IDH1 and IDH2 Mutations in Gliomas

  • Adam L. Cohen
  • Sheri L. Holmen
  • Howard ColmanEmail author
Neuro-Oncology (LE Abrey, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Neuro-Oncology


Mutations in isocitrate dehydrogenase (IDH) 1 and 2, originally discovered in 2008, occur in the vast majority of low-grade gliomas and secondary high-grade gliomas. These mutations, which occur early in gliomagenesis, change the function of the enzymes, causing them to produce 2-hydroxyglutarate, a possible oncometabolite, and to not produce NADPH. IDH mutations are oncogenic, although whether the mechanism is through alterations in hydroxylases, redox potential, cellular metabolism, or gene expression is not clear. The mutations also drive increased methylation in gliomas. Gliomas with mutated IDH1 and IDH2 have improved prognosis compared with gliomas with wild-type IDH. Mutated IDH can now be detected by immunohistochemistry and magnetic resonance spectroscopy. No drugs currently target mutated IDH, although this remains an area of active research.


Isocitrate dehydrogenase Astrocytoma Oligodendroglioma Glioblastoma 2-Hydroxyglutarate Carcinogenesis Prognosis Mutations 



The authors thank Rowan Arave for assistance with preparation of the figure.

Conflict of Interest

Adam Cohen declares no conflict of interest.

Sheri Holmen declares no conflict of interest.

Howard Colman has been a consultant to Roche and has received royalties from Castle Biosciences.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Dolecek T, Propp J, Stroup N, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol. 2012;15 suppl 5:v1–v49.CrossRefGoogle Scholar
  2. 2.
    Scherer HJ. A critical review: the pathology of cerebral gliomas. J Neurol Psychiatry. 1940;3(2):147–77.PubMedCrossRefGoogle Scholar
  3. 3.
    Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64(19):6892–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9(3):157–73.PubMedCrossRefGoogle Scholar
  5. 5.
    Verhaak RG, Hoadley KA, Purdom E, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.PubMedCrossRefGoogle Scholar
  6. 6.
    Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–22.PubMedCrossRefGoogle Scholar
  7. 7.
    Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12.PubMedCrossRefGoogle Scholar
  8. 8.
    Balss J, Meyer J, Mueller W, et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008;116(6):597–602.PubMedCrossRefGoogle Scholar
  9. 9.
    Bleeker FE, Lamba S, Leenstra S, et al. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat. 2009;30(1):7–11.PubMedCrossRefGoogle Scholar
  10. 10.
    • Hartmann C, Meyer J, Balss J, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 2009;118(4):469–74. This article describes the largest series of gliomas typed for IDH mutations. It established the distribution of IDH mutations by histologic subtype and grade.PubMedCrossRefGoogle Scholar
  11. 11.
    Kang MR, Kim MS, Oh JE, et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer. 2009;125(2):353–5.PubMedCrossRefGoogle Scholar
  12. 12.
    • Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009;27(25):4150–4. This article reinforced the clinical relevance of IDH mutation by validating that it is prognostic independent of age, grade, and MGMT status.PubMedCrossRefGoogle Scholar
  13. 13.
    •• Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174(4):1149–53. This article established that IDH mutations occur before other known genetic changes, including TP53 mutation and 1p/19q deletion, during the course of gliomagenesis.PubMedCrossRefGoogle Scholar
  14. 14.
    ••Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73. This was the first work to identify IDH mutations in gliomas.PubMedCrossRefGoogle Scholar
  15. 15.
    Sonoda Y, Kumabe T, Nakamura T, et al. Analysis of IDH1 and IDH2 mutations in Japanese glioma patients. Cancer Sci. 2009;100(10):1996–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–66.PubMedCrossRefGoogle Scholar
  17. 17.
    Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17(1):72–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Amary MF, Bacsi K, Maggiani F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224(3):334–43.PubMedCrossRefGoogle Scholar
  19. 19.
    Mauzo SH, Lee M, Petros J, et al. Immunohistochemical demonstration of isocitrate dehydrogenase 1 (IDH1) mutation in a small subset of prostatic carcinomas. Appl Immunohistochem Mol Morphol. 2012.Google Scholar
  20. 20.
    Ang D, Vansandt AM, Beadling C, et al. Biphasic papillary and lobular breast carcinoma with PIK3CA and IDH1 mutations. Diagn Mol Pathol. 2012;21(4):221–4.PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang Y, Wei H, Tang K, et al. Mutation analysis of isocitrate dehydrogenase in acute lymphoblastic leukemia. Genet Test Mol Biomarkers. 2012;16(8):991–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Ghiam AF, Cairns RA, Thoms J, et al. IDH mutation status in prostate cancer. Oncogene. 2012;31(33):3826.PubMedCrossRefGoogle Scholar
  23. 23.
    Tefferi A, Jimma T, Sulai NH, et al. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F. Leukemia. 2011.Google Scholar
  24. 24.
    Kloosterhof NK, Bralten LB, Dubbink HJ, French PJ, van den Bent MJ. Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma? Lancet Oncol. 2011;12(1):83–91.PubMedCrossRefGoogle Scholar
  25. 25.
    Pollard PJ, Ratcliffe PJ. Cancer. Puzzling patterns of predisposition. Science. 2009;324(5924):192–4.PubMedCrossRefGoogle Scholar
  26. 26.
    Lee SM, Koh HJ, Park DC, et al. Cytosolic NADP(+)-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic Biol Med. 2002;32(11):1185–96.PubMedCrossRefGoogle Scholar
  27. 27.
    Watanabe T, Vital A, Nobusawa S, Kleihues P, Ohgaki H. Selective acquisition of IDH1 R132C mutations in astrocytomas associated with Li-Fraumeni syndrome. Acta Neuropathol. 2009;117(6):653–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Xu X, Zhao J, Xu Z, et al. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem. 2004;279(32):33946–57.PubMedCrossRefGoogle Scholar
  29. 29.
    Bayley JP, Devilee P. Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree? Curr Opin Genet Dev. 2010;20(3):324–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Yan H, Bigner DD, Velculescu V, Parsons DW. Mutant metabolic enzymes are at the origin of gliomas. Cancer Res. 2009;69(24):9157–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Pansuriya TC, van Eijk R. d'Adamo P, et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet. 2011;43(12):1256–61.PubMedCrossRefGoogle Scholar
  32. 32.
    Ranger A, Szymczak A. Do intracranial neoplasms differ in Ollier disease and maffucci syndrome? An in-depth analysis of the literature. Neurosurgery. 2009;65(6):1106–13. discussion 13-5.PubMedCrossRefGoogle Scholar
  33. 33.
    • Koivunen P, Lee S, Duncan CG, et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012;483(7390):484–8. This article demonstrated that 2-HG is an oncometabolite that can transform normal astrocytes into a malignant phenotype.PubMedCrossRefGoogle Scholar
  34. 34.
    Lu C, Ward PS, Kapoor GS. et al. Nature: IDH mutation impairs histone demethylation and results in a block to cell differentiation; 2012.Google Scholar
  35. 35.
    Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–67.PubMedCrossRefGoogle Scholar
  36. 36.
    Yang B, Zhong C, Peng Y, Lai Z, Ding J. Molecular mechanisms of "off-on switch" of activities of human IDH1 by tumor-associated mutation R132H. Cell Res. 2010;20(11):1188–200.PubMedCrossRefGoogle Scholar
  37. 37.
    Zhao S, Guan KL. IDH1 mutant structures reveal a mechanism of dominant inhibition. Cell Res. 2010;20(12):1279–81.PubMedCrossRefGoogle Scholar
  38. 38.
    Zhao S, Lin Y, Xu W, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;324(5924):261–5.PubMedCrossRefGoogle Scholar
  39. 39.
    •• Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44. This article changed the paradigm for understanding IDH mutations by demonstrating that in addition to losing the normal function of IDH, the mutants gained the ability to convert α-kG to 2-HG.PubMedCrossRefGoogle Scholar
  40. 40.
    Jin G, Reitman ZJ, Spasojevic I, et al. 2-Hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations. PLoS One. 2011;6(2):e16812.PubMedCrossRefGoogle Scholar
  41. 41.
    Garber K. Oncometabolite? IDH1 discoveries raise possibility of new metabolism targets in brain cancers and leukemia. J Natl Cancer Inst. 2010;102(13):926–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Kranendijk M, Struys EA, Salomons GS, Van der Knaap MS, Jakobs C. Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis. 2012;35(4):571–87.PubMedCrossRefGoogle Scholar
  43. 43.
    Patay Z, Mills JC, Lobel U, et al. Cerebral neoplasms in L-2 hydroxyglutaric aciduria: 3 new cases and meta-analysis of literature data. AJNR Am J Neuroradiol. 2012;33(5):940–3.PubMedCrossRefGoogle Scholar
  44. 44.
    Pietrak B, Zhao H, Qi H, et al. A tale of two subunits: how the neomorphic R132H IDH1 mutation enhances production of alphaHG. Biochemistry. 2011;50(21):4804–12.PubMedCrossRefGoogle Scholar
  45. 45.
    Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.PubMedCrossRefGoogle Scholar
  46. 46.
    Sasaki M, Knobbe CB, Munger JC, et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 2012.Google Scholar
  47. 47.
    Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–92.PubMedCrossRefGoogle Scholar
  48. 48.
    Christensen BC, Smith AA, Zheng S, et al. DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. J Natl Cancer Inst. 2011;103(2):143–53.PubMedCrossRefGoogle Scholar
  49. 49.
    Laffaire J, Everhard S, Idbaih A, et al. Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis. Neuro Oncol. 2011;13(1):84–98.PubMedCrossRefGoogle Scholar
  50. 50.
    •• Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012. This article linked the hypermethylated phenotype in gliomas to IDH mutation but showed that IDH mutations are necessary and sufficient for establishing the methylator phenotype.Google Scholar
  51. 51.
    Fu Y, Zheng S, Zheng Y, et al. Glioma derived isocitrate dehydrogenase-2 mutations induced up-regulation of HIF-1alpha and beta-catenin signaling: possible impact on glioma cell metastasis and chemo-resistance. Int J Biochem Cell Biol. 2012;44(5):770–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Labussiere M, Idbaih A, Wang XW, et al. All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology. 2010;74(23):1886–90. This article showed that 1p/19q deletion, the hallmark of oligodendrogliomas, never occurs without first having IDH mutation.PubMedCrossRefGoogle Scholar
  53. 53.
    Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature. 1990;348(6303):747–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Paugh BS, Qu C, Jones C, et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol. 2010;28(18):3061–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Pollack IF, Hamilton RL, Sobol RW, et al. IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group. Childs Nerv Syst. 2011;27(1):87–94.PubMedCrossRefGoogle Scholar
  56. 56.
    Jenkins RB, Xiao Y, Sicotte H, et al. A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation. Nat Genet. 2012;44(10):1122–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Combs SE, Rieken S, Wick W, et al. Prognostic significance of IDH-1 and MGMT in patients with glioblastoma: one step forward, and one step back? Radiat Oncol. 2011;6:115.PubMedCrossRefGoogle Scholar
  58. 58.
    Weller M, Felsberg J, Hartmann C, et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol. 2009;27(34):5743–50.PubMedCrossRefGoogle Scholar
  59. 59.
    Li S, Chou AP, Chen W. et al. Neuro Oncol: Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation; 2012.Google Scholar
  60. 60.
    Juratli TA, Kirsch M, Robel K, et al. IDH mutations as an early and consistent marker in low-grade astrocytomas WHO grade II and their consecutive secondary high-grade gliomas. J Neurooncol. 2012.Google Scholar
  61. 61.
    SongTao Q, Lei Y, Si G, et al. IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. Cancer Sci. 2012;103(2):269–73.PubMedCrossRefGoogle Scholar
  62. 62.
    Houillier C, Wang X, Kaloshi G, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2010;75(17):1560–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Hartmann C, Hentschel B, Tatagiba M, et al. Molecular markers in low-grade gliomas: predictive or prognostic? Clin Cancer Res. 2011;17(13):4588–99.PubMedCrossRefGoogle Scholar
  64. 64.
    Taal W, Dubbink HJ, Zonnenberg CB, et al. First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response. Neuro Oncol. 2011;13(2):235–41.PubMedCrossRefGoogle Scholar
  65. 65.
    van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC Brain Tumor Group study 26951. J Clin Oncol. 2012.Google Scholar
  66. 66.
    Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009;27(35):5874–80.PubMedCrossRefGoogle Scholar
  67. 67.
    • Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A. Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol. 2009;118(5):599–601. The description of this monoclonal antibody allowed the detection of the commonest IDH mutation using immunohistochemistry, allowing easy detection for both research and clinical purposes.PubMedCrossRefGoogle Scholar
  68. 68.
    •• Choi C, Ganji SK, Deberardinis RJ, et al. 2-Hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med. 2012. This description of detection of 2-HG by magnetic resonance spectroscopy provides the first pathognomonic sign of gliomas that can be detected by imaging.Google Scholar
  69. 69.
    Piaskowski S, Bienkowski M, Stoczynska-Fidelus E, et al. Glioma cells showing IDH1 mutation cannot be propagated in standard cell culture conditions. Br J Cancer. 2011;104(6):968–70.PubMedCrossRefGoogle Scholar
  70. 70.
    Bralten LB, Kloosterhof NK, Balvers R, et al. IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo. Ann Neurol. 2011;69(3):455–63.PubMedCrossRefGoogle Scholar
  71. 71.
    Luchman HA, Stechishin OD, Dang NH, et al. An in vivo patient-derived model of endogenous IDH1-mutant glioma. Neuro Oncol. 2012;14(2):184–91.PubMedCrossRefGoogle Scholar
  72. 72.
    Jin G, Pirozzi CJ, Chen LH, et al. Mutant IDH1 is required for IDH1 mutated tumor cell growth. Oncotarget. 2012;3(8):774–82.PubMedGoogle Scholar
  73. 73.
    Kranendijk M, Salomons GS, Gibson KM, et al. A lymphoblast model for IDH2 gain-of-function activity in d-2-hydroxyglutaric aciduria type II: novel avenues for biochemical and therapeutic studies. Biochim Biophys Acta. 2011;1812(11):1380–4.PubMedCrossRefGoogle Scholar
  74. 74.
    Gerardo Valadez J, Grover VK, Carter MD, et al. Identification of Hedgehog pathway responsive glioblastomas by isocitrate dehydrogenase mutation. Cancer Lett. 2013;328(2):297–306.PubMedCrossRefGoogle Scholar
  75. 75.
    Fathi AT, Abdel-Wahab O. Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy. Adv Hematol. 2012;2012:469592.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Adam L. Cohen
    • 1
  • Sheri L. Holmen
    • 2
  • Howard Colman
    • 3
    Email author
  1. 1.Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  2. 2.Department of Surgery, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  3. 3.Department of Neurosurgery, Huntsman Cancer InstituteUniverity of UtahSalt Lake CityUSA

Personalised recommendations