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Molecular pathogenesis of IDH mutations in gliomas

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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.

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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

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Acknowledgments

The author thanks Dr Sylvia Kocialkowski for the critical reading of the manuscript.

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Authors and Affiliations

  1. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Koichi Ichimura

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Correspondence to Koichi Ichimura.

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Ichimura, K. Molecular pathogenesis of IDH mutations in gliomas. Brain Tumor Pathol 29, 131–139 (2012). https://doi.org/10.1007/s10014-012-0090-4

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  • DOI: https://doi.org/10.1007/s10014-012-0090-4

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