Sarcoma classification by DNA methylation profiling.

Journal: Nature communications
PMID: 33479225

Abstract

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.

Authors

  • Christian Koelsche
    Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Daniel Schrimpf
    Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Damian Stichel
    Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Martin Sill
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. m.sill@kitz-heidelberg.de.
  • Felix Sahm
    Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • David E Reuss
    Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Mirjam Blattner
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Barbara Worst
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Christoph E Heilig
    Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Katja Beck
    Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Peter Horak
    Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Simon Kreutzfeldt
    Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Elke Paff
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Sebastian Stark
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Pascal Johann
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Florian Selt
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Jonas Ecker
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Dominik Sturm
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Kristian W Pajtler
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Annekathrin Reinhardt
    Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Annika K Wefers
    Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Philipp Sievers
    Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Azadeh Ebrahimi
    Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Abigail Suwala
    Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Francisco Fernández-Klett
    Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Belén Casalini
    Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Andrey Korshunov
    Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Volker Hovestadt
    Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Felix K F Kommoss
    Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Mark Kriegsmann
    Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Matthias Schick
    Genomics and Proteomics Core Facility, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Melanie Bewerunge-Hudler
    Genomics and Proteomics Core Facility, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Till Milde
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Olaf Witt
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Andreas E Kulozik
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Marcel Kool
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Laura Romero-Pérez
    Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Thomas G P Grünewald
    Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Thomas Kirchner
    German Cancer Research Center (DKFZ), Division of Computer Assisted Medical Interventions (CAMI), He, Germany.
  • Wolfgang Wick
    Neurology Clinic, Heidelberg University Hospital, Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Michael Platten
    Neurology Clinic, Heidelberg University Hospital, Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany.
  • Andreas Unterberg
    Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
  • Matthias Uhl
    Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
  • Amir Abdollahi
    Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
  • Jürgen Debus
    Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; Heidelberg Institute of Radiation Oncology, Heidelberg, Germany; Heidelberg Ion-Beam Therapy Center, Heidelberg, Germany.
  • Burkhard Lehner
    Department of Orthopaedics, Trauma Surgery and Paraplegiology, Heidelberg University Hospital, Heidelberg, Germany.
  • Christian Thomas
    Institute of Neuropathology, University Hospital Münster, Münster, Germany.
  • Martin Hasselblatt
    Institute of Neuropathology, University Hospital Münster, Münster, Germany.
  • Werner Paulus
    Institute of Neuropathology, University Hospital Muenster, Pottkamp 2, 48149, Muenster, Germany.
  • Christian Hartmann
    Department of Neuropathology, Institute of Pathology, Hannover Medical School (MHH), Hannover, Germany.
  • Ori Staszewski
    Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Marco Prinz
    BIOSS Centre for Biological Signalling Studies, Freiburg, Germany.
  • Jürgen Hench
    Department of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland.
  • Stephan Frank
    Department of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland.
  • Yvonne M H Versleijen-Jonkers
    Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Marije E Weidema
    Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Thomas Mentzel
    Dermatopathology Bodensee, Friedrichshafen, Germany.
  • Klaus Griewank
    Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen, Essen, Germany.
  • Enrique de Álava
    Department of Pathology, Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital, CSIC/University of Sevilla/CIBERONC, Seville, Spain.
  • Juan Díaz Martín
    Department of Pathology, Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital, CSIC/University of Sevilla/CIBERONC, Seville, Spain.
  • Miguel A Idoate Gastearena
    Department of Pathological Anatomy, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain.
  • Kenneth Tou-En Chang
    Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Republic of Singapore.
  • Sharon Yin Yee Low
    Department of Neurosurgery, National Neuroscience Institute, Singapore, Republic of Singapore.
  • Adrian Cuevas-Bourdier
    National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg.
  • Michel Mittelbronn
    National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg.
  • Martin Mynarek
    Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Stefan Rutkowski
    Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Ulrich Schüller
    Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany; Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Germany; Research Institute Children's Cancer Center, Hamburg, Germany; Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Germany.
  • Viktor F Mautner
    Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Jens Schittenhelm
    Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany.
  • Jonathan Serrano
    Department of Pathology, New York University School of Medicine, New York, NY, USA.
  • Matija Snuderl
    Department of Pathology, New York University, New York, NY, USA.
  • Reinhard Büttner
    Institute of Pathology, University Hospital Cologne, Cologne, Germany.
  • Thomas Klingebiel
    Department of Pediatric Hematology and Oncology, University Children's Hospital, Frankfurt/Main, Germany.
  • Rolf Buslei
    Institute of Pathology, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Germany.
  • Manfred Gessler
    Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Würzburg University, Würzburg, Germany.
  • Pieter Wesseling
    Department of Pathology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; Brain Tumor Center Amsterdam, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; Department of Pathology, Princess Máxima Center for Pediatric Oncology and University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
  • Winand N M Dinjens
    Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
  • Sebastian Brandner
    Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, UK.
  • Zane Jaunmuktane
    Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
  • Iben Lyskjær
    Research Department of Pathology, University College London, London, UK.
  • Peter Schirmacher
    Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.
  • Albrecht Stenzinger
    From the Division of Radiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany (P.S., J.P.R., P.K., H.P.S., D.B.); Medical Image Computing, German Cancer Research Center (DKFZ), Heidelberg, Germany (S.K., K.H.M.H.); Department of Urology, University of Heidelberg Medical Center, Heidelberg, Germany (J.P.R., M.H.); Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany (M.W.); Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany (P.K.); Junior Group Medical Imaging and Radiology-Cancer Prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany (S.B.); Division of Medical Physics, German Cancer Research Center (DKFZ), Heidelberg, Germany (T.A.K.); Institute of Pathology, University of Heidelberg Medical Center, Heidelberg, Germany (A.S.); and German Cancer Consortium (DKTK), Heidelberg, Germany (H.P.S., K.H.M.H., D.B.).
  • Benedikt Brors
    Applied Bioinformatics, Deutsches Krebsforschungszentrum, Heidelberg, 69120, Germany.
  • Hanno Glimm
    Translational and Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Christoph Heining
    Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Dresden, Germany.
  • Oscar M Tirado
    Sarcoma Research Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), CIBERONC, Barcelona, Catalonia, Spain.
  • Miguel Sáinz-Jaspeado
    Sarcoma Research Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), CIBERONC, Barcelona, Catalonia, Spain.
  • Jaume Mora
    Department of Pediatric Onco-Hematology and Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain.
  • Javier Alonso
    Pediatric Solid Tumor Laboratory, Human Genetic Department, Research Institute of Rare Diseases, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
  • Xavier Garcia Del Muro
    Medical Oncology Service, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona, Barcelona, Catalonia, Spain.
  • Sebastian Moran
    Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
  • Manel Esteller
    Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.
  • Jamal K Benhamida
    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Marc Ladanyi
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Eva Wardelmann
    Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany.
  • Cristina Antonescu
    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Adrienne Flanagan
    Department of Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, UK.
  • Uta Dirksen
    Pediatrics III Pediatric Hematology, Oncology, Immunology, Cardiology, Pulmonology, West German Cancer Center, University Hospital Essen, Essen, Germany.
  • Peter Hohenberger
    Division of Surgical Oncology and Thoracic Surgery, Mannheim University Medical Center, University of Heidelberg, Mannheim, Germany.
  • Daniel Baumhoer
    Bone Tumour Reference Centre at the Institute of Pathology, University Hospital Basel and University of Basel, Basel, Switzerland.
  • Wolfgang Hartmann
    Division of Translational Pathology, Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany.
  • Christian Vokuhl
    Department of Pediatric Pathology, University Hospital of Schleswig-Holstein, Kiel, Germany.
  • Uta Flucke
    Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Iver Petersen
    Institute of Pathology, SRH Poliklinik Gera GmbH, Gera, Germany.
  • Gunhild Mechtersheimer
    Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • David Capper
    German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), 69210 Heidelberg, Germany. frederick.klauschen@charite.de david.capper@charite.de.
  • David T W Jones
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Stefan Fröhling
    National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
  • Stefan M Pfister
    Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Andreas von Deimling
    Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

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