A microenvironment-determined risk continuum refines subtyping in meningioma and reveals determinants of machine learning-based tumor classification
Nature Genetics, vol. 58, pp. 341–354
Abstract
Classification of tumors in neuro-oncology today relies on molecular patterns (mostly DNA methylation) and their machine learning-supported interpretation. Understanding the process of algorithmic interpretation is essential for safe application in clinical routine. This is paradigmatically true for the most common primary intracranial tumor in adults, meningioma. Here, by applying multiomic profiling and multiple lines of orthogonal computational evaluation in multiple independent datasets, we found that not only tumor cell characteristics but also incremental changes in the tumor microenvironment (TME) have impact on epigenetic meningioma classification and clinical outcome. Besides revealing the decisive role of non-neoplastic cells in the CNS methylation classifier, this challenges the model of distinct meningioma subgroups toward a TME-determined risk continuum. This refines current controversies in molecular meningioma subtyping. In addition, we apply these learnings to devise and validate a simple diagnostic approach for increased clinical prediction accuracy based on immunohistochemistry, which is also applicable in resource-limited settings.
Authors 68
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Leiden University Medical Center · Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Pathology, Brain Tumor Center, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands. S.L.N.Maas@lumc.nl
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. S.L.N.Maas@lumc.nl
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
Division of AI in Oncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
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University of Toronto · Hopp Children's Cancer Center Heidelberg
Affiliation as printed
Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung · Pathologisches Institut · Ludwig-Maximilians-Universität München
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
Institute of Pathology, Ludwig Maximilians University Hospital Munich, Munich, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Affiliation as printed
Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Broad Institute · Boston Children's Hospital · Dana-Farber Cancer Institute
Affiliation as printed
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA
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Affiliation as printed
Division of AI in Oncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
German Cancer Research Center (DKFZ), Heidelberg, Germany
Systems Immunology & Single-Cell Biology, Heidelberg, Germany
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German Cancer Research Center · Hopp Children's Cancer Center Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
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Friedrich-Alexander-Universität Erlangen-Nürnberg
Affiliation as printed
Translational Neurosurgery, Neurosurgical Clinic, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
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Friedrich-Alexander-Universität Erlangen-Nürnberg
Affiliation as printed
Translational Neurosurgery, Neurosurgical Clinic, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
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University of Augsburg · University Hospital Augsburg
Affiliation as printed
Department of Neurosurgery, University Hospital Augsburg, Augsburg, Germany
Translational oncological Neurosurgery, Faculty of Medicine, Augsburg University, Augsburg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Centre National de la Recherche Scientifique · Inserm · Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Pitié-Salpêtrière Hospital · Institut du Cerveau
Affiliation as printed
Neurovascular interfaces in Brain Tumors and vascular malformations - CRICM INSERM U1127 CNRS UMR 7225 - Brain Institute, Hôpital de la Pitié-Salpêtrière, Paris, France
Sorbonne Université - Department of Neurosurgery, Groupe Hospitalier Pitié-Salpêtrière, APHP, Paris, France
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Affiliation as printed
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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German Cancer Research Center · Hopp Children's Cancer Center Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · Heidelberg University · University Hospital Heidelberg · Heidelberg Institute for Stem Cell Technology and Experimental Medicine · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
German Cancer Consortium (DKTK), DKFZ, Core Center Heidelberg, Heidelberg, Germany
German Cancer Research Center (DKFZ), JRG Hematology and Immune Engineering, Heidelberg, Germany
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Pathology, Brain Tumor Center, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
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German Cancer Research Center · Heidelberg University · University Hospital Heidelberg · National Center for Tumor Diseases · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Division of Translational Medical Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), DKFZ, Core Center Heidelberg, Heidelberg, Germany
National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
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University of Zurich · Kantonsspital Winterthur · University Hospital Zurich
Affiliation as printed
Department of Neurology, Kantonsspital Winterthur, Winterthur, Switzerland
Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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Affiliation as printed
Faculty of Health, Peninsula Medical School, University of Plymouth, Plymouth, UK
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Heidelberg University · University Medical Centre Mannheim
Affiliation as printed
Department of Neurosurgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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Affiliation as printed
Department of Neuropathology, University Hospital Magdeburg, Magdeburg, Germany
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Universitätsklinikum des Saarlandes · Saarland University
Affiliation as printed
Department of Pediatric Hematology and Oncology, University Medical Center of Saarland, Saarland University, Homburg/Saar, Germany
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Université Paris-Sud · Centre National de la Recherche Scientifique · Inserm · Université Paris Sciences et Lettres · Université Paris-Saclay · Institut Curie
Affiliation as printed
Institut Curie, PSL Research University, INSERM U1330/CNRS EMR 8001. Children's Oncology Research Unit (CONCERT), Paris, France
Université Paris Sud, Université Paris-Saclay, INSERM U1330/CNRS EMR 8001. Children's Oncology Research Unit (CONCERT), Paris, France
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German Cancer Research Center · National Center for Tumor Diseases
Affiliation as printed
Division of Molecular Genetics, German Cancer Research Center (DKFZ), and NCT Heidelberg, Heidelberg, Germany
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Düsseldorf University Hospital · Heinrich Heine University Düsseldorf
Affiliation as printed
Institute of Neuropathology, Heinrich Heine University, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany
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German Cancer Research Center · University Medical Centre Mannheim · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Department of Neurology, University Hospital and Medical Faculty Mannheim, Mannheim, Germany
German Cancer Consortium (DKTK), DKFZ, Core Center Heidelberg, Heidelberg, Germany
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Technical University of Munich · Technische Universität Braunschweig
Affiliation as printed
Braunschweig Integrated Centre of Systems Biology (BRICS), TU Braunschweig, Braunschweig, Germany
Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany
Institute of Data Science in Biomedicine, Technische Universität Braunschweig, Braunschweig, Germany
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Technical University of Munich
Affiliation as printed
Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany
Data Science in Systems Biology, School of Life Sciences, Technical University of Munich, Freising, Germany
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University Hospital Carl Gustav Carus · Technical University of Munich · Technische Universität Dresden
Affiliation as printed
CIOBio, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany
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Universität Hamburg · University of Southern Denmark · Technical University of Munich
Affiliation as printed
Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany
Computational Biomedicine Lab, Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark
Institute for Computational Systems Biology, University of Hamburg, Hamburg, Germany
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German Cancer Research Center · Hopp Children's Cancer Center Heidelberg · Jena University Hospital · Friedrich Schiller University Jena
Affiliation as printed
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
Comprehensive Cancer Center Central Germany (CCCG), Jena, Germany
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
University Hospital Jena, Department of Pediatrics and Adolescent Medicine, Friedrich Schiller University Jena, Jena, Germany
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Technion – Israel Institute of Technology · Rambam Health Care Campus
Affiliation as printed
Department of Neurosurgery, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion, Haifa, Israel
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Affiliation as printed
Department of Neurosurgery, Tel Aviv Medical Center, Tel Aviv, Israel, and School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Heidelberg University · University Medical Centre Mannheim
Affiliation as printed
Department of Neurosurgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany
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Affiliation as printed
Single-cell Open Lab, German Cancer Research Centre (DKFZ), Heidelberg, Germany
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University of Zurich · Kantonsspital St. Gallen · University Hospital Zurich
Affiliation as printed
Department of Neurosurgery and Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
Department of Neurosurgery, HOCH Health Ostschweiz, Kantonsspital St. Gallen, St. Gallen, Switzerland
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Neurosurgery, Brain Tumor Center, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Affiliation as printed
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
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University of Zurich · University Hospital Zurich
Affiliation as printed
Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland
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Justus-Liebig-Universität Gießen
Affiliation as printed
Institute of Neuropathology, Justus-Liebig-University Gießen, Giessen, Germany
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German Cancer Research Center · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
German Cancer Consortium (DKTK), DKFZ, Core Center Heidelberg, Heidelberg, Germany
German Cancer Research Center (DKFZ), Heidelberg, Germany
Systems Immunology & Single-Cell Biology, Heidelberg, Germany
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Affiliation as printed
Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
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Affiliation as printed
Department of Neurology, University Hospital Tübingen, Eberhard-Karls-University Tübingen, Tübingen, Germany
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · Hopp Children's Cancer Center Heidelberg
Affiliation as printed
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
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German Cancer Research Center · Heidelberg University · University Hospital Heidelberg · National Center for Tumor Diseases · Hopp Children's Cancer Center Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
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German Cancer Research Center · Heidelberg University · National Center for Tumor Diseases
Affiliation as printed
Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University & German Cancer Research Center (DKFZ), Heidelberg, Germany
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Centre National de la Recherche Scientifique · Inserm · Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Pitié-Salpêtrière Hospital · Institut du Cerveau
Affiliation as printed
Neurovascular interfaces in Brain Tumors and vascular malformations - CRICM INSERM U1127 CNRS UMR 7225 - Brain Institute, Hôpital de la Pitié-Salpêtrière, Paris, France
Sorbonne Université - Department of Neurosurgery, Groupe Hospitalier Pitié-Salpêtrière, APHP, Paris, France
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Northwestern University · University of Freiburg · Friedrich-Alexander-Universität Erlangen-Nürnberg · University Medical Center Freiburg · Universitätsklinikum Erlangen · Northwestern Medicine
Affiliation as printed
Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, and Malnati Brain Tumor Institute, Northwestern Medicine, Chicago, IL, USA
Department of Neurosurgery, Medical Centre-University of Freiburg, Freiburg, Germany
Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany
Faculty of Medicine, Freiburg University, Freiburg, Germany
Microenvironment and Immunology Research Laboratory, Friedrich-Alexander Universität Nürnberg-Erlangen, Erlangen, Germany
Translational Neurosurgery, Neurosurgical Clinic, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
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Broad Institute · Boston Children's Hospital · Dana-Farber Cancer Institute
Affiliation as printed
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA
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German Cancer Research Center · Heidelberg University · Robert Bosch Hospital · Universitätsklinikum Tübingen · University of Tübingen
Affiliation as printed
Division of AI in Oncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
Faculty of Mathematics and Computer Science, Heidelberg University, Heidelberg, Germany
Medical Faculty, Eberhard-Karls-University, Tübingen, Germany
Robert Bosch Center for Tumor Diseases, Stuttgart, Germany
University Hospital Tübingen, Tübingen, Germany
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Affiliation as printed
Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Augsburg, Germany
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Felix Sahm corresponding
German Cancer Research Center · Heidelberg University · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany. Felix.Sahm@med.uni-heidelberg.de
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany. Felix.Sahm@med.uni-heidelberg.de
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