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Nature. 2018 Mar 22;555(7697):469-474. doi: 10.1038/nature26000. Epub 2018 Mar 14.

DNA methylation-based classification of central nervous system tumours.

Capper D1,2,3,4, Jones DTW5,6, Sill M5,6,7, Hovestadt V8, Schrimpf D1,2, Sturm D5,6,9, Koelsche C1,2, Sahm F1,2, Chavez L5,6, Reuss DE1,2, Kratz A1,2, Wefers AK1,2, Huang K1,2, Pajtler KW5,6,9, Schweizer L1,3, Stichel D1,2, Olar A10,11,12, Engel NW13,14, Lindenberg K2, Harter PN15,16, Braczynski AK15,16, Plate KH15,16, Dohmen H17, Garvalov BK17, Coras R18, Hölsken A18, Hewer E19, Bewerunge-Hudler M20, Schick M20, Fischer R20, Beschorner R21, Schittenhelm J21, Staszewski O22, Wani K23, Varlet P24, Pages M24, Temming P25, Lohmann D26, Selt F5,9,27, Witt H5,6,9, Milde T5,9,27, Witt O5,9,27, Aronica E28,29,30, Giangaspero F31,32, Rushing E33, Scheurlen W34, Geisenberger C35,36, Rodriguez FJ37, Becker A38, Preusser M39, Haberler C40, Bjerkvig R41,42, Cryan J43, Farrell M43, Deckert M44, Hench J45, Frank S45, Serrano J46, Kannan K46, Tsirigos A46, Brück W47, Hofer S48, Brehmer S49, Seiz-Rosenhagen M49, Hänggi D49, Hans V50,51, Rozsnoki S52, Hansford JR53,54,55, Kohlhof P56, Kristensen BW57, Lechner M58, Lopes B59, Mawrin C60, Ketter R61, Kulozik A5,9, Khatib Z62, Heppner F3,63,64, Koch A3, Jouvet A65, Keohane C66, Mühleisen H67, Mueller W68, Pohl U69, Prinz M22,70, Benner A7, Zapatka M8, Gottardo NG71,72,73, Driever PH74, Kramm CM75, Müller HL76, Rutkowski S77, von Hoff K74,77, Frühwald MC78, Gnekow A78, Fleischhack G25, Tippelt S25, Calaminus G79, Monoranu CM80, Perry A81, Jones C82, Jacques TS83, Radlwimmer B8, Gessi M38, Pietsch T38, Schramm J84, Schackert G85, Westphal M86, Reifenberger G87,88, Wesseling P89,90, Weller M91, Collins VP92, Blümcke I18, Bendszus M93, Debus J94, Huang A95, Jabado N96, Northcott PA97, Paulus W52, Gajjar A98, Robinson GW98, Taylor MD99, Jaunmuktane Z100,101,102, Ryzhova M103, Platten M104, Unterberg A35, Wick W105, Karajannis MA106, Mittelbronn M15,16,107,108,109,110, Acker T17, Hartmann C111, Aldape K112, Schüller U14,113,114,115, Buslei R18,116, Lichter P8, Kool M5,6, Herold-Mende C35, Ellison DW117, Hasselblatt M52, Snuderl M118, Brandner S100,102, Korshunov A1,2, von Deimling A1,2, Pfister SM5,6,9.

Author information

1
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
2
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Berlin, Germany.
4
German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany.
6
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
8
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
9
Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany.
10
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
11
Department of Neurosurgery, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
12
Hollings Cancer Center, Charleston, South Carolina 29425, USA.
13
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.
14
Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.
15
Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main, Germany.
16
German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, German Cancer Research Center (DKFZ) Heidelberg, Germany.
17
Institute of Neuropathology, University of Giessen, Giessen, Germany.
18
Neuropathological Institute, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
19
Institute of Pathology, University of Bern, Bern, Switzerland.
20
Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
21
Institute of Pathology and Neuropathology, Department of Neuropathology, University Hospital Tübingen, Tübingen, Germany.
22
Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
23
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
24
Department of Neuropathology, Centre Hospitalier Sainte Anne, Paris, France.
25
Pediatrics III, Pediatric Oncology and Hematology, University Hospital Essen, Essen, Germany.
26
Eye Cancer Research Group, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
27
CCU Pediatric Oncology (G340), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
28
Department of (Neuro)Pathology, Academic Medisch Centrum (AMC), University of Amsterdam, Amsterdam, The Netherlands.
29
Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
30
Stichting Epilepsie Instellingen Nederland (SEIN), Amsterdam, The Netherlands.
31
Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Rome, Italy.
32
IRCCS Neuromed, Pozzilli, Italy.
33
Department of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
34
Cnopf'sche Kinderklinik Nuremberg, Nuremberg, Germany.
35
Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
36
Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
37
Division of Neuropathology of the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
38
Department of Neuropathology, University of Bonn, Bonn, Germany.
39
Department of Medicine I, Comprehensive Cancer Center Vienna, CNS Unit (CCC-CNS), Medical University of Vienna, Vienna, Austria.
40
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
41
Department of Biomedicine, University of Bergen, Bergen, Norway.
42
NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
43
Department of Neuropathology, Beaumont Hospital, Dublin, Ireland.
44
Department of Neuropathology, University Hospital of Cologne, Cologne, Germany.
45
Department of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland.
46
NYU Langone Medical Center, New York, New York, USA.
47
Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
48
Division of Oncology, Luzerner Kantonsspital, Luzern, Switzerland.
49
Department of Neurosurgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
50
Institut für Neuropathologie, Evangelisches Krankenhaus Bielefeld gGmbH, Bielefeld, Germany.
51
Institut für Neuropathologie, Universitätskinikum Essen, Essen, Germany.
52
Institute of Neuropathology, University Hospital Münster, Münster, Germany.
53
Children's Cancer Centre, Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
54
Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
55
Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.
56
Institute for Pathology, Katharinenhospital Stuttgart, Stuttgart, Germany.
57
Department of Pathology, Odense University Hospital, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
58
University College London Cancer Institute and University College London Hospitals, London, UK.
59
Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.
60
Institute of Neuropathology, Otto-von-Guericke-University, Magdeburg, Germany.
61
Department of Neurosurgery, University Hospital Saarland, Homburg, Saar, Germany.
62
Nicklaus Children's Hospital Brain Institute, Miami, Florida 33155, USA.
63
Cluster of Excellence, NeuroCure, Berlin, Germany.
64
Berlin Institute of Health (BIH), Berlin, Germany.
65
Département de Pathologie et Neuropathologie, Hôpital Neurologique, Hospices Civils de Lyon, Lyon, France.
66
Department of Neuropathology, Cork University Hospital, Cork, Ireland.
67
Department of Pathology, Ludwigsburg Hospital, Ludwigsburg, Germany.
68
Department of Neuropathology, Leipzig University, Leipzig, Germany.
69
Department of Cellular Pathology, Queen's Hospital, Romford, UK.
70
BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
71
Department of Pediatric Oncology and Haematology, Princess Margaret Hospital for Children, GPO Box D184, Perth, Western Australia 6840, Australia.
72
Telethon Kids Institute, University of Western Australia, PO Box 855, Perth, Western Australia 6872, Australia.
73
School of Paediatrics and Child Health, University of Western Australia, GPO Box D184, Perth, Western Australia 6840, Australia.
74
Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
75
Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany.
76
Department of Pediatrics and Pediatric Hematology/Oncology, Klinikum Oldenburg AöR, Medical Campus University Oldenburg, 26133 Oldenburg, Germany.
77
Department for Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
78
Children's Hospital Augsburg, Swabian Children's Cancer Centre, Augsburg, Germany.
79
Department of Pediatric Hematology/Oncology, University of Bonn Medical Center, Bonn, Germany.
80
Department of Neuropathology, Insitute of Pathology, Comprehensive Cancer Center (CCC) Mainfranken, University of Würzburg, Würzburg, Germany.
81
Department of Pathology, University of California San Francisco, San Francisco, California, USA.
82
Division of Molecular Pathology, Institute of Cancer Research, London, UK.
83
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.
84
Medical Faculty, University of Bonn Medical School, Bonn, Germany.
85
Department of Neurosurgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
86
Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
87
Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
88
German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany.
89
Department of Pathology, Princess Máxima Center for Pediatric Oncology and University Medical Center Utrecht, Utrecht, The Netherlands.
90
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
91
Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
92
Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Cambridge, UK.
93
Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
94
Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
95
Department of Pediatrics, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
96
Division of Hematology/Oncology, McGill University, Montreal, Quebec, Canada.
97
Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
98
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
99
Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
100
Division of Neuropathology, UCL Hospitals, Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK.
101
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK.
102
Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK.
103
NN Burdenko Neurosurgical Institute, Moscow, Russia.
104
Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
105
Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
106
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
107
NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
108
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg, Luxembourg.
109
Laboratoire national de santé (LNS), Dudelange, Luxembourg.
110
Luxembourg Centre of Neuropathology (LCNP), Luxembourg, Luxembourg.
111
Department of Neuropathology, Hannover Medical School (MHH), Hannover, Germany.
112
Department of Pathology, University of Toronto, Toronto, Ontario, Canada.
113
Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
114
Research Institute Children's Cancer Center, Hamburg, Germany.
115
Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
116
Section Neuropathology, Institute of Pathology, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Germany.
117
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
118
Division of Neuropathology, Department of Pathology, NYU Langone Medical Center, New York, New York, USA.

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.

PMID:
29539639
PMCID:
PMC6093218
DOI:
10.1038/nature26000
[Indexed for MEDLINE]
Free PMC Article

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