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IDH1 and IDH2 Mutations in Gliomas

Current Neurology and Neuroscience Reports volume 13, Article number: 345 (2013) Cite this article

Abstract

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.

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References

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  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.

    Article  Google Scholar 

  2. Scherer HJ. A critical review: the pathology of cerebral gliomas. J Neurol Psychiatry. 1940;3(2):147–77.

    PubMed  Article  CAS  Google Scholar 

  3. Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64(19):6892–9.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  7. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  22. Ghiam AF, Cairns RA, Thoms J, et al. IDH mutation status in prostate cancer. Oncogene. 2012;31(33):3826.

    PubMed  Article  CAS  Google Scholar 

  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.

  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.

    PubMed  Article  CAS  Google Scholar 

  25. Pollard PJ, Ratcliffe PJ. Cancer. Puzzling patterns of predisposition. Science. 2009;324(5924):192–4.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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. 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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  37. Zhao S, Guan KL. IDH1 mutant structures reveal a mechanism of dominant inhibition. Cell Res. 2010;20(12):1279–81.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  46. Sasaki M, Knobbe CB, Munger JC, et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 2012.

  47. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–92.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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. 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.

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

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Acknowledgment

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.

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Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA

    Adam L. Cohen

  2. Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA

    Sheri L. Holmen

  3. Department of Neurosurgery, Huntsman Cancer Institute, Univerity of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA

    Howard Colman

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  1. Adam L. Cohen
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Correspondence to Howard Colman.

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Cohen, A.L., Holmen, S.L. & Colman, H. IDH1 and IDH2 Mutations in Gliomas. Curr Neurol Neurosci Rep 13, 345 (2013). https://doi.org/10.1007/s11910-013-0345-4

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Keywords

  • Isocitrate dehydrogenase
  • Astrocytoma
  • Oligodendroglioma
  • Glioblastoma
  • 2-Hydroxyglutarate
  • Carcinogenesis
  • Prognosis
  • Mutations