Malignant Glioma: Isocitrate Dehydrogenases 1 and 2 Mutations

Abstract

Mutations in the cytoplasmic NADP⁺-dependent isocitrate dehydrogenase, IDH1, frequently occur in gliomas. The mutations are somatic, almost always heterozygous, and occur at R132, an active site residue of IDH1 that is important for its catalytic function. IDH1 mutations occur in >70% of WHO grades II and III astrocytomas and oligodendrogliomas, as well as WHO grade IV secondary glioblastomas, and more rarely in other glioma subtypes. IDH2 is the mitochondrial homolog of IDH1, and mutations in IDH2 R172, the analogous residue to IDH1 R132, also occur in these subtypes of gliomas, albeit at a much lower frequency. R132H and R172K are the most common IDH1 and IDH2 mutations observed in gliomas, respectively, though alterations to other amino acids at these hotspots have also been observed. IDH1 mutations frequently co-occur with loss of chromosomes 1p and 19q or point mutations of TP53, and they appear to occur before other genetic alterations during glioma pathogenesis. Furthermore, IDH1 mutations are associated with a younger age at diagnosis and a better prognosis for many glioma subtypes. The frequency of IDH1 and IDH2 mutations in specific glioma subtypes suggests that testing for these mutations may help to guide clinical decision-making for glioma patients, and PCR- and antibody-based tests have been developed to determine tumor mutation status. The IDH1 and IDH2 mutations abolish the normal function of the encoded enzymes to oxidize isocitrate to α-ketoglutarate and confer a neomorphic gain of enzymatic activity to reduce α-ketoglutarate to 2-hydroxyglutarate. This gain of function suggests that IDH1 and IDH2 mutations are oncogenic, but the mechanism by which this promotes glioma pathogenesis remains unknown.