Skip to main content

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 Neuropathologica volume 118, pages 469–474 (2009)Cite this article

Abstract

Somatic mutations in the IDH1 gene encoding cytosolic NADP+-dependent isocitrate dehydrogenase have been shown in the majority of astrocytomas, oligodendrogliomas and oligoastrocytomas of WHO grades II and III. IDH2 encoding mitochondrial NADP+-dependent isocitrate dehydrogenase is also mutated in these tumors, albeit at much lower frequencies. Preliminary data suggest an importance of IDH1 mutation for prognosis showing that patients with anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas harboring IDH1 mutations seem to fare much better than patients without this mutation in their tumors. To determine mutation types and their frequencies, we examined 1,010 diffuse gliomas. We detected 716 IDH1 mutations and 31 IDH2 mutations. We found 165 IDH1 (72.7%) and 2 IDH2 mutations (0.9%) in 227 diffuse astrocytomas WHO grade II, 146 IDH1 (64.0%) and 2 IDH2 mutations (0.9%) in 228 anaplastic astrocytomas WHO grade III, 105 IDH1 (82.0%) and 6 IDH2 mutations (4.7%) in 128 oligodendrogliomas WHO grade II, 121 IDH1 (69.5%) and 9 IDH2 mutations (5.2%) in 174 anaplastic oligodendrogliomas WHO grade III, 62 IDH1 (81.6%) and 1 IDH2 mutations (1.3%) in 76 oligoastrocytomas WHO grade II and 117 IDH1 (66.1%) and 11 IDH2 mutations (6.2%) in 177 anaplastic oligoastrocytomas WHO grade III. We report on an inverse association of IDH1 and IDH2 mutations in these gliomas and a non-random distribution of the mutation types within the tumor entities. IDH1 mutations of the R132C type are strongly associated with astrocytoma, while IDH2 mutations predominantly occur in oligodendroglial tumors. In addition, patients with anaplastic glioma harboring IDH1 mutations were on average 6 years younger than those without these alterations.

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

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1

References

  1. Balss J, Meyer J, Mueller W et al (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602

    PubMed  Article  CAS  Google Scholar 

  2. Bleeker FE, Lamba S, Leenstra S 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

    PubMed  Article  CAS  Google Scholar 

  3. Coons SW, Johnson PC, Scheithauer BW et al (1997) Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas. Cancer 79:1381–1393

    PubMed  Article  CAS  Google Scholar 

  4. Geisbrecht BV, Gould SJ (1999) The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase. J Biol Chem 274:30527–30533

    PubMed  Article  CAS  Google Scholar 

  5. Grzeschik KH (1976) Assignment of a gene for human mitochondrial isocitrate dehydrogenase (ICD-M, EC 1.1.1.41) to chromosome 15. Hum Genet 34:23–28

    PubMed  Article  CAS  Google Scholar 

  6. Hartong DT, Dange M, McGee TL et al (2008) Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle. Nat Genet 40:1230–1234

    PubMed  Article  CAS  Google Scholar 

  7. Huh TL, Kim YO, Oh IU et al (1996) Assignment of the human mitochondrial NAD+-specific isocitrate dehydrogenase alpha subunit (IDH3A) gene to 15q25.1→q25.2 by in situ hybridization. Genomics 32:295–296

    PubMed  Article  CAS  Google Scholar 

  8. Ichimura K, Pearson DM, Kocialkowski S et al (2009) IDH1 mutations are present in the majority of common adult gliomas but are rare in primary glioblastomas. Neurol Oncol. 12 May 2009. [Epub ahead of print]

  9. Kang MR, Kim MS, Oh JE et al (2009) Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer 125(2):353–355

    PubMed  Article  CAS  Google Scholar 

  10. Kim YO, Park SH, Kang YJ et al (1999) Assignment of mitochondrial NAD(+)-specific isocitrate dehydrogenase beta subunit gene (IDH3B) to human chromosome band 20p13 by in situ hybridization and radiation hybrid mapping. Cytogenet Cell Genet 86:240–241

    PubMed  Article  CAS  Google Scholar 

  11. Loenarz C, Schofield CJ (2008) Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol 4:152–156

    PubMed  Article  CAS  Google Scholar 

  12. Louis DN, Ohgaki H, Wiestler OD et al (2007) WHO classification of tumours of the central nervous system. In: World Health Organization classification of tumours, 4th edn. International Agency for Research on Cancer, Lyon

  13. Narahara K, Kimura S, Kikkawa K et al (1985) Probable assignment of soluble isocitrate dehydrogenase (IDH1) to 2q33.3. Hum Genet 71:37–40

    PubMed  Article  CAS  Google Scholar 

  14. Parsons DW, Jones S, Zhang X et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    PubMed  Article  CAS  Google Scholar 

  15. Ramachandran N, Colman RF (1980) Chemical characterization of distinct subunits of pig heart DPN-specific isocitrate dehydrogenase. J Biol Chem 255:8859–8864

    PubMed  CAS  Google Scholar 

  16. Shechter I, Dai P, Huo L et al (2003) IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells. J Lipid Res 44:2169–2180

    PubMed  Article  CAS  Google Scholar 

  17. Watanabe T, Nobusawa S, Kleihues P et al (2009) IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174:1149–1153

    PubMed  Article  CAS  Google Scholar 

  18. Watanabe T, Vital A, Nobusawa S et al (2009) Selective acquisition of IDH1 R132C mutations in astrocytomas associated with Li-Fraumeni syndrome. Acta Neuropathol 117:653–656

    PubMed  Article  CAS  Google Scholar 

  19. Weiss C, Zeng Y, Huang J et al (2000) Bovine NAD+-dependent isocitrate dehydrogenase: alternative splicing and tissue-dependent expression of subunit 1. Biochemistry 39:1807–1816

    PubMed  Article  CAS  Google Scholar 

  20. Wick W, Stoffels M, Engel C et al (2009) NOA-04 randomized phase III study of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. J Clin Oncol (in press)

  21. Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773

    PubMed  Article  CAS  Google Scholar 

  22. Zhao S, Lin Y, Xu W et al (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324:261–265

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank F. Mößler and K. Lindenberg for skillful technical assistance. This work was supported by the Bundesministerium für Bildung und Forschung (BMBF) by a grant to AvD, CH, WW and GR (grant number 01ES0729-30).

Author information

Affiliations

  1. Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 220/221, 69120, Heidelberg, Germany

    Christian Hartmann, David Capper, Wolf Mueller & Andreas von Deimling

  2. Clinical Cooperation Unit Neuropathology G380, German Cancer Research Center, 69120, Heidelberg, Germany

    Christian Hartmann, Jochen Meyer, Jörg Balss, Arne Christians & Andreas von Deimling

  3. Department of Neuropathology, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany

    Jörg Felsberg, Marietta Wolter & Guido Reifenberger

  4. Department of Neuropathology, Otto von Guericke Universität Magdeburg, 39120, Magdeburg, Germany

    Christian Mawrin

  5. Department of Neurooncology, Clinical Cooperation Unit Neurooncology DKFZ, Ruprecht-Karls-Universität Heidelberg, 69120, Heidelberg, Germany

    Wolfgang Wick

  6. Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland

    Michael Weller

  7. Department of Neurosurgery, Ruprecht-Karls-Universität Heidelberg, 69120, Heidelberg, Germany

    Christel Herold-Mende & Andreas Unterberg

  8. Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Judith W. M. Jeuken & Peter Wesseling

Authors
  1. Christian Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jochen Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jörg Balss
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Capper
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wolf Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Arne Christians
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jörg Felsberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marietta Wolter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christian Mawrin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wolfgang Wick
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael Weller
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christel Herold-Mende
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Andreas Unterberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Judith W. M. Jeuken
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Peter Wesseling
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Guido Reifenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Andreas von Deimling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas von Deimling.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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 118, 469–474 (2009). https://doi.org/10.1007/s00401-009-0561-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-009-0561-9

Keywords

  • IDH1
  • IDH2
  • Mutation
  • Glioma
  • Astrocytoma
  • Oligodendroglioma
  • Oligoastrocytoma