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

Authors: Ward, P. S.; Cross, J. R.; Lu, C.; Weigert, O.; Abdel-Wahab, O.; Levine, R. L.; Weinstock, D. M.; Sharp, K. A.; Thompson, C. B.
Article Title: Identification of additional IDH mutations associated with oncometabolite R(-)-2-hydroxyglutarate production
Abstract: 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. © 2012 Macmillan Publishers Limited All rights reserved.
Keywords: idh1; idh2; nadph; 2-hydroxyglutarate; oncometabolite
Journal Title: Oncogene
Volume: 31
Issue: 19
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2012-05-10
Start Page: 2491
End Page: 2498
Language: English
DOI: 10.1038/onc.2011.416
PROVIDER: scopus
PMCID: PMC3271133
PUBMED: 21996744
Notes: --- - "Export Date: 4 June 2012" - "CODEN: ONCNE" - "Source: Scopus"
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MSK Authors
  1. Ross Levine
    496 Levine
  2. Chao Lu
    19 Lu
  3. Patrick Shea Ward
    16 Ward
  4. Justin Robert Cross
    51 Cross
  5. Craig Bernie Thompson
    120 Thompson