Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

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

Oncogene volume 31, pages 2491–2498 (2012)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F et al. (2011). IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224: 334–343.

    Article  CAS  Google Scholar 

  • Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP et al. (2009). IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 30: 7–11.

    Article  CAS  Google Scholar 

  • Ceccarelli C, Grodsky NB, Ariyaratne N, Colman RF, Bahnson BJ . (2002). Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate. Insights into the enzyme mechanism. J Biol Chem 277: 43454–43462.

    Article  CAS  Google Scholar 

  • Cooper DN, Youssoufian H . (1988). The CpG dinucleotide and human genetic disease. Hum Genet 78: 151–155.

    Article  CAS  Google Scholar 

  • Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. (2009). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462: 739–744.

    Article  CAS  Google Scholar 

  • DeLano WL . (2006). The PyMOL Molecular Graphics System. DeLano Scientific.

    Google Scholar 

  • Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al. (2010). Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18: 553–567.

    Article  CAS  Google Scholar 

  • Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D et al. (2011). COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 39: D945–D950.

    Article  CAS  Google Scholar 

  • Hemerly JP, Bastos AU, Cerutti JM . (2010). Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. Eur J Endocrinol 163: 747–755.

    Article  CAS  Google Scholar 

  • Ho PA, Alonzo TA, Kopecky KJ, Miller KL, Kuhn J, Zeng R et al. (2010). Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study. Leukemia 24: 909–913.

    Article  CAS  Google Scholar 

  • Jin G, Reitman ZJ, Spasojevic I, Batinic-Haberle I, Yang J, Schmidt-Kittler O et al. (2011). 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations. PLoS One 6: e16812.

    Article  CAS  Google Scholar 

  • Kamerling JP, Duran M, Gerwig GJ, Ketting D, Bruinvis L, Vliegenthart JF et al. (1981). Determination of the absolute configuration of some biologically important urinary 2-hydroxydicarboxylic acids by capillary gas—liquid chromatography. J Chromatogr 222: 276–283.

    Article  CAS  Google Scholar 

  • Kranendijk M, Struys EA, van Schaftingen E, Gibson KM, Kanhai WA, van der Knaap MS et al. (2010). IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330: 336.

    Article  CAS  Google Scholar 

  • Lemons JM, Feng XJ, Bennett BD, Legesse-Miller A, Johnson EL, Raitman I et al. (2010). Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol 8: e1000514.

    Article  Google Scholar 

  • Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D et al. (2010). IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 28: 2348–2355.

    Article  CAS  Google Scholar 

  • Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. (2009). Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361: 1058–1066.

    Article  CAS  Google Scholar 

  • Murugan AK, Bojdani E, Xing M . (2010). Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem Biophys Res Commun 393: 555–559.

    Article  CAS  Google Scholar 

  • Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al. (2010). Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17: 510–522.

    Article  CAS  Google Scholar 

  • Parsons DW, Jones S, Zhang X, Lin JC, Leary LJ, Angenendt P et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science 321: 1807–1812.

    Article  CAS  Google Scholar 

  • Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J et al. (2010). Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28: 3061–3068.

    Article  Google Scholar 

  • Pusch S, Sahm F, Meyer J, Mittelbronn M, Hartmann C, von Deimling A . (2011). Glioma IDH1 mutation patterns off the beaten track. Neuropathol Appl Neurobiol 37: 428–430.

    Article  CAS  Google Scholar 

  • Rakheja D, Mitui M, Boriack RL, DeBerardinis RJ . (2011). Isocitrate dehydrogenase 1/2 mutational analyses and 2-hydroxyglutarate measurements in Wilms tumors. Pediatr Blood Cancer 56: 379–383.

    Article  Google Scholar 

  • Shibata T, Kokubu A, Miyamoto M, Sasajima Y, Yamazaki N . (2011). Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation. Am J Pathol 178: 1395–1402.

    Article  CAS  Google Scholar 

  • Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al. (2010). The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225–234.

    Article  CAS  Google Scholar 

  • Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E et al. (2004). Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem 279: 33946–33957.

    Article  CAS  Google Scholar 

  • Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al. (2009). IDH1 and IDH2 mutations in gliomas. N Engl J Med 360: 765–773.

    CAS  Google Scholar 

  • Zou Y, Zeng Y, Zhang DF, Zou SH, Cheng YF, Yao YG . (2010). IDH1 and IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia but rare in other types of hematological disorders. Biochem Biophys Res Commun 402: 378–383.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    P S Ward, J R Cross, C Lu & C B Thompson

  2. Department of Cancer Biology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    P S Ward & C Lu

  3. Dana-Farber Cancer Institute, Boston, MA, USA

    O Weigert & D M Weinstock

  4. Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    O Abel-Wahab & R L Levine

  5. Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA

    K A Sharp

Authors
  1. P S Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J R Cross
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. O Weigert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O Abel-Wahab
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R L Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D M Weinstock
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K A Sharp
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C B Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C B Thompson.

Ethics declarations

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.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1038/onc.2011.416

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.416

Keywords

This article is cited by

Search

Advanced search

Quick links