Glioma is a type of tumor originating from glial cells in the brain and spinal cord. It primarily affects astrocytes, oligodendrocytes, and ependymal cells. Mutations in the Isocitrate Dehydrogenase 1 (IDH1) and Isocitrate Dehydrogenase 2 (IDH2) genes are pivotal in gliomagenesis, particularly in diffuse lower-grade gliomas and secondary glioblastomas. These mutations, especially at R132 in IDH1 and R172 in IDH2, confer a neomorphic activity converting α-ketoglutarate (α-KG) to D-2-hydroxyglutarate (2-HG). Elevated 2-HG disrupts α-KG–dependent dioxygenases, resulting in genome-wide epigenetic modifications, collectively termed the glioma CpG island methylator phenotype (G-CIMP). Clinically, these mutations correlate with younger age at diagnosis, favorable prognosis, and improved survival. IDH mutations are now essential in the 2021 WHO classification of CNS tumors. Targeted therapies such as ivosidenib, enasidenib, and vorasidenib aim to reverse 2-HG accumulation. This commentary outlines the molecular basis, clinical impact, and therapeutic opportunities related to IDH1/2 mutations in glioma.
Keywords: IDH1, IDH2, glioma, 2-hydroxyglutarate, epigenetic dysregulation, G-CIMP, targeted therapy.
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