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


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

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This work was supported in part by grants from the NCI and NIH. RL Levine is a HHMI Early Career Award Recipient and Geoffrey Beene Junior Faculty Chair at MSKCC. DM Weinstock is supported by a Stand Up To Cancer Innovative Research Grant and American Cancer Society Research Scholar Grant.

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Correspondence to C B Thompson.

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Competing interests

Dr Thompson's work has been funded by the NCI and NIH. He is a co-founder of Agios Pharmaceuticals, is the chair of its scientific advisory board and has financial interest in the company. The remaining authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Oncogene website

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Ward, P., Cross, J., Lu, C. et al. Identification of additional IDH mutations associated with oncometabolite R(−)-2-hydroxyglutarate production. Oncogene 31, 2491–2498 (2012).

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