IDH1 or IDH2 mutations are found in >70% of lower grade diffusely infiltrative gliomas and in >90% of secondary glioblastoma. IDH mutational status has been reported to be a favorable prognostic indicator relative to wild-type gliomas of similar histology, regardless of grade. Therapeutic strategies exploiting mutated IDH protein, including through direct inhibition and vaccine-based approaches, are currently the subject of preclinical research and clinical trials.

IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies. A case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR+) breast adenocarcinoma has been reported (5). IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma, suggesting future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme.

IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies. Mutations in IDH1 and IDH2 have been reported in intrahepatic cholangiocarcinomas. IDH1 mutation has been associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate. IDH1 mutation has been described to be a feature of intrahepatic cholangiocarcinomas.

IDH1 is an enzyme localized to the cytoplasm and peroxisomes and involved in citrate metabolism. Mutations at Arg132 of IDH1 are typically heterozygous mutations and considered gain of function mutations that lead to increased levels of 2-hydroxyglutarate which are believed to alter epigenetic regulation (ie, DNA methylation) in AML. Mutations of IDH1 appear to be mutually exclusive of mutations in TET2, another gene involved in regulation of DNA methylation, and also exclusive of mutations in IDH2. Mutations of IDH1 have been shown to lead to increased DNA methylation in AML. Recurrent missense mutation of Arg 132 in IDH1 has been reported in approximately 5-15% of cases of acute myeloid leukemia and is often associated with a normal karyotype, wild type CEBPA, wild type FLT3 and the presence of NPM1 mutations. In addition, this mutation has been reported in approximately 10-20% of cases with leukemic transformation of myeloproliferative neoplasms and has been reported in less than 5% of chronic phase primary myelofibrosis, less than 5% of myelodysplastic syndrome and rare cases of polycythemia vera, essential thrombocytosis and chronic myelomonocytic leukemia. The prognostic impact of IDH1 mutations in AML appears uncertain, however, in the settings of primary myelofibrosis and polycythemia vera, the presence of IDH1 mutation is independently associated with inferior survival. Mutant IDH1 represents a therapeutic target in some clinical settings.