DNA methylation-based classification of central nervous system tumours,Nature

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DNA methylation-based classification of central nervous system tumours
Nature ( IF 50.5 ) Pub Date : 2018-03-14 , DOI: 10.1038/nature26000
David Capper _{1,

2,

3,

4} , David T W Jones _{5,

6} , Martin Sill _{5,

6,

7} , Volker Hovestadt ₈ , Daniel Schrimpf _{1,

2} , Dominik Sturm _{5,

6,

9} , Christian Koelsche _{1,

2} , Felix Sahm _{1,

2} , Lukas Chavez _{5,

6} , David E Reuss _{1,

2} , Annekathrin Kratz _{1,

2} , Annika K Wefers _{1,

2} , Kristin Huang _{1,

2} , Kristian W Pajtler _{5,

6,

9} , Leonille Schweizer _{1,

3} , Damian Stichel _{1,

2} , Adriana Olar _{10,

11,

12} , Nils W Engel _{13,

14} , Kerstin Lindenberg ₂ , Patrick N Harter _{15,

16} , Anne K Braczynski _{15,

16} , Karl H Plate _{15,

16} , Hildegard Dohmen ₁₇ , Boyan K Garvalov ₁₇ , Roland Coras ₁₈ , Annett Hölsken ₁₈ , Ekkehard Hewer ₁₉ , Melanie Bewerunge-Hudler ₂₀ , Matthias Schick ₂₀ , Roger Fischer ₂₀ , Rudi Beschorner ₂₁ , Jens Schittenhelm ₂₁ , Ori Staszewski ₂₂ , Khalida Wani ₂₃ , Pascale Varlet ₂₄ , Melanie Pages ₂₄ , Petra Temming ₂₅ , Dietmar Lohmann ₂₆ , Florian Selt _{5,

9,

27} , Hendrik Witt _{5,

6,

9} , Till Milde _{5,

9,

27} , Olaf Witt _{5,

9,

27} , Eleonora Aronica _{28,

29,

30} , Felice Giangaspero _{31,

32} , Elisabeth Rushing ₃₃ , Wolfram Scheurlen ₃₄ , Christoph Geisenberger _{35,

36} , Fausto J Rodriguez ₃₇ , Albert Becker ₃₈ , Matthias Preusser ₃₉ , Christine Haberler ₄₀ , Rolf Bjerkvig _{41,

42} , Jane Cryan ₄₃ , Michael Farrell ₄₃ , Martina Deckert ₄₄ , Jürgen Hench ₄₅ , Stephan Frank ₄₅ , Jonathan Serrano ₄₆ , Kasthuri Kannan ₄₆ , Aristotelis Tsirigos ₄₆ , Wolfgang Brück ₄₇ , Silvia Hofer ₄₈ , Stefanie Brehmer ₄₉ , Marcel Seiz-Rosenhagen ₄₉ , Daniel Hänggi ₄₉ , Volkmar Hans _{50,

51} , Stephanie Rozsnoki ₅₂ , Jordan R Hansford _{53,

54,

55} , Patricia Kohlhof ₅₆ , Bjarne W Kristensen ₅₇ , Matt Lechner ₅₈ , Beatriz Lopes ₅₉ , Christian Mawrin ₆₀ , Ralf Ketter ₆₁ , Andreas Kulozik _{5,

9} , Ziad Khatib ₆₂ , Frank Heppner _{3,

63,

64} , Arend Koch ₃ , Anne Jouvet ₆₅ , Catherine Keohane ₆₆ , Helmut Mühleisen ₆₇ , Wolf Mueller ₆₈ , Ute Pohl ₆₉ , Marco Prinz _{22,

70} , Axel Benner ₇ , Marc Zapatka ₈ , Nicholas G Gottardo _{71,

72,

73} , Pablo Hernáiz Driever ₇₄ , Christof M Kramm ₇₅ , Hermann L Müller ₇₆ , Stefan Rutkowski ₇₇ , Katja von Hoff _{74,

77} , Michael C Frühwald ₇₈ , Astrid Gnekow ₇₈ , Gudrun Fleischhack ₂₅ , Stephan Tippelt ₂₅ , Gabriele Calaminus ₇₉ , Camelia-Maria Monoranu ₈₀ , Arie Perry ₈₁ , Chris Jones ₈₂ , Thomas S Jacques ₈₃ , Bernhard Radlwimmer ₈ , Marco Gessi ₃₈ , Torsten Pietsch ₃₈ , Johannes Schramm ₈₄ , Gabriele Schackert ₈₅ , Manfred Westphal ₈₆ , Guido Reifenberger _{87,

88} , Pieter Wesseling _{89,

90} , Michael Weller ₉₁ , Vincent Peter Collins ₉₂ , Ingmar Blümcke ₁₈ , Martin Bendszus ₉₃ , Jürgen Debus ₉₄ , Annie Huang ₉₅ , Nada Jabado ₉₆ , Paul A Northcott ₉₇ , Werner Paulus ₅₂ , Amar Gajjar ₉₈ , Giles W Robinson ₉₈ , Michael D Taylor ₉₉ , Zane Jaunmuktane _{100,

101,

102} , Marina Ryzhova ₁₀₃ , Michael Platten ₁₀₄ , Andreas Unterberg ₃₅ , Wolfgang Wick ₁₀₅ , Matthias A Karajannis ₁₀₆ , Michel Mittelbronn _{15,

16,

107,

108,

109,

110} , Till Acker ₁₇ , Christian Hartmann ₁₁₁ , Kenneth Aldape ₁₁₂ , Ulrich Schüller _{14,

113,

114,

115} , Rolf Buslei _{18,

116} , Peter Lichter ₈ , Marcel Kool _{5,

6} , Christel Herold-Mende ₃₅ , David W Ellison ₁₁₇ , Martin Hasselblatt ₅₂ , Matija Snuderl ₁₁₈ , Sebastian Brandner _{100,

102} , Andrey Korshunov _{1,

2} , Andreas von Deimling _{1,

2} , Stefan M Pfister _{5,

6,

9}

Affiliation

Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Berlin, Germany.
German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Department of Neurosurgery, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Hollings Cancer Center, Charleston, South Carolina 29425, USA.
Department of Oncology and Hematology with Sections Bone Marrow Transplant and Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg, Hamburg, Germany.
Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.
Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main, Germany.
German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, German Cancer Research Center (DKFZ) Heidelberg, Germany.
Institute of Neuropathology, University of Giessen, Giessen, Germany.
Neuropathological Institute, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Institute of Pathology, University of Bern, Bern, Switzerland.
Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Institute of Pathology and Neuropathology, Department of Neuropathology, University Hospital Tübingen, Tübingen, Germany.
Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Department of Neuropathology, Centre Hospitalier Sainte Anne, Paris, France.
Pediatrics III, Pediatric Oncology and Hematology, University Hospital Essen, Essen, Germany.
Eye Cancer Research Group, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
CCU Pediatric Oncology (G340), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
Department of (Neuro)Pathology, Academic Medisch Centrum (AMC), University of Amsterdam, Amsterdam, The Netherlands.
Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
Stichting Epilepsie Instellingen Nederland (SEIN), Amsterdam, The Netherlands.
Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Rome, Italy.
IRCCS Neuromed, Pozzilli, Italy.
Department of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
Cnopf'sche Kinderklinik Nuremberg, Nuremberg, Germany.
Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Division of Neuropathology of the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Neuropathology, University of Bonn, Bonn, Germany.
Department of Medicine I, Comprehensive Cancer Center Vienna, CNS Unit (CCC-CNS), Medical University of Vienna, Vienna, Austria.
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
Department of Biomedicine, University of Bergen, Bergen, Norway.
NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
Department of Neuropathology, Beaumont Hospital, Dublin, Ireland.
Department of Neuropathology, University Hospital of Cologne, Cologne, Germany.
Department of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland.
NYU Langone Medical Center, New York, New York, USA.
Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
Division of Oncology, Luzerner Kantonsspital, Luzern, Switzerland.
Department of Neurosurgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
Institut für Neuropathologie, Evangelisches Krankenhaus Bielefeld gGmbH, Bielefeld, Germany.
Institut für Neuropathologie, Universitätskinikum Essen, Essen, Germany.
Institute of Neuropathology, University Hospital Münster, Münster, Germany.
Children's Cancer Centre, Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.
Institute for Pathology, Katharinenhospital Stuttgart, Stuttgart, Germany.
Department of Pathology, Odense University Hospital, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
University College London Cancer Institute and University College London Hospitals, London, UK.
Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.
Institute of Neuropathology, Otto-von-Guericke-University, Magdeburg, Germany.
Department of Neurosurgery, University Hospital Saarland, Homburg, Saar, Germany.
Nicklaus Children's Hospital Brain Institute, Miami, Florida 33155, USA.
Cluster of Excellence, NeuroCure, Berlin, Germany.
Berlin Institute of Health (BIH), Berlin, Germany.
Département de Pathologie et Neuropathologie, Hôpital Neurologique, Hospices Civils de Lyon, Lyon, France.
Department of Neuropathology, Cork University Hospital, Cork, Ireland.
Department of Pathology, Ludwigsburg Hospital, Ludwigsburg, Germany.
Department of Neuropathology, Leipzig University, Leipzig, Germany.
Department of Cellular Pathology, Queen's Hospital, Romford, UK.
BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
Department of Pediatric Oncology and Haematology, Princess Margaret Hospital for Children, GPO Box D184, Perth, Western Australia 6840, Australia.
Telethon Kids Institute, University of Western Australia, PO Box 855, Perth, Western Australia 6872, Australia.
School of Paediatrics and Child Health, University of Western Australia, GPO Box D184, Perth, Western Australia 6840, Australia.
Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany.
Department of Pediatrics and Pediatric Hematology/Oncology, Klinikum Oldenburg AöR, Medical Campus University Oldenburg, 26133 Oldenburg, Germany.
Department for Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Children's Hospital Augsburg, Swabian Children's Cancer Centre, Augsburg, Germany.
Department of Pediatric Hematology/Oncology, University of Bonn Medical Center, Bonn, Germany.
Department of Neuropathology, Insitute of Pathology, Comprehensive Cancer Center (CCC) Mainfranken, University of Würzburg, Würzburg, Germany.
Department of Pathology, University of California San Francisco, San Francisco, California, USA.
Division of Molecular Pathology, Institute of Cancer Research, London, UK.
Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health and Histopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Medical Faculty, University of Bonn Medical School, Bonn, Germany.
Department of Neurosurgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Pathology, Princess Máxima Center for Pediatric Oncology and University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Cambridge, UK.
Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
Department of Pediatrics, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Division of Hematology/Oncology, McGill University, Montreal, Quebec, Canada.
Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Division of Neuropathology, UCL Hospitals, Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK.
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK.
Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK.
NN Burdenko Neurosurgical Institute, Moscow, Russia.
Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg, Luxembourg.
Laboratoire national de santé (LNS), Dudelange, Luxembourg.
Luxembourg Centre of Neuropathology (LCNP), Luxembourg, Luxembourg.
Department of Neuropathology, Hannover Medical School (MHH), Hannover, Germany.
Department of Pathology, University of Toronto, Toronto, Ontario, Canada.
Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
Research Institute Children's Cancer Center, Hamburg, Germany.
Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
Section Neuropathology, Institute of Pathology, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Germany.
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
Division of Neuropathology, Department of Pathology, NYU Langone Medical Center, New York, New York, USA.

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.

中文翻译：

基于 DNA 甲基化的中枢神经系统肿瘤分类

准确的病理诊断对于癌症患者的最佳治疗至关重要。对于大约 100 种已知的中枢神经系统肿瘤类型，诊断过程的标准化已被证明特别具有挑战性——许多肿瘤类型的组织病理学诊断中观察者之间存在显着差异。在这里，我们提出了一种针对所有实体和年龄组的基于 DNA 甲基化的中枢神经系统肿瘤分类的综合方法，并展示了其在常规诊断环境中的应用。我们表明，与标准方法相比，该方法的可用性可能会对诊断精度产生重大影响，导致高达 12% 的预期病例的诊断发生变化。为了更广泛的可访问性，我们设计了一个免费的在线分类器工具，使用该工具不需要任何额外的现场数据处理。我们的结果为跨其他癌症实体生成基于机器学习的肿瘤分类器提供了蓝图，有可能从根本上改变肿瘤病理学。

更新日期：2018-03-14

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