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Acta Neuropathologica

, Volume 128, Issue 4, pp 561–571 | Cite as

Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma

  • Benedikt Wiestler
  • David Capper
  • Martin Sill
  • David T. W. Jones
  • Volker Hovestadt
  • Dominik Sturm
  • Christian Koelsche
  • Anna Bertoni
  • Leonille Schweizer
  • Andrey Korshunov
  • Elisa K. Weiß
  • Maximilian G. Schliesser
  • Alexander Radbruch
  • Christel Herold-Mende
  • Patrick Roth
  • Andreas Unterberg
  • Christian Hartmann
  • Torsten Pietsch
  • Guido Reifenberger
  • Peter Lichter
  • Bernhard Radlwimmer
  • Michael Platten
  • Stefan M. Pfister
  • Andreas von Deimling
  • Michael Weller
  • Wolfgang Wick
Original Paper

Abstract

The outcome of patients with anaplastic gliomas varies considerably. Whether a molecular classification of anaplastic gliomas based on large-scale genomic or epigenomic analyses is superior to histopathology for reflecting distinct biological groups, predicting outcomes and guiding therapy decisions has yet to be determined. Epigenome-wide DNA methylation analysis, using a platform which also allows the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas, and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering of DNA methylation patterns revealed two main groups correlated with IDH status: CpG island methylator phenotype (CIMP) positive (77.5 %) or negative (22.5 %). CIMPpos (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q. CIMPneg (IDH wild type) tumors showed hallmark copy-number alterations of glioblastomas, and clustered together with CIMPneg glioblastomas without forming separate groups based on WHO grade. Notably, there was no molecular evidence for a distinct biological entity representing anaplastic oligoastrocytoma. Tumor classification based on CIMP and 1p/19q status was significantly associated with survival, allowing a better prediction of outcome than the current histopathological classification: patients with CIMPpos tumors with 1p/19q codeletion (CIMP-codel) had the best prognosis, followed by patients with CIMPpos tumors but intact 1p/19q status (CIMP-non-codel). Patients with CIMPneg anaplastic gliomas (GBM-like) had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped by IDH and 1p/19q status into three molecular groups that show clear links to underlying biology and a significant association with clinical outcome in a prospective trial cohort.

Keywords

Anaplastic glioma IDH G-CIMP 1p/19q 450 k 

Notes

Acknowledgments

The work was supported by the German Cancer Aid (Deutsche Krebshilfe, “Molecular classification of anaplastic gliomas in the NOA-04 trial”, project 110624) to WW and MW and the Personalized Oncology Program of the NCT Heidelberg.

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Benedikt Wiestler
    • 1
    • 6
  • David Capper
    • 2
    • 7
  • Martin Sill
    • 11
  • David T. W. Jones
    • 9
  • Volker Hovestadt
    • 10
  • Dominik Sturm
    • 9
  • Christian Koelsche
    • 2
    • 7
  • Anna Bertoni
    • 10
  • Leonille Schweizer
    • 2
    • 7
  • Andrey Korshunov
    • 2
    • 7
  • Elisa K. Weiß
    • 1
    • 6
  • Maximilian G. Schliesser
    • 1
  • Alexander Radbruch
    • 4
  • Christel Herold-Mende
    • 3
  • Patrick Roth
    • 16
  • Andreas Unterberg
    • 3
  • Christian Hartmann
    • 2
    • 7
    • 12
  • Torsten Pietsch
    • 13
  • Guido Reifenberger
    • 14
    • 15
  • Peter Lichter
    • 10
  • Bernhard Radlwimmer
    • 10
  • Michael Platten
    • 6
    • 8
  • Stefan M. Pfister
    • 5
    • 9
  • Andreas von Deimling
    • 2
    • 7
  • Michael Weller
    • 16
  • Wolfgang Wick
    • 1
    • 6
    • 17
  1. 1.Clinical Cooperation Unit NeurooncologyGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  2. 2.Clinical Cooperation Unit NeuropathologyGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Department of NeurosurgeryHeidelberg University HospitalHeidelbergGermany
  4. 4.Department of NeuroradiologyHeidelberg University HospitalHeidelbergGermany
  5. 5.Department of Pediatric Oncology, Hematology, and ImmunologyHeidelberg University HospitalHeidelbergGermany
  6. 6.Department of NeurooncologyHeidelberg University HospitalHeidelbergGermany
  7. 7.Department of NeuropathologyHeidelberg University HospitalHeidelbergGermany
  8. 8.Clinical Cooperation Unit Neuroimmunology and Brain Tumor ImmunologyGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  9. 9.Division of Pediatric NeurooncologyGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  10. 10.Division of Molecular GeneticsGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  11. 11.Division of BiostatisticsGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  12. 12.Department for Neuropathology, Institute of PathologyMedical University of HannoverHannoverGermany
  13. 13.Department of NeuropathologyUniversity of Bonn Medical CenterBonnGermany
  14. 14.Department of NeuropathologyHeinrich-Heine-UniversityDüsseldorfGermany
  15. 15.DKTK, partner site Essen/DüsseldorfDüsseldorfGermany
  16. 16.Department of NeurologyUniversity Hospital ZurichZurichSwitzerland
  17. 17.Department of Neurooncology, Neurology Clinic and National Center for Tumor DiseasesUniversity of Heidelberg and German Cancer Research CenterHeidelbergGermany

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