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Acta Neuropathologica

, Volume 130, Issue 3, pp 407–417 | Cite as

Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities

  • David E. Reuss
  • Annekathrin Kratz
  • Felix Sahm
  • David Capper
  • Daniel Schrimpf
  • Christian Koelsche
  • Volker Hovestadt
  • Melanie Bewerunge-Hudler
  • David T. W. Jones
  • Jens Schittenhelm
  • Michel Mittelbronn
  • Elisabeth Rushing
  • Matthias Simon
  • Manfred Westphal
  • Andreas Unterberg
  • Michael Platten
  • Werner Paulus
  • Guido Reifenberger
  • Joerg-Christian Tonn
  • Kenneth Aldape
  • Stefan M. Pfister
  • Andrey Korshunov
  • Michael Weller
  • Christel Herold-Mende
  • Wolfgang Wick
  • Sebastian Brandner
  • Andreas von DeimlingEmail author
Original Paper

Abstract

IDH wild type (IDHwt) anaplastic astrocytomas WHO grade III (AA III) are associated with poor outcome. To address the possibilities of molecular subsets among astrocytoma or of diagnostic reclassification, we analyzed a series of 160 adult IDHwt tumors comprising 120 AA III and 40 diffuse astrocytomas WHO grade II (A II) for molecular hallmark alterations and established methylation and copy number profiles. Based on molecular profiles and hallmark alterations the tumors could be grouped into four major sets. 124/160 (78 %) tumors were diagnosed as the molecular equivalent of conventional glioblastoma (GBM), and 15/160 (9 %) as GBM-H3F3A mutated (GBM-H3). 13/160 (8 %) exhibited a distinct methylation profile that was most similar to GBM-H3-K27, however, lacked the H3F3A mutation. This group was enriched for tumors of infratentorial and midline localization and showed a trend towards a more favorable prognosis. All but one of the 120 IDHwt AA III could be assigned to these three groups. 7 tumors recruited from the 40 A II, comprised a variety of molecular signatures and all but one were reclassified into distinct WHO entities of lower grades. Interestingly, TERT mutations were exclusively restricted to the molecular GBM (78 %) and associated with poor clinical outcome. However, the GBM-H3 group lacking TERT mutations appeared to fare even worse. Our data demonstrate that most of the tumors diagnosed as IDHwt astrocytomas can be allocated to other tumor entities on a molecular basis. The diagnosis of IDHwt diffuse astrocytoma or anaplastic astrocytoma should be used with caution.

Keywords

IDH1 IDH2 Astrocytoma Glioblastoma Classification TERT H3F3A 

Notes

Acknowledgments

Part of this work was undertaken at UCLH/UCL which received funding from NIHR. We thank Maria Fernanda Ruiz, Kerstin Lindenberg, Viktoria Zeller for technical assistance. FS is a fellow of the Medical Faculty Heidelberg Physician-Scientist Program. Supported by the Bundesministerium für Bildung und Forschung (BMBF) program SYS-GLIO and the German Cancer Net (DKTK) joint funding project “Next generation molecular diagnostics of malignant gliomas”.

Supplementary material

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Supplementary material 5 (XLSX 26 kb) Supplementary Table 2: Molecular alterations in 160 patients with IDHwt astrocytoma

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • David E. Reuss
    • 1
    • 2
  • Annekathrin Kratz
    • 1
    • 2
  • Felix Sahm
    • 1
    • 2
  • David Capper
    • 1
    • 2
  • Daniel Schrimpf
    • 1
    • 2
  • Christian Koelsche
    • 1
    • 2
  • Volker Hovestadt
    • 3
  • Melanie Bewerunge-Hudler
    • 4
  • David T. W. Jones
    • 5
  • Jens Schittenhelm
    • 6
  • Michel Mittelbronn
    • 7
    • 8
  • Elisabeth Rushing
    • 9
  • Matthias Simon
    • 10
  • Manfred Westphal
    • 11
  • Andreas Unterberg
    • 12
  • Michael Platten
    • 13
    • 14
  • Werner Paulus
    • 15
  • Guido Reifenberger
    • 16
    • 17
  • Joerg-Christian Tonn
    • 18
  • Kenneth Aldape
    • 19
  • Stefan M. Pfister
    • 5
    • 20
  • Andrey Korshunov
    • 1
    • 2
  • Michael Weller
    • 21
  • Christel Herold-Mende
    • 12
  • Wolfgang Wick
    • 13
    • 22
  • Sebastian Brandner
    • 23
    • 24
  • Andreas von Deimling
    • 1
    • 2
    Email author
  1. 1.Department of NeuropathologyInstitute of Pathology, University of HeidelbergHeidelbergGermany
  2. 2.CCU NeuropathologyGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Division of Molecular GeneticsGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Genomics and Proteomics Core Facility, Microarray UnitGerman Cancer Research Center (DKFZ)HeidelbergGermany
  5. 5.Division of Pediatric NeurooncologyGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  6. 6.Department of NeuropathologyInstitute of Pathology and Neuropathology, University TübingenTübingenGermany
  7. 7.Institute of Neurology (Edinger Institute)Goethe UniversityFrankfurtGermany
  8. 8.German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  9. 9.Institute of NeuropathologyUniversitätsspital ZürichZürichSwitzerland
  10. 10.Department of NeurosurgeryUniversity Hospital BonnBonnGermany
  11. 11.Department of NeurosurgeryUniversity Hospital Hamburg EppendorfHamburgGermany
  12. 12.Department of NeurosurgeryUniversity of HeidelbergHeidelbergGermany
  13. 13.Neurology ClinicHeidelberg University HospitalHeidelbergGermany
  14. 14.DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor ImmunologyGerman Cancer Research CenterHeidelbergGermany
  15. 15.Institute of NeuropathologyUniversity Hospital MünsterMünsterGermany
  16. 16.Department of NeuropathologyHeinrich Heine UniversityDüsseldorfGermany
  17. 17.German Cancer Consortium (DKTK) Partner Site Essen/DüsseldorfDüsseldorfGermany
  18. 18.Department of NeurosurgeryKlinikum Grosshadern, Ludwigs-Maximilians-UniversityMunichGermany
  19. 19.MacFeeters-Hamilton Brain Tumour Center, Princess Margaret Cancer CenterTorontoCanada
  20. 20.Department of Pediatric Oncology, Hematology and ImmunologyUniversity Medical CenterHeidelbergGermany
  21. 21.Department of NeurologyUniversity Hospital ZürichZürichSwitzerland
  22. 22.Clinical Cooperation Unit NeurooncologyGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  23. 23.Division of NeuropathologyThe National Hospital for Neurology, Neurosurgery, University College of London, NHS Foundation TrustLondonUK
  24. 24.Department of NeurodegenerationUCL Institute of NeurologyLondonUK

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