DNA methylation-based classification of central nervous system tumours

David Capper, David T. W. Jones, Martin Sill, Volker Hovestadt, Daniel Schrimpf, Dominik Sturm, Christian Koelsche, Felix Sahm, Lukas Chavez, David E. Reuss, Annekathrin Kratz, Annika K. Wefers, Kristin Huang, Kristian W. Pajtler, Leonille Schweizer, Damian Stichel, Adriana Olar, Nils W. Engel, Kerstin Lindenberg, Patrick N. Harter, Anne K. Braczynski, Karl H. Plate, Hildegard Dohmen, Boyan K. Garvalov, Roland Coras, Annett Hölsken, Ekkehard Hewer, Melanie Bewerunge-Hudler, Matthias Schick, Roger Fischer, Rudi Beschorner, Jens Schittenhelm, Ori Staszewski, Khalida Wani, Pascale Varlet, Melanie Pages, Petra Temming, Dietmar Lohmann, Florian Selt, Hendrik Witt, Till Milde, Olaf Witt, Eleonora Aronica, Felice Giangaspero, Elisabeth Rushing, Wolfram Scheurlen, Christoph Geisenberger, Fausto J. Rodriguez, Albert Becker, Matthias Preusser, Christine Haberler, Rolf Bjerkvig, Jane Cryan, Michael Farrell, Martina Deckert, Jürgen Hench, Stephan Frank, Jonathan Serrano, Kasthuri Kannan, Aristotelis Tsirigos, Wolfgang Brück, Silvia Hofer, Stefanie Brehmer, Marcel Seiz-Rosenhagen, Daniel Hänggi, Volkmar Hans, Stephanie Rozsnoki, Jordan R. Hansford, Patricia Kohlhof, Bjarne W. Kristensen, Matt Lechner, Beatriz Lopes, Christian Mawrin, Ralf Ketter, Andreas Kulozik, Ziad Khatib, Frank Heppner, Arend Koch, Anne Jouvet, Catherine Keohane, Helmut Mühleisen, Wolf Mueller, Ute Pohl, Marco Prinz, Axel Benner, Marc Zapatka, Nicholas G. Gottardo, Pablo Hernáiz Driever, Christof M. Kramm, Hermann L. Müller, Stefan Rutkowski, Katja von Hoff, Michael C. Frühwald, Astrid Gnekow, Gudrun Fleischhack, Stephan Tippelt, Gabriele Calaminus, Camelia-Maria Monoranu, Arie Perry, Chris Jones, Thomas S. Jacques, Bernhard Radlwimmer, Marco Gessi, Torsten Pietsch, Johannes Schramm, Gabriele Schackert, Manfred Westphal, Guido Reifenberger, Pieter Wesseling, Michael Weller, Vincent Peter Collins, Ingmar Blümcke, Martin Bendszus, Jürgen Debus, Annie Huang, Nada Jabado, Paul A. Northcott, Werner Paulus, Amar Gajjar, Giles W. Robinson, Michael D. Taylor, Zane Jaunmuktane, Marina Ryzhova, Michael Platten, Andreas Unterberg, Wolfgang Wick, Matthias A. Karajannis, Michel Mittelbronn, Till Acker, Christian Hartmann, Kenneth Aldape, Ulrich Schüller, Rolf Buslei, Peter Lichter, Marcel Kool, Christel Herold-Mende, David W. Ellison, Martin Hasselblatt, Matija Snuderl, Sebastian Brandner, Andrey Korshunov, Andreas von Deimling () and Stefan M. Pfister ()
Additional contact information
David Capper: University Hospital Heidelberg
David T. W. Jones: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Martin Sill: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Volker Hovestadt: German Cancer Research Center (DKFZ)
Daniel Schrimpf: University Hospital Heidelberg
Dominik Sturm: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Christian Koelsche: University Hospital Heidelberg
Felix Sahm: University Hospital Heidelberg
Lukas Chavez: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
David E. Reuss: University Hospital Heidelberg
Annekathrin Kratz: University Hospital Heidelberg
Annika K. Wefers: University Hospital Heidelberg
Kristin Huang: University Hospital Heidelberg
Kristian W. Pajtler: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Leonille Schweizer: University Hospital Heidelberg
Damian Stichel: University Hospital Heidelberg
Adriana Olar: Medical University of South Carolina
Nils W. Engel: Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg
Kerstin Lindenberg: Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Patrick N. Harter: Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main
Anne K. Braczynski: Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main
Karl H. Plate: Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main
Hildegard Dohmen: Institute of Neuropathology, University of Giessen
Boyan K. Garvalov: Institute of Neuropathology, University of Giessen
Roland Coras: Neuropathological Institute, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg
Annett Hölsken: Neuropathological Institute, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg
Ekkehard Hewer: Institute of Pathology, University of Bern
Melanie Bewerunge-Hudler: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ)
Matthias Schick: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ)
Roger Fischer: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ)
Rudi Beschorner: Institute of Pathology and Neuropathology, University Hospital Tübingen
Jens Schittenhelm: Institute of Pathology and Neuropathology, University Hospital Tübingen
Ori Staszewski: Institute of Neuropathology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg
Khalida Wani: University of Texas MD Anderson Cancer Center
Pascale Varlet: Centre Hospitalier Sainte Anne
Melanie Pages: Centre Hospitalier Sainte Anne
Petra Temming: Pediatrics III, Pediatric Oncology and Hematology, University Hospital Essen
Dietmar Lohmann: Eye Cancer Research Group, Faculty of Medicine, University of Duisburg-Essen
Florian Selt: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Hendrik Witt: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Till Milde: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Olaf Witt: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Eleonora Aronica: Academic Medisch Centrum (AMC), University of Amsterdam
Felice Giangaspero: Oncological and Anatomo-Pathological Sciences, Sapienza University
Elisabeth Rushing: University Hospital Zurich
Wolfram Scheurlen: Cnopf’sche Kinderklinik Nuremberg
Christoph Geisenberger: Heidelberg University Hospital
Fausto J. Rodriguez: Division of Neuropathology of the Johns Hopkins University School of Medicine
Albert Becker: University of Bonn
Matthias Preusser: Comprehensive Cancer Center Vienna, CNS Unit (CCC-CNS), Medical University of Vienna
Christine Haberler: Institute of Neurology, Medical University of Vienna
Rolf Bjerkvig: University of Bergen
Jane Cryan: Beaumont Hospital
Michael Farrell: Beaumont Hospital
Martina Deckert: University Hospital of Cologne
Jürgen Hench: Institute of Pathology, Basel University Hospital
Stephan Frank: Institute of Pathology, Basel University Hospital
Jonathan Serrano: NYU Langone Medical Center
Kasthuri Kannan: NYU Langone Medical Center
Aristotelis Tsirigos: NYU Langone Medical Center
Wolfgang Brück: Institute of Neuropathology, University Medical Center Göttingen
Silvia Hofer: Luzerner Kantonsspital
Stefanie Brehmer: University Medical Center Mannheim, University of Heidelberg
Marcel Seiz-Rosenhagen: University Medical Center Mannheim, University of Heidelberg
Daniel Hänggi: University Medical Center Mannheim, University of Heidelberg
Volkmar Hans: Institut für Neuropathologie, Evangelisches Krankenhaus Bielefeld gGmbH
Stephanie Rozsnoki: Institute of Neuropathology, University Hospital Münster
Jordan R. Hansford: Children’s Cancer Centre, Royal Children’s Hospital, University of Melbourne, Melbourne
Patricia Kohlhof: Institute for Pathology, Katharinenhospital Stuttgart
Bjarne W. Kristensen: Odense University Hospital, University of Southern Denmark
Matt Lechner: University College London Cancer Institute and University College London Hospitals
Beatriz Lopes: University of Virginia
Christian Mawrin: Institute of Neuropathology, Otto-von-Guericke-University
Ralf Ketter: University Hospital Saarland
Andreas Kulozik: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Ziad Khatib: Nicklaus Children’s Hospital Brain Institute
Frank Heppner: Charité — Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Arend Koch: Charité — Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Anne Jouvet: Hôpital Neurologique, Hospices Civils de Lyon
Catherine Keohane: Cork University Hospital
Helmut Mühleisen: Ludwigsburg Hospital
Wolf Mueller: Leipzig University
Ute Pohl: Queen’s Hospital
Marco Prinz: Institute of Neuropathology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg
Axel Benner: German Cancer Research Center (DKFZ)
Marc Zapatka: German Cancer Research Center (DKFZ)
Nicholas G. Gottardo: Princess Margaret Hospital for Children
Pablo Hernáiz Driever: Charité-Universitätsmedizin Berlin
Christof M. Kramm: University Medical Center Göttingen
Hermann L. Müller: Klinikum Oldenburg AöR, Medical Campus University Oldenburg
Stefan Rutkowski: University Hospital Hamburg-Eppendorf
Katja von Hoff: Charité-Universitätsmedizin Berlin
Michael C. Frühwald: Children’s Hospital Augsburg, Swabian Children’s Cancer Centre
Astrid Gnekow: Children’s Hospital Augsburg, Swabian Children’s Cancer Centre
Gudrun Fleischhack: Pediatrics III, Pediatric Oncology and Hematology, University Hospital Essen
Stephan Tippelt: Pediatrics III, Pediatric Oncology and Hematology, University Hospital Essen
Gabriele Calaminus: University of Bonn Medical Center
Camelia-Maria Monoranu: Insitute of Pathology, Comprehensive Cancer Center (CCC) Mainfranken, University of Würzburg
Arie Perry: University of California San Francisco
Chris Jones: Institute of Cancer Research
Thomas S. Jacques: Developmental Biology and Cancer Programme, Great Ormond Street Hospital for Children NHS Foundation Trust
Bernhard Radlwimmer: German Cancer Research Center (DKFZ)
Marco Gessi: University of Bonn
Torsten Pietsch: University of Bonn
Johannes Schramm: Medical Faculty, University of Bonn Medical School
Gabriele Schackert: University Hospital Carl Gustav Carus, Technische Universität Dresden
Manfred Westphal: University Hospital Hamburg-Eppendorf
Guido Reifenberger: Heinrich Heine University Düsseldorf
Pieter Wesseling: Princess Máxima Center for Pediatric Oncology and University Medical Center Utrecht
Michael Weller: University Hospital and University of Zurich
Vincent Peter Collins: University of Cambridge
Ingmar Blümcke: Neuropathological Institute, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg
Martin Bendszus: Heidelberg University Hospital
Jürgen Debus: Heidelberg University Hospital
Annie Huang: Laboratory Medicine and Pathobiology, University of Toronto
Nada Jabado: McGill University
Paul A. Northcott: St Jude Children’s Research Hospital
Werner Paulus: Institute of Neuropathology, University Hospital Münster
Amar Gajjar: St Jude Children’s Research Hospital
Giles W. Robinson: St Jude Children’s Research Hospital
Michael D. Taylor: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto
Zane Jaunmuktane: UCL Hospitals, Institute of Neurology, University College London, Queen Square
Marina Ryzhova: NN Burdenko Neurosurgical Institute
Michael Platten: Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University
Andreas Unterberg: Heidelberg University Hospital
Wolfgang Wick: Heidelberg University Hospital
Matthias A. Karajannis: Memorial Sloan Kettering Cancer Center
Michel Mittelbronn: Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main
Till Acker: Institute of Neuropathology, University of Giessen
Christian Hartmann: Hannover Medical School (MHH)
Kenneth Aldape: University of Toronto
Ulrich Schüller: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University
Rolf Buslei: Neuropathological Institute, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg
Peter Lichter: German Cancer Research Center (DKFZ)
Marcel Kool: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Christel Herold-Mende: Heidelberg University Hospital
David W. Ellison: St Jude Children’s Research Hospital
Martin Hasselblatt: Institute of Neuropathology, University Hospital Münster
Matija Snuderl: NYU Langone Medical Center
Sebastian Brandner: UCL Hospitals, Institute of Neurology, University College London, Queen Square
Andrey Korshunov: University Hospital Heidelberg
Andreas von Deimling: University Hospital Heidelberg
Stefan M. Pfister: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)

Nature, 2018, vol. 555, issue 7697, 469-474

Abstract: Abstract Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging—with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

Date: 2018
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Citations: View citations in EconPapers (28)

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DOI: 10.1038/nature26000

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