Article
Improved prognostic stratification of patients with diffuse cerebral WHO grade II and III gliomas using genome- and transcriptome-wide molecular profiling
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Authors
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Guido Reifenberger
- Heinrich Heine University, Neuropathology, Duesseldorf, Germany
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Ruthild G. Weber
- Hannover Medical School, Department of Human Genetics, Hannover, Germany
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Edith Willscher
- University of Leipzig, Interdisciplinary Institute for Bioinformatics, Leipzig, Germany
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Vera Riehmer
- Hannover Medical School, Department of Human Genetics, Hannover, Germany
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Bettina Hentschel
- University of Leipzig, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany
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Markus Kreuz
- University of Leipzig, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany
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Jörg Felsberg
- Heinrich Heine University, Neuropathology, Duesseldorf, Germany
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Ulrike Beyer
- Hannover Medical School, Department of Human Genetics, Hannover, Germany
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Henry Löffler-Wirth
- University of Leipzig, Interdisciplinary Institute for Bioinformatics, Leipzig, Germany
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Kerstin Kaulich
- Heinrich Heine University, Neuropathology, Duesseldorf, Germany
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Joachim Steinbach
- University Hospital Frankfurt, Dr. Senckenberg Institute of Neurooncology, Frankfurt, Germany
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Christian Hartmann
- Hannover Medical School, Department of Neuropathology, Hannover, Germany
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Dorothee Gramatzki
- University Hospital Zurich, Department of Neurology, Zurich, Austria
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Johannes Schramm
- University of Bonn Medical School, Department of Neurosurgery, Bonn, Germany
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Manfred Westphal
- University Medical Center Hamburg-Eppendorf, Department of Neurosurgery, Hamburg, Germany
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Gabriele Schackert
- Technical University Dresden, Department of Neurosurgery, Dresden, Germany
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Matthias Simon
- University of Bonn Medical School, Department of Neurosurgery, Bonn, Germany
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Tobias Martens
- University Medical Center Hamburg-Eppendorf, Department of Neurosurgery, Hamburg, Germany
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Jan Boström
- University of Bonn Medical School, Department of Neurosurgery, Bonn, Germany
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Christian Hagel
- University Medical Center Hamburg-Eppendorf, Institute of Neuropathology, Hamburg, Germany
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Michael Sabel
- Heinrich-Heine-University Düsseldorf, Department of Neurosurgery, Düsseldorf, Germany
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Dietmar Krex
- Technical University Dresden, Department of Neurosurgery, Dresden, Germany
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Jörg C. Tonn
- Ludwig Maximilians University Munich, Department of Neurosurgery, Munich, Germany
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Wick Wolfgang
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Department of Neurooncology, Heidelberg, Germany
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Susan Noell
- University Hospital Tübingen, Interdisciplinary Division of Neuro-Oncology, Departments of Vascular Neurology and Neurosurgery, Tübingen, Germany; Hertie Institute for Clinical Brain Research, Laboratory of Clinical and Experimental Neuro-Oncology, Tübingen, Germany
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Uwe Schlegel
- University Hospital Knappschaftskrankenhaus Bochum-Langendreer, Department of Neurology, Bochum, Germany
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Bernhard Radlwimmer
- German Cancer Research Center (DKFZ) Heidelberg, Division of Molecular Genetics, Heidelberg, Germany
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Torsten Pietsch
- University of Bonn Medical School, Department of Neuropathology, Bonn, Germany
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Markus Loeffler
- University of Leipzig, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany
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Andreas von Deimling
- University Hospital Heidelberg, Department of Neuropathology, Heidelberg, Germany
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Hans Binder
- University of Leipzig, Interdisciplinary Institute for Bioinformatics, Leipzig, Germany
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Michael Weller
- University Hospital Zurich, Department of Neurology, Zurich, Switzerland
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German Glioma Network
| Published: | August 25, 2015 |
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Outline
Text
Introduction and objectives: Classification of cerebral gliomas of WHO grades II and III is associated with considerable interobserver variability. We evaluated whether genomic and transcriptomic profiling can improve stratification of patients with diffuse and anaplastic gliomas into prognostically relevant groups.
Patients and methods: We investigated tissue 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. All tumors were profiled using microarray-based genome- and transcriptome-wide analyses. The results were related to histology, molecular biomarkers, including IDH1/2 mutation, 1p/19q codeletion and TERT promoter mutations, and patient outcome.
Results: Supervised analysis of genomic profiles in relation to IDH1/2 mutation status identified five genetically distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Bioinformatic evaluation of the expression data stratified by IDH1/2 mutation status revealed eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild-type). Expression groups were only partially linked to the genomic groups. Correlation of molecular findings with clinical outcome defined three major prognostic groups, each with characteristic genomic aberrations. Patients with IDH1/2 mutant and 1p/19q codeleted tumors had the best prognosis, while patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on 7q (+7q), loss on 10q (-10q), TERT promoter mutation and oncogene amplification, showed the worst prognosis. Patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype demonstrated intermediate outcome. This molecular subgrouping provided a better prognostic stratification of the patients than histological classification.
Conclusions: Our study indicates that DNA copy number-based molecular profiling of WHO grade II and III gliomas can distinguish biologically distinct tumor groups and provides prognostically relevant information beyond histological classification and established molecular markers like IDH1/2 mutation and 1p/19q codeletion.
