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Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

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Abstract

Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (−10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/−10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.

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Abbreviations

AII:

Diffuse astrocytoma WHO grade II

AAIII:

Anaplastic astrocytoma WHO grade III

AOIII:

Anaplastic oligodendroglioma WHO grade III

AOAIII:

Anaplastic oligoastrocytoma WHO grade III

ATRX:

ATP-dependent X-linked helicase

BRAF:

v-raf murine sarcoma viral oncogene homolog B1

CDK:

Cyclin-dependent kinase

CGH:

Comparative genomic hybridization

CIC:

Drosophila homolog of capicua

EGFR:

Epidermal growth factor receptor

GB IV:

Glioblastoma WHO grade IV

gCIMP:

Glioma CpG island methylator phenotype

GGN:

German Glioma Network

GO:

Gene ontology

IDH:

Isocitrate dehydrogenase

KPS:

Karnofsky performance score

MAPK:

Mitogen-activated protein kinase

MDM:

Murine double minute

MGMT:

O6-methylguanine DNA methyltransferase

OII:

Oligodendroglioma WHO grade II

OAII:

Oligoastrocytoma WHO grade II

OS:

Overall survival

PDGFRA:

Platelet-derived growth factor receptor-α

PFS:

Progression-free survival

PTEN:

Phosphatase and tensin homolog on chromosome 10

SOM:

Self-organizing map

TERT:

Telomerase reverse transcriptase

TMZ:

Temozolomide

TP53:

Tumor protein p53

WHO:

World Health Organization

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Acknowledgments

This study was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe, grant no. 70-3163-Wi 3) and by the German Cancer Consortium (DKTK). The authors would like to thank the staff at the clinical centers of the German Glioma Network for their great support as well as our patients and their relatives. We also acknowledge Thorsten Wachtmeister, Center for Biological and Medical Research, Heinrich Heine University Düsseldorf, for his support of the Affymetrix chip hybridizations.

Conflict of interest

MiW has received research grants from Acceleron, Actelion, Bayer, Isarna, Merck Serono, MSD, Piqur and Roche, and honoraria for lectures or advisory boards from Celldex, Isarna, Magforce, Merck Serono, MSD and Roche. GR has received research grants from Roche and Meck as well as honoraria for advisory boards or lectures from Merck Serono, Amgen and Roche. TP has received grants for reference pathology from Antisense Pharma and Merck Serono and honoraria for lectures from Roche. US has received honoraria for lectures or advisory boards from GSK, medac and Roche. TM has received honoraria for lectures from medac and Cyberonics and for advisory boards from Novocure. JCT has received honoraria for lectures or advisory boards from Merck Serono, medac and Roche. CHar has received grants for research and advisory board activities from Apogenix and Oncowave. The other authors declare that they have no conflicts of interest.

Funding

This study was funded by the German Cancer Aid (Grant No. 70-3163-Wi 3).

Access to gene expression data

The gene expression data reported in this study are deposited in the gene expression omnibus (GEO) database at http://www.ncbi.nlm.nih.gov/geo/ under accession number GSE61374 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=qhyzsoqmhbibxch&acc=GSE61374).

Author information

Authors and Affiliations

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

    Michael Weller & Dorothee Gramatzki

  2. Department of General Neurology, University Hospital Tübingen, Tübingen, Germany

    Michael Weller & Joachim P. Steinbach

  3. Department of Human Genetics, Hannover Medical School, Hannover, Germany

    Ruthild G. Weber, Vera Riehmer & Ulrike Beyer

  4. Interdisciplinary Centre for Bioinformatics, University of Leipzig, Leipzig, Germany

    Edith Willscher, Henry Löffler-Wirth & Hans Binder

  5. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

    Bettina Hentschel, Markus Kreuz & Markus Loeffler

  6. Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany

    Jörg Felsberg, Kerstin Kaulich & Guido Reifenberger

  7. German Cancer Consortium (DKTK), and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Kerstin Kaulich, Joachim P. Steinbach & Guido Reifenberger

  8. Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Frankfurt, Germany

    Joachim P. Steinbach

  9. Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), and German Cancer Research Center (DKFZ), and Department of Neuropathology, University of Heidelberg, Heidelberg, Germany

    Christian Hartmann & Andreas von Deimling

  10. Department of Neuropathology, Hannover Medical School, Hannover, Germany

    Christian Hartmann

  11. Department of Neurosurgery, University of Bonn Medical School, Bonn, Germany

    Johannes Schramm, Matthias Simon & Jan Boström

  12. Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Manfred Westphal & Tobias Martens

  13. Department of Neurosurgery, Technical University Dresden, Dresden, Germany

    Gabriele Schackert & Dietmar Krex

  14. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Christian Hagel

  15. Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany

    Michael Sabel

  16. Department of Neurosurgery, Ludwig Maximilians University Munich, Munich, Germany

    Jörg C. Tonn

  17. Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), and German Cancer Research Center (DKFZ), and Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany

    Wolfgang Wick

  18. Interdisciplinary Division of Neuro-Oncology, Departments of Vascular Neurology and Neurosurgery, University Hospital Tübingen, and Laboratory of Clinical and Experimental Neuro-Oncology, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany

    Susan Noell

  19. Department of Neurology, University Hospital Knappschaftskrankenhaus Bochum-Langendreer, Bochum, Germany

    Uwe Schlegel

  20. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Bernhard Radlwimmer

  21. Department of Neuropathology, University of Bonn Medical School, Bonn, Germany

    Torsten Pietsch

Authors
  1. Michael Weller
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  2. Ruthild G. Weber
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  3. Edith Willscher
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  4. Vera Riehmer
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  5. Bettina Hentschel
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  6. Markus Kreuz
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  7. Jörg Felsberg
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  9. Henry Löffler-Wirth
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  12. Christian Hartmann
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  14. Johannes Schramm
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  20. Christian Hagel
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  21. Michael Sabel
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  23. Jörg C. Tonn
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  24. Wolfgang Wick
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  25. Susan Noell
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  30. Andreas von Deimling
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  31. Hans Binder
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  32. Guido Reifenberger
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Corresponding author

Correspondence to Michael Weller.

Additional information

M. Weller and R. G. Weber: share first authorship.

H. Binder and G. Reifenberger: share last authorship.

For the German Glioma Network.

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Weller, M., Weber, R.G., Willscher, E. et al. Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups. Acta Neuropathol 129, 679–693 (2015). https://doi.org/10.1007/s00401-015-1409-0

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