Identification of additional IDH mutations associated with oncometabolite R (−)-2-hydroxyglutarate production

摘要: Mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or its mitochondrial homolog IDH2 can lead to R(-)-2-hydroxyglutarate (2HG) production. To date, mutations three active site arginine residues, IDH1 R132, R172 and R140, have been shown result the neomorphic production of 2HG. Here we report on additional 2HG-producing mutations: R100, which is affected adult glioma, G97, mutated colon cancer cell lines pediatric glioblastoma, Y139. All these new mutants stereospecifically produced 2HG's (R) enantiomer. In contrast, find that SNPs V71I V178I, as well a number other single-sample reports IDH non-synonymous mutation, did not elevate cellular 2HG levels cells retained wild-type ability for isocitrate-dependent NADPH Finally, existence rare, but recurring found lymphoma thyroid cancer, while failing nonetheless displayed loss function, indicating possible tumorigenic mechanism non-2HG-producing subset some malignancies. These data broaden our understanding how may contribute through either R(-)-2HG reduced enzymatic activity, highlight potential value metabolite screening identifying IDH-mutated tumors associated with elevated oncometabolite levels.