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