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Acta Neuropathologica

, Volume 129, Issue 1, pp 133–146 | Cite as

ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma

  • David E. Reuss
  • Felix Sahm
  • Daniel Schrimpf
  • Benedikt Wiestler
  • David Capper
  • Christian Koelsche
  • Leonille Schweizer
  • Andrey Korshunov
  • David T. W. Jones
  • Volker Hovestadt
  • Michel Mittelbronn
  • Jens Schittenhelm
  • Christel Herold-Mende
  • Andreas Unterberg
  • Michael Platten
  • Michael Weller
  • Wolfgang Wick
  • Stefan M. Pfister
  • Andreas von Deimling
Original Paper

Abstract

Diffuse gliomas are represented in the 2007 WHO classification as astrocytomas, oligoastrocytomas and oligodendrogliomas of grades II and III and glioblastomas WHO grade IV. Molecular data on these tumors have a major impact on prognosis and therapy of the patients. Consequently, the inclusion of molecular parameters in the WHO definition of brain tumors is being planned and has been forwarded as the “ISN-Haarlem” consensus. We, here, analyze markers of special interest including ATRX, IDH and 1p/19q codeletion in a series of 405 adult patients. Among the WHO 2007 classified tumors were 152 astrocytomas, 61 oligodendrogliomas, 63 oligoastrocytomas and 129 glioblastomas. Following the concepts of the “ISN-Haarlem”, we rediagnosed the series to obtain “integrated” diagnoses with 155 tumors being astrocytomas, 100 oligodendrogliomas and 150 glioblastomas. In a subset of 100 diffuse gliomas from the NOA-04 trial with long-term follow-up data available, the “integrated” diagnosis had a significantly greater prognostic power for overall and progression-free survival compared to WHO 2007. Based on the “integrated” diagnoses, loss of ATRX expression was close to being mutually exclusive to 1p/19q codeletion, with only 2 of 167 ATRX-negative tumors exhibiting 1p/19q codeletion. All but 4 of 141 patients with loss of ATRX expression and diffuse glioma carried either IDH1 or IDH2 mutations. Interestingly, the majority of glioblastoma patients with loss of ATRX expression but no IDH mutations exhibited an H3F3A mutation. Further, all patients with 1p/19 codeletion carried a mutation in IDH1 or IDH2. We present an algorithm based on stepwise analysis with initial immunohistochemistry for ATRX and IDH1-R132H followed by 1p/19q analysis followed by IDH sequencing which reduces the number of molecular analyses and which has a far better association with patient outcome than WHO 2007.

Keywords

ATRX IDH Diffuse glioma Glioblastoma Oligodendroglioma Astrocytoma 7p/10q H3F3A 1p/19q 

Notes

Acknowledgments

The authors (WW, MW) conducting this work represent the Neurooncology Working Group (NOA) of the German Cancer Society. We gratefully acknowledge the contributions of Ulrike Ernemann, MD and Christoph Meisner, PhD (Tübingen, Germany), Guido Reifenberger, MD and Michael C. Sabel, MD (Düsseldorf, Germany), Susanne Koeppen, MD (Essen, Germany), Otmar Wiestler, MD and Thorsten Pietsch, MD (Bonn, Germany) and Ralf Ketter, MD to the first publication of the study. The study was supported by the Medical Faculty Heidelberg PostDoc Fellowship and the DKFZ Intramural Funding Program, Priority Topic Intratumoral Heterogeneity, to FS. BW is a scholar of the NCT Heidelberg School of Oncology Postdoc Program. We thank Tanja Göck and Viktoria Zeller for excellent technical assistance.

Supplementary material

401_2014_1370_MOESM1_ESM.xlsx (42 kb)
Supplementary material 1 (XLSX 42 kb)
401_2014_1370_MOESM2_ESM.xlsx (10 kb)
Supplementary material 2 (XLSX 10 kb)
401_2014_1370_MOESM3_ESM.pdf (27 kb)
Supplementary material 3 (PDF 26 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • David E. Reuss
    • 1
    • 2
  • Felix Sahm
    • 1
    • 2
  • Daniel Schrimpf
    • 1
    • 2
  • Benedikt Wiestler
    • 3
    • 4
  • David Capper
    • 1
    • 2
  • Christian Koelsche
    • 1
    • 2
  • Leonille Schweizer
    • 1
    • 2
  • Andrey Korshunov
    • 1
    • 2
  • David T. W. Jones
    • 5
  • Volker Hovestadt
    • 6
  • Michel Mittelbronn
    • 7
    • 8
  • Jens Schittenhelm
    • 9
  • Christel Herold-Mende
    • 10
  • Andreas Unterberg
    • 10
  • Michael Platten
    • 3
    • 11
  • Michael Weller
    • 12
  • Wolfgang Wick
    • 3
    • 4
  • Stefan M. Pfister
    • 5
    • 13
  • Andreas von Deimling
    • 1
    • 2
  1. 1.German Cancer Consortium (DKTK), CCU Neuropathology, German Cancer Research Center (DKFZ)HeidelbergGermany
  2. 2.Department Neuropathology, Institute of PathologyUniversity of HeidelbergHeidelbergGermany
  3. 3.Neurology ClinicHeidelberg University HospitalHeidelbergGermany
  4. 4.Clinical Cooperation Unit NeurooncologyGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  5. 5.Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  6. 6.Division of Molecular GeneticsGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  7. 7.Institute of Neurology (Edinger Institute)Goethe UniversityFrankfurtGermany
  8. 8.German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  9. 9.Department of Neuropathology, Institute of Pathology and NeuropathologyUniversity TuebingenTuebingenGermany
  10. 10.Department of NeurosurgeryUniversity of HeidelbergHeidelbergGermany
  11. 11.DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor ImmunologyGerman Cancer Research CenterHeidelbergGermany
  12. 12.Department of NeurologyUniversity Hospital ZurichZurichSwitzerland
  13. 13.Department of Pediatric Oncology, Hematology and ImmunologyUniversity Medical CenterHeidelbergGermany

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