Anaplastic astrocytoma WHO grade III

pGB

Primary glioblastoma WHO grade IV

sGB

Secondary glioblastoma WHO grade IV

O

Oligodendroglioma WHO grade II

AO

Anaplastic oligodendroglioma WHO grade III

OA

Oligoastrocytoma WHO grade II

AOA

Anaplastic oligoastrocytoma WHO grade III

αKG

α-Ketoglutarate

HIF-1α

Hypoxia-inducible factor 1-alpha

VEGF

Vascular endothelial growth factor

PHD

Prolyl hydroxylase

G-CIMP

Glioma CpG island methylator phenotype

5mC

5-Methylcytosine

5hmC

5-Hydroxymethylcytosine

HGA

Hydroxyglutaric aciduria

HGDH

Hydroxyglutarate dehydrogenase

GSH

Glutathione

GSSG

Glutathione disulfide

ROS

Reactive oxygen species

NADP+

Nicotinamide adenine dinucleotide phosphate

NADPH

Nicotinamide adenine dinucleotide phosphate (reduced form)

G6PD

Glucose 6-phosphate dehydrogenase

FFPE

Formalin-fixed paraffin-embedded

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