IDH1IDH2

IDH1 and IDH2 are genes that encode two related enzymes, cytosolic IDH1 and mitochondrial IDH2, which belong to the family of isocitrate dehydrogenases. Both enzymes catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) while generating NADPH, a reducing equivalent important for fatty acid synthesis and redox balance. IDH1 resides in the cytosol and peroxisomes, whereas IDH2 operates in mitochondria.

Mutations in IDH1 and IDH2 are common in several human cancers and have distinct pathogenic mechanisms. The most frequent IDH1 mutation is at arginine 132 (R132), and the common IDH2 mutations occur at arginines 140 and 172 (R140, R172). These alterations confer a neomorphic enzyme activity that reduces α-KG to the oncometabolite 2-hydroxyglutarate (2-HG). Elevated 2-HG levels can disrupt α-KG–dependent dioxygenases, including TET enzymes and histone demethylases, leading to widespread epigenetic changes and a hypermethylation phenotype that contributes to oncogenesis.

Clinical significance and applications vary by cancer type. IDH1/IDH2 mutations are characteristic of many lower-grade gliomas and secondary glioblastomas, as well as some cartilaginous tumors and intrahepatic cholangiocarcinomas and certain leukemias. In gliomas, IDH mutations are generally associated with better prognosis and distinct therapeutic responses. Targeted therapies have emerged, including IDH1 inhibitors (e.g., ivosidenib) and IDH2 inhibitors (e.g., enasidenib), used in select, mutation-defined indications. Diagnostic approaches combine sequencing panels with immunohistochemistry for IDH1 R132H and, when needed, measurement of 2-HG.

Genomic context: IDH1 is located on chromosome 2q33.3 and IDH2 on chromosome 15q26.1.