title: Metabolism of glioma and IDH1/IDH2 mutations.
abstract: Many known oncogenic signaling pathways involved in gliomagenesis have strong consequences on tumor cell metabolism, and promote the switch from oxidative phosphorylation to aerobic glycolysis, for ATP generation. However, the interest on metabolism has been recently renewed by the discovery of recurrent mutation of IDH1 genes by systematic sequencing of a glioblastoma series. IDH1 encodes the cytoplasmic NADP dependent isocitrate dehydrogenase1 that catalyzes the oxidative decarboxylation of isocitrate into α-ketoglutarate. IDH1, more rarely IDH2, is mutated in 40% of gliomas (roughly 70% of low-grade gliomas, 50% of grade III, and 5 to 10% of primary glioblastomas). IDH1/IDH2 mutations are associated with genomic profile, being present in nearly all the 1p19q codeleted gliomas, and virtually absent in gliomas with EGFR amplification. It is a strong and independent predictor of survival, whatever grade considered. IDH1/IDH2 mutation results in a new enzymatic activity transforming α-ketoglutarate into 2-hydroxyglutarate (2-HG). The oncometabolite 2-HG accumulates in the cell and acts as a competitive inhibitor of many α-ketoglutarate dependent cellular reactions. The cellular consequences of this mutation offer potential targets for the development of novel therapeutics.
authors: UMR S975, centre de recherche de l'institut du cerveau et de la moelle épinière, université Pierre-et-Marie-Curie Paris-6, 47 boulevard de l'Hôpital, Paris cedex 13, France.
authors: M
authors: M
authors: Rossetto
authors: P
authors: P
authors: Ciccarino
authors: B
authors: B
authors: Boisselier
authors: M
authors: M
authors: Labussiere
authors: M
authors: M
authors: Sanson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000187:drug effects / Q000235:genetics*; D009154:Mutation / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human