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Gliomatosis cerebri: no evidence for a separate brain tumor entity

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An Erratum to this article was published on 07 January 2016

Abstract

Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification.

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Abbreviations

A_IDH:

Astrocytoma IDH mutant

CIMP:

CpG island methylator phenotype

CNS:

Central nervous system

EGFR:

Epidermal growth factor receptor

GBM_G34:

Glioblastoma WHO grade IV H3F3A-G34 mutant subgroup

GBM_RTK1:

Glioblastoma WHO grade IV receptor tyrosine kinase 1 subgroup

GBM_RTK2:

Glioblastoma WHO grade IV receptor tyrosine kinase 2 (classic) subgroup

GBM_mes:

Glioblastoma WHO grade IV mesenchymal subgroup

GC:

Gliomatosis cerebri

H3F3A:

H3 histone, family 3A

IDH:

Isocitrate dehydrogenase

MGMT:

O6-Methylguanine DNA methyltransferase

mOS:

Median overall survival

MRI:

Magnetic resonance imaging

O_IDH:

Oligodendroglioma IDH mutant and 1p/19q codeleted

TP53:

Tumor protein p53

WHO:

World Health Organization

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Acknowledgments

The authors would like to thank the German Cancer Research Center Genomics and Proteomics Core Facility (DKFZ GPCF) and Britta Friedensdorf, Düsseldorf, for excellent technical support.

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Author notes

    Authors and Affiliations

    1. Division of Neurooncology, Department of Neurology, University Medical Center Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany

      Ulrich Herrlinger, Martin Glas & Moritz Stuplich

    2. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany

      David T. W. Jones & Stefan M. Pfister

    3. German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany

      David T. W. Jones, Volker Hovestadt, David Capper, Andreas von Deimling, Peter Lichter & Stefan M. Pfister

    4. Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn, Bonn, Germany

      Martin Glas

    5. Division of Neuroradiology, Department of Radiology, University of Bonn, Bonn, Germany

      Elke Hattingen

    6. Department of Neurology, University of Zurich, Zurich, Switzerland

      Dorothee Gramatzki & Michael Weller

    7. Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

      Jörg Felsberg & Guido Reifenberger

    8. Department of Neuropathology, University of Bonn, Bonn, Germany

      Gerrit H. Gielen

    9. Department of Neurosurgery, University of Bonn, Bonn, Germany

      Matthias Simon

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

      Volker Hovestadt & Peter Lichter

    11. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany

      David Capper & Andreas von Deimling

    12. Department of Neuropathology, University of Heidelberg, Heidelberg, Germany

      David Capper & Andreas von Deimling

    13. Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany

      Stefan M. Pfister

    14. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, Partner Site Essen/Düsseldorf, Düsseldorf, Germany

      Guido Reifenberger

    15. Dr. Senckenberg Institute of Neurooncology, University of Frankfurt, Frankfurt, Germany

      Oliver Bähr & Joachim P. Steinbach

    16. Department of Neurosurgery, University of Münster, Münster, Germany

      Dorothee Wiewrodt

    17. Department of Neurology, Klinikum Ludwigsburg, Ludwigsburg, Germany

      Martin Schabet

    Authors
    1. Ulrich Herrlinger
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    Corresponding author

    Correspondence to Ulrich Herrlinger.

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    Funding

    This study was supported by the German Cancer Consortium (DKTK) joint funding project ‘Next Generation Molecular Diagnostics of Malignant Gliomas’.

    Conflict of interest

    UH has received advisory board honoraria from Roche, Mundipharma and Novocure, speakers honoraria from Roche, Medac and Mundipharma, travel reimbursement from Roche and Medac, grant support from Roche; MG has received advisory board honoraria from Roche and Mundipharma, speakers honoraria from Novartis, Roche and UCB, travel reimbursement from Roche and Medac; JPS has received advisory board honoraria from Roche and Mundipharma, speakers honoraria and travel reimbursement from Medac and Roche, grant support from Merck; MW has received advisory board honoraria from Celldex, Immunocellular Therapeutics, Magforce, Isarna MSD, Merck, Northwest Biotherapeutics, Novocure, Pfizer, Roche and Teva, Grant support from Acceleron, Actelion, Alpinia Institute, Bayer, Isarna, MSD, Merck, Novocure, PIQUR and Roche. All other authors do not have any conflict of interest.

    Additional information

    U. Herrlinger, D. T. W. Jones and M. Glas share first authorship.

    M. Weller and G. Reifenberger share last authorship.

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    Herrlinger, U., Jones, D.T.W., Glas, M. et al. Gliomatosis cerebri: no evidence for a separate brain tumor entity. Acta Neuropathol 131, 309–319 (2016). https://doi.org/10.1007/s00401-015-1495-z

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    • DOI: https://doi.org/10.1007/s00401-015-1495-z

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