Article

DNA methylation-based classification of central nervous system tumours

  • Nature volume 555, pages 469474 (22 March 2018)
  • doi:10.1038/nature26000
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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.

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Acknowledgements

We thank U. Lass, A. Habel, I. Oezen for technical and administrative support, the Microarray unit of the Genomics and Proteomics Core Facility (DKFZ) for methylation services, the German Glioma Network and the Neuroonkologische Arbeitsgemeinschaft for sharing their data. This research was supported by the DKFZ-Heidelberg Center for Personalized Oncology (DKFZ-HIPO_036), the German Childhood Cancer Foundation (DKS 2015.01), an Illumina Medical Research Grant, the DKTK joint funding project ‘Next Generation Molecular Diagnostics of Malignant Gliomas’, the A Kids’ Brain Tumour Cure (PLGA) Foundation, the Brain Tumour Charity (UK) for the Everest Centre for Paediatric Low-Grade Brain Tumour Research, the Friedberg Charitable Foundation and the Sohn Conference Foundation (to M. Snuderl and M. Karajannis), the RKA-Förderpool (Project 37) and Stichting Kinderen Kankervrij and Stichting AMC Foundation (to E. Aronica), NIH/NCI 5T32CA163185 (to A.O.), NIH/NCI Cancer Center Support Grant P30 CA008748 to MSKCC, the Luxembourg National Research Fond (FNR PEARL P16/BM/11192868 to M.M.) and the National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre (S.Bra.).

Author information

Author notes

    • Volker Hovestadt

    Present addresses: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA (V.Ho.); Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA (V.Ho.).

    • David Capper
    • , David T. W. Jones
    • , Martin Sill
    •  & Volker Hovestadt

    These authors contributed equally to this work.

    • Andreas von Deimling
    •  & Stefan M. Pfister

    These authors jointly supervised this work.

Affiliations

  1. Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany

    • David Capper
    • , Daniel Schrimpf
    • , Christian Koelsche
    • , Felix Sahm
    • , David E. Reuss
    • , Annekathrin Kratz
    • , Annika K. Wefers
    • , Kristin Huang
    • , Leonille Schweizer
    • , Damian Stichel
    • , Andrey Korshunov
    •  & Andreas von Deimling
  2. Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    • David Capper
    • , Daniel Schrimpf
    • , Christian Koelsche
    • , Felix Sahm
    • , David E. Reuss
    • , Annekathrin Kratz
    • , Annika K. Wefers
    • , Kristin Huang
    • , Damian Stichel
    • , Kerstin Lindenberg
    • , Andrey Korshunov
    •  & Andreas von Deimling
  3. Charité — Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Berlin, Germany

    • David Capper
    • , Leonille Schweizer
    • , Frank Heppner
    •  & Arend Koch
  4. German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany

    • David Capper
  5. Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany

    • David T. W. Jones
    • , Martin Sill
    • , Dominik Sturm
    • , Lukas Chavez
    • , Kristian W. Pajtler
    • , Florian Selt
    • , Hendrik Witt
    • , Till Milde
    • , Olaf Witt
    • , Andreas Kulozik
    • , Marcel Kool
    •  & Stefan M. Pfister
  6. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    • David T. W. Jones
    • , Martin Sill
    • , Dominik Sturm
    • , Lukas Chavez
    • , Kristian W. Pajtler
    • , Hendrik Witt
    • , Marcel Kool
    •  & Stefan M. Pfister
  7. Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    • Martin Sill
    •  & Axel Benner
  8. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    • Volker Hovestadt
    • , Marc Zapatka
    • , Bernhard Radlwimmer
    •  & Peter Lichter
  9. Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany

    • Dominik Sturm
    • , Kristian W. Pajtler
    • , Florian Selt
    • , Hendrik Witt
    • , Till Milde
    • , Olaf Witt
    • , Andreas Kulozik
    •  & Stefan M. Pfister
  10. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA

    • Adriana Olar
  11. Department of Neurosurgery, Medical University of South Carolina, Charleston, South Carolina 29425, USA

    • Adriana Olar
  12. Hollings Cancer Center, Charleston, South Carolina 29425, USA

    • Adriana Olar
  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

    • Nils W. Engel
  14. Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany

    • Nils W. Engel
    •  & Ulrich Schüller
  15. Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main, Germany

    • Patrick N. Harter
    • , Anne K. Braczynski
    • , Karl H. Plate
    •  & Michel Mittelbronn
  16. German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, German Cancer Research Center (DKFZ) Heidelberg, Germany

    • Patrick N. Harter
    • , Anne K. Braczynski
    • , Karl H. Plate
    •  & Michel Mittelbronn
  17. Institute of Neuropathology, University of Giessen, Giessen, Germany

    • Hildegard Dohmen
    • , Boyan K. Garvalov
    •  & Till Acker
  18. Neuropathological Institute, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany

    • Roland Coras
    • , Annett Hölsken
    • , Ingmar Blümcke
    •  & Rolf Buslei
  19. Institute of Pathology, University of Bern, Bern, Switzerland

    • Ekkehard Hewer
  20. Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany

    • Melanie Bewerunge-Hudler
    • , Matthias Schick
    •  & Roger Fischer
  21. Institute of Pathology and Neuropathology, Department of Neuropathology, University Hospital Tübingen, Tübingen, Germany

    • Rudi Beschorner
    •  & Jens Schittenhelm
  22. Institute of Neuropathology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

    • Ori Staszewski
    •  & Marco Prinz
  23. Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Khalida Wani
  24. Department of Neuropathology, Centre Hospitalier Sainte Anne, Paris, France

    • Pascale Varlet
    •  & Melanie Pages
  25. Pediatrics III, Pediatric Oncology and Hematology, University Hospital Essen, Essen, Germany

    • Petra Temming
    • , Gudrun Fleischhack
    •  & Stephan Tippelt
  26. Eye Cancer Research Group, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany

    • Dietmar Lohmann
  27. CCU Pediatric Oncology (G340), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

    • Florian Selt
    • , Till Milde
    •  & Olaf Witt
  28. Department of (Neuro)Pathology, Academic Medisch Centrum (AMC), University of Amsterdam, Amsterdam, The Netherlands

    • Eleonora Aronica
  29. Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands

    • Eleonora Aronica
  30. Stichting Epilepsie Instellingen Nederland (SEIN), Amsterdam, The Netherlands

    • Eleonora Aronica
  31. Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Rome, Italy

    • Felice Giangaspero
  32. IRCCS Neuromed, Pozzilli, Italy

    • Felice Giangaspero
  33. Department of Neuropathology, University Hospital Zurich, Zurich, Switzerland

    • Elisabeth Rushing
  34. Cnopf’sche Kinderklinik Nuremberg, Nuremberg, Germany

    • Wolfram Scheurlen
  35. Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany

    • Christoph Geisenberger
    • , Andreas Unterberg
    •  & Christel Herold-Mende
  36. Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands

    • Christoph Geisenberger
  37. Division of Neuropathology of the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    • Fausto J. Rodriguez
  38. Department of Neuropathology, University of Bonn, Bonn, Germany

    • Albert Becker
    • , Marco Gessi
    •  & Torsten Pietsch
  39. Department of Medicine I, Comprehensive Cancer Center Vienna, CNS Unit (CCC-CNS), Medical University of Vienna, Vienna, Austria

    • Matthias Preusser
  40. Institute of Neurology, Medical University of Vienna, Vienna, Austria

    • Christine Haberler
  41. Department of Biomedicine, University of Bergen, Bergen, Norway

    • Rolf Bjerkvig
  42. NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg

    • Rolf Bjerkvig
  43. Department of Neuropathology, Beaumont Hospital, Dublin, Ireland

    • Jane Cryan
    •  & Michael Farrell
  44. Department of Neuropathology, University Hospital of Cologne, Cologne, Germany

    • Martina Deckert
  45. Department of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland

    • Jürgen Hench
    •  & Stephan Frank
  46. NYU Langone Medical Center, New York, New York, USA

    • Jonathan Serrano
    • , Kasthuri Kannan
    •  & Aristotelis Tsirigos
  47. Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany

    • Wolfgang Brück
  48. Division of Oncology, Luzerner Kantonsspital, Luzern, Switzerland

    • Silvia Hofer
  49. Department of Neurosurgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany

    • Stefanie Brehmer
    • , Marcel Seiz-Rosenhagen
    •  & Daniel Hänggi
  50. Institut für Neuropathologie, Evangelisches Krankenhaus Bielefeld gGmbH, Bielefeld, Germany

    • Volkmar Hans
  51. Institut für Neuropathologie, Universitätskinikum Essen, Essen, Germany

    • Volkmar Hans
  52. Institute of Neuropathology, University Hospital Münster, Münster, Germany

    • Stephanie Rozsnoki
    • , Werner Paulus
    •  & Martin Hasselblatt
  53. Children’s Cancer Centre, Royal Children’s Hospital, University of Melbourne, Melbourne, Victoria, Australia

    • Jordan R. Hansford
  54. Murdoch Children’s Research Institute, University of Melbourne, Melbourne, Victoria, Australia

    • Jordan R. Hansford
  55. Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia

    • Jordan R. Hansford
  56. Institute for Pathology, Katharinenhospital Stuttgart, Stuttgart, Germany

    • Patricia Kohlhof
  57. Department of Pathology, Odense University Hospital, Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    • Bjarne W. Kristensen
  58. University College London Cancer Institute and University College London Hospitals, London, UK

    • Matt Lechner
  59. Department of Pathology, University of Virginia, Charlottesville, Virginia, USA

    • Beatriz Lopes
  60. Institute of Neuropathology, Otto-von-Guericke-University, Magdeburg, Germany

    • Christian Mawrin
  61. Department of Neurosurgery, University Hospital Saarland, Homburg, Saar, Germany

    • Ralf Ketter
  62. Nicklaus Children’s Hospital Brain Institute, Miami, Florida 33155, USA

    • Ziad Khatib
  63. Cluster of Excellence, NeuroCure, Berlin, Germany

    • Frank Heppner
  64. Berlin Institute of Health (BIH), Berlin, Germany

    • Frank Heppner
  65. Département de Pathologie et Neuropathologie, Hôpital Neurologique, Hospices Civils de Lyon, Lyon, France

    • Anne Jouvet
  66. Department of Neuropathology, Cork University Hospital, Cork, Ireland

    • Catherine Keohane
  67. Department of Pathology, Ludwigsburg Hospital, Ludwigsburg, Germany

    • Helmut Mühleisen
  68. Department of Neuropathology, Leipzig University, Leipzig, Germany

    • Wolf Mueller
  69. Department of Cellular Pathology, Queen’s Hospital, Romford, UK

    • Ute Pohl
  70. BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany

    • Marco Prinz
  71. Department of Pediatric Oncology and Haematology, Princess Margaret Hospital for Children, GPO Box D184, Perth, Western Australia 6840, Australia

    • Nicholas G. Gottardo
  72. Telethon Kids Institute, University of Western Australia, PO Box 855, Perth, Western Australia 6872, Australia

    • Nicholas G. Gottardo
  73. School of Paediatrics and Child Health, University of Western Australia, GPO Box D184, Perth, Western Australia 6840, Australia

    • Nicholas G. Gottardo
  74. Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany

    • Pablo Hernáiz Driever
    •  & Katja von Hoff
  75. Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany

    • Christof M. Kramm
  76. Department of Pediatrics and Pediatric Hematology/Oncology, Klinikum Oldenburg AöR, Medical Campus University Oldenburg, 26133 Oldenburg, Germany

    • Hermann L. Müller
  77. Department for Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    • Stefan Rutkowski
    •  & Katja von Hoff
  78. Children’s Hospital Augsburg, Swabian Children’s Cancer Centre, Augsburg, Germany

    • Michael C. Frühwald
    •  & Astrid Gnekow
  79. Department of Pediatric Hematology/Oncology, University of Bonn Medical Center, Bonn, Germany

    • Gabriele Calaminus
  80. Department of Neuropathology, Insitute of Pathology, Comprehensive Cancer Center (CCC) Mainfranken, University of Würzburg, Würzburg, Germany

    • Camelia-Maria Monoranu
  81. Department of Pathology, University of California San Francisco, San Francisco, California, USA

    • Arie Perry
  82. Division of Molecular Pathology, Institute of Cancer Research, London, UK

    • Chris Jones
  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

    • Thomas S. Jacques
  84. Medical Faculty, University of Bonn Medical School, Bonn, Germany

    • Johannes Schramm
  85. Department of Neurosurgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    • Gabriele Schackert
  86. Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    • Manfred Westphal
  87. Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    • Guido Reifenberger
  88. German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany

    • Guido Reifenberger
  89. Department of Pathology, Princess Máxima Center for Pediatric Oncology and University Medical Center Utrecht, Utrecht, The Netherlands

    • Pieter Wesseling
  90. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

    • Pieter Wesseling
  91. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland

    • Michael Weller
  92. Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Cambridge, UK

    • Vincent Peter Collins
  93. Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany

    • Martin Bendszus
  94. Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany

    • Jürgen Debus
  95. Department of Pediatrics, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    • Annie Huang
  96. Division of Hematology/Oncology, McGill University, Montreal, Quebec, Canada

    • Nada Jabado
  97. Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA

    • Paul A. Northcott
  98. Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA

    • Amar Gajjar
    •  & Giles W. Robinson
  99. Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    • Michael D. Taylor
  100. Division of Neuropathology, UCL Hospitals, Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK

    • Zane Jaunmuktane
    •  & Sebastian Brandner
  101. Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK

    • Zane Jaunmuktane
  102. Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK

    • Zane Jaunmuktane
    •  & Sebastian Brandner
  103. NN Burdenko Neurosurgical Institute, Moscow, Russia

    • Marina Ryzhova
  104. Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    • Michael Platten
  105. Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany

    • Wolfgang Wick
  106. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Matthias A. Karajannis
  107. NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg

    • Michel Mittelbronn
  108. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg, Luxembourg

    • Michel Mittelbronn
  109. Laboratoire national de santé (LNS), Dudelange, Luxembourg

    • Michel Mittelbronn
  110. Luxembourg Centre of Neuropathology (LCNP), Luxembourg, Luxembourg

    • Michel Mittelbronn
  111. Department of Neuropathology, Hannover Medical School (MHH), Hannover, Germany

    • Christian Hartmann
  112. Department of Pathology, University of Toronto, Toronto, Ontario, Canada

    • Kenneth Aldape
  113. Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany

    • Ulrich Schüller
  114. Research Institute Children’s Cancer Center, Hamburg, Germany

    • Ulrich Schüller
  115. Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany

    • Ulrich Schüller
  116. Section Neuropathology, Institute of Pathology, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Germany

    • Rolf Buslei
  117. Department of Pathology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA

    • David W. Ellison
  118. Division of Neuropathology, Department of Pathology, NYU Langone Medical Center, New York, New York, USA

    • Matija Snuderl

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Contributions

D.C. and D.T.W.J. composed the reference cohort and defined methylation classes; M.Si. and V.Ho. developed and technically validated the classification algorithm; D.Sc. developed the classification website; D.C., D.T.W.J., M.Si., A.Ben., V.Ho., D.Sc., D.Sti., M.Z., A.v.D. and S.M.P. developed additional methodology and software; D.C., D.T.W.J., M.Si., D.Stu., C.Ko., F.Sa., L.C., D.E.R., A.Kr., A.K.W., K.H., L.S., P.N.H., K.H.P., J.Schi., G.R., M.Pri, W.B., F.Se., H.W., T.M., O.W., S.Bre., M.S.-R., D.H., A.Ku., C.M.K., H.L.M., S.Ru., K.v.H., M.C.F., A.Gn., G.F., S.T., G.C., C.-M.M., M.G., T.P., M.B., J.D., M.Pl., A.U., W.W., M.M., C.Har., C.H.-M., M.H., A.Kor., A.v.D. and S.M.P. performed the prospective cohort analysis; P.N.H., K.H.P., H.D., B.K.G., J.H., S.F., P.W., Z.J., T.A., S.Bra. generated and collected the external centre data; K.W.P., A.O., N.W.E., A.K.B., R.C., A.Hö., E.H., R.Be., J.Schi., O.S., K.W., P.V., M.Pa., P.T., D.L., E.A., F.G., E.R., W.S., C.G., F.J.R., A.Bec., M.Pre., C.Hab., R.Bj., J.C., M.F., M.D., S.H., V.Ha., S.Ro., J.R.H., P.K., B.W.K., M.L., B.L., C.M., R.K., Z.K., F.H., A.Koc., A.J., C.Ke., H.M., W.M., U.P., M.Pri., N.G.G., P.H.D., A.P., C.J., T.S.J., B.R., T.P., J.Schr., G.S., M.Wes., G.R., P.W., M.Wel., V.P.C., I.B., A.Hu., N.J., P.A.N., W.P., A.Ga., G.W.R., M.D.T., M.R., M.A.K., M.M., C.Har., K.A., U.S., R.Bu., P.L., M.K., C.H.-M., D.W.E., M.H., S.Bra., A.Kor., A.v.D. and S.M.P. provided reference cohort material and data; K.L., M.B.-H., M.Sc. and R.F. performed methylation profiling; J.Se., K.K., A.T., M.K. and M.Sn. performed technical validation experiments; A.v.D. and S.M.P. supervised the project. The manuscript underwent an internal collaboration-wide review process. All authors approved the final version of the manuscript.

Competing interests

A patent for a “DNA-methylation based method for classifying tumor species of the brain” has been applied for by the Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts and Ruprecht-Karls-Universität Heidelberg (EP 3067432 A1) with S.M.P., A.v.D., D.T.W.J., D.C., V.Ho., M.Si., M.B.-H. and M.Sc. as inventors. The other authors declare no competing interests.

Corresponding authors

Correspondence to Andreas von Deimling or Stefan M. Pfister.

Reviewer Information Nature thanks S. Pomeroy, M. L. Suva, R. Verhaak and S. Yip for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    Overview of reference methylation class characteristics. This table gives an overview of the main characteristics of the 82 tumour and 9 non-tumour methylation classes including full names of the methylation class, association of class with a methylation class family, number of cases per class, class age characteristics, male / female ratio, tumour localization, most frequent pathological diagnoses and a running text summarizing typical class features. Further, the Hex colour code of the reference classes used throughout this manuscript is provided.

  2. 2.

    Supplementary Table 2

    Case by case list of reference cohort. This table gives case-by-case details of the n=2801 biologically independent samples constituting the reference cohort including the Sentrix ID (.idat), tissue source, clinical data, methylation class and technical specifications.

  3. 3.

    Supplementary Table 3

    Single class sensitivity and specificity. This table provides single class specificity and sensitivity for the ≥0.9 calibrated classifier score for methylation class families and methylation classes that are not assigned to a methylation class family. In addition single class specificity and sensitivity is provided for the ≥0.5 calibrated classifier score for methylation classes that are part of a methylation class family and that can be used for subclassification for individual family member identification. The data was generated using n=2801 biologically independent samples.

  4. 4.

    Supplementary Table 4

    Case by case list of prospective validation cohort. This table gives case-by-case details of the n=1104 biologically independent samples constituting the prospective clinical cohort including information on the tissue source, clinical data, methylation class prediction (Classifier version V11b2), interpretation of classification and technical specifications.

  5. 5.

    Supplementary Table 5

    Case by case list of of discordant cases. This table gives case-by-case details of the n=139 biologically independent samples with discordant results between pathological diagnosis and methylation profiling. The cases are categorized into reclassified ("establishing new diagnosis", n=129) or misleading profile (n=10). Information on the orthogonal methods used for reassessment as well as the key information resulting in reclassification is provided.

  6. 6.

    Supplementary Table 6

    Case by case list of external diagnostic cohort. This table gives case-by-case details of the n=401 biologically independent samples constituting the external centre diagnostic cohort including clinical data, original pathological diagnosis, methylation class prediction, interpretation of classification and the final pathological diagnosis (after integration with classifier result).

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