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Sarcoma classification by DNA methylation profiling

Author

Listed:
  • Christian Koelsche

    (Institute of Pathology, Heidelberg University Hospital
    German Cancer Research Center (DKFZ)
    Institute of Pathology, Heidelberg University Hospital)

  • Daniel Schrimpf

    (Institute of Pathology, Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Damian Stichel

    (German Cancer Research Center (DKFZ))

  • Martin Sill

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Felix Sahm

    (Institute of Pathology, Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • David E. Reuss

    (Institute of Pathology, Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Mirjam Blattner

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Barbara Worst

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Christoph E. Heilig

    (National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK))

  • Katja Beck

    (National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK)
    German Cancer Research Center (DKFZ))

  • Peter Horak

    (National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK))

  • Simon Kreutzfeldt

    (National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK))

  • Elke Paff

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Sebastian Stark

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Pascal Johann

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Florian Selt

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Jonas Ecker

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Dominik Sturm

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Kristian W. Pajtler

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Annekathrin Reinhardt

    (Institute of Pathology, Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Annika K. Wefers

    (Institute of Pathology, Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Philipp Sievers

    (Institute of Pathology, Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Azadeh Ebrahimi

    (German Cancer Research Center (DKFZ))

  • Abigail Suwala

    (Institute of Pathology, Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Francisco Fernández-Klett

    (Institute of Pathology, Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Belén Casalini

    (German Cancer Research Center (DKFZ))

  • Andrey Korshunov

    (Institute of Pathology, Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Volker Hovestadt

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital and Harvard Medical School)

  • Felix K. F. Kommoss

    (Institute of Pathology, Heidelberg University Hospital)

  • Mark Kriegsmann

    (Institute of Pathology, Heidelberg University Hospital)

  • Matthias Schick

    (German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Melanie Bewerunge-Hudler

    (German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Till Milde

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Olaf Witt

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Andreas E. Kulozik

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Heidelberg University Hospital)

  • Marcel Kool

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Laura Romero-Pérez

    (Institute of Pathology, Faculty of Medicine, LMU Munich)

  • Thomas G. P. Grünewald

    (Institute of Pathology, Faculty of Medicine, LMU Munich)

  • Thomas Kirchner

    (Institute of Pathology, Faculty of Medicine, LMU Munich)

  • Wolfgang Wick

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Michael Platten

    (Mannheim University Medical Center, University of Heidelberg
    German Cancer Research Center (DKFZ))

  • Andreas Unterberg

    (Heidelberg University Hospital)

  • Matthias Uhl

    (Heidelberg University Hospital
    National Center for Radiation Research in Oncology (NCRO))

  • Amir Abdollahi

    (Heidelberg University Hospital
    National Center for Radiation Research in Oncology (NCRO)
    Heidelberg Ion-Beam Therapy Center (HIT)
    National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ))

  • Jürgen Debus

    (Heidelberg University Hospital
    National Center for Radiation Research in Oncology (NCRO)
    Heidelberg Ion-Beam Therapy Center (HIT)
    National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ))

  • Burkhard Lehner

    (Heidelberg University Hospital)

  • Christian Thomas

    (University Hospital Münster)

  • Martin Hasselblatt

    (University Hospital Münster)

  • Werner Paulus

    (University Hospital Münster)

  • Christian Hartmann

    (Institute of Pathology, Hannover Medical School (MHH))

  • Ori Staszewski

    (University of Freiburg
    University of Freiburg)

  • Marco Prinz

    (University of Freiburg
    Signalling Research Centers BIOSS and CIBSS, University of Freiburg
    University of Freiburg)

  • Jürgen Hench

    (Basel University Hospital)

  • Stephan Frank

    (Basel University Hospital)

  • Yvonne M. H. Versleijen-Jonkers

    (Radboud University Medical Center)

  • Marije E. Weidema

    (Radboud University Medical Center)

  • Thomas Mentzel

    (Dermatopathology Bodensee)

  • Klaus Griewank

    (University Hospital Essen, West German Cancer Center, University Duisburg-Essen)

  • Enrique Álava

    (Virgen del Rocio University Hospital, CSIC/University of Sevilla/CIBERONC
    School of Medicine. University of Seville)

  • Juan Díaz Martín

    (Virgen del Rocio University Hospital, CSIC/University of Sevilla/CIBERONC)

  • Miguel A. Idoate Gastearena

    (University of Navarra)

  • Kenneth Tou-En Chang

    (KK Women’s and Children’s Hospital)

  • Sharon Yin Yee Low

    (National Neuroscience Institute)

  • Adrian Cuevas-Bourdier

    (Laboratoire National de Santé (LNS))

  • Michel Mittelbronn

    (Laboratoire National de Santé (LNS)
    Luxembourg Center of Neuropathology (LCNP)
    University of Luxembourg
    Luxembourg Institute of Health (LIH))

  • Martin Mynarek

    (University Medical Center Hamburg-Eppendorf)

  • Stefan Rutkowski

    (University Medical Center Hamburg-Eppendorf)

  • Ulrich Schüller

    (University Medical Center Hamburg-Eppendorf
    University Medical Center Hamburg-Eppendorf
    Research Institute Children’s Cancer Center Hamburg)

  • Viktor F. Mautner

    (University Medical Center Hamburg-Eppendorf)

  • Jens Schittenhelm

    (University Hospital of Tübingen)

  • Jonathan Serrano

    (New York University School of Medicine)

  • Matija Snuderl

    (New York University School of Medicine)

  • Reinhard Büttner

    (Cologne University Hospital)

  • Thomas Klingebiel

    (University Children’s Hospital)

  • Rolf Buslei

    (Institute of Pathology, Sozialstiftung Bamberg, Klinikum am Bruderwald)

  • Manfred Gessler

    (Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Würzburg University)

  • Pieter Wesseling

    (Princess Máxima Center for Pediatric Oncology
    Amsterdam University Medical Centers/VUmc)

  • Winand N. M. Dinjens

    (Erasmus MC Cancer Institute)

  • Sebastian Brandner

    (University College London
    University College London Hospitals NHS Foundation Trust)

  • Zane Jaunmuktane

    (University College London Hospitals NHS Foundation Trust
    University College London)

  • Iben Lyskjær

    (University College London)

  • Peter Schirmacher

    (Institute of Pathology, Heidelberg University Hospital)

  • Albrecht Stenzinger

    (Institute of Pathology, Heidelberg University Hospital)

  • Benedikt Brors

    (German Cancer Research Center (DKFZ))

  • Hanno Glimm

    (National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ)
    National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
    National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus Dresden at TU Dresden
    German Cancer Consortium (DKTK))

  • Christoph Heining

    (National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
    National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus Dresden at TU Dresden
    German Cancer Consortium (DKTK))

  • Oscar M. Tirado

    (Bellvitge Biomedical Research Institute (IDIBELL), CIBERONC)

  • Miguel Sáinz-Jaspeado

    (Bellvitge Biomedical Research Institute (IDIBELL), CIBERONC)

  • Jaume Mora

    (Hospital Sant Joan de Déu)

  • Javier Alonso

    (Human Genetic Department, Research Institute of Rare Diseases, Instituto de Salud Carlos III (ISCIII))

  • Xavier Garcia Muro

    (University of Barcelona)

  • Sebastian Moran

    (Bellvitge Biomedical Research Institute (IDIBELL))

  • Manel Esteller

    (Josep Carreras Leukaemia Research Institute (IJC), Badalona
    Centro de Investigacion Biomedica en Red Cancer (CIBERONC)
    Institucio Catalana de Recerca i Estudis Avançats (ICREA)
    University of Barcelona (UB))

  • Jamal K. Benhamida

    (Memorial Sloan Kettering Cancer Center)

  • Marc Ladanyi

    (Memorial Sloan Kettering Cancer Center)

  • Eva Wardelmann

    (University Hospital Münster)

  • Cristina Antonescu

    (Memorial Sloan Kettering Cancer Center)

  • Adrienne Flanagan

    (Royal National Orthopaedic Hospital NHS Trust
    University College London Cancer Institute)

  • Uta Dirksen

    (University Hospital Essen
    International Ewing Sarcoma Study Group, German Cancer Consortium (DKTK), West German Cancer Center (WTZ), University Duisburg-Essen)

  • Peter Hohenberger

    (University of Heidelberg)

  • Daniel Baumhoer

    (University Hospital Basel and University of Basel)

  • Wolfgang Hartmann

    (University Hospital Münster)

  • Christian Vokuhl

    (University Hospital of Schleswig-Holstein)

  • Uta Flucke

    (Radboud University Medical Center)

  • Iver Petersen

    (Institute of Pathology, SRH Poliklinik Gera GmbH
    Institute of Pathology)

  • Gunhild Mechtersheimer

    (Institute of Pathology, Heidelberg University Hospital)

  • David Capper

    (Charité Universitätsmedizin Berlin)

  • David T. W. Jones

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Stefan Fröhling

    (National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK))

  • Stefan M. Pfister

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Andreas Deimling

    (Institute of Pathology, Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

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.

Suggested Citation

  • Christian Koelsche & Daniel Schrimpf & Damian Stichel & Martin Sill & Felix Sahm & David E. Reuss & Mirjam Blattner & Barbara Worst & Christoph E. Heilig & Katja Beck & Peter Horak & Simon Kreutzfeldt, 2021. "Sarcoma classification by DNA methylation profiling," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20603-4
    DOI: 10.1038/s41467-020-20603-4
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    Cited by:

    1. Yang Zhou & Partho Sarothi Ray & Jianguo Zhu & Frank Stein & Mandy Rettel & Thileepan Sekaran & Sudeep Sahadevan & Joel I. Perez-Perri & Eva K. Roth & Ola Myklebost & Leonardo A. Meza-Zepeda & Andreas, 2024. "Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Julia Schöpf & Sebastian Uhrig & Christoph E. Heilig & Kwang-Seok Lee & Tatjana Walther & Alexander Carazzato & Anna Maria Dobberkau & Dieter Weichenhan & Christoph Plass & Mark Hartmann & Gaurav D. D, 2024. "Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Felix K. F. Kommoss & Anne-Sophie Chong & Anne-Laure Chong & Elke Pfaff & David T. W. Jones & Laura S. Hiemcke-Jiwa & Lennart A. Kester & Uta Flucke & Manfred Gessler & Daniel Schrimpf & Felix Sahm & , 2023. "Genomic characterization of DICER1-associated neoplasms uncovers molecular classes," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Philipp Jurmeister & Stefanie Glöß & Renée Roller & Maximilian Leitheiser & Simone Schmid & Liliana H. Mochmann & Emma Payá Capilla & Rebecca Fritz & Carsten Dittmayer & Corinna Friedrich & Anne Thiem, 2022. "DNA methylation-based classification of sinonasal tumors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Suganth Suppiah & Sheila Mansouri & Yasin Mamatjan & Jeffrey C. Liu & Minu M. Bhunia & Vikas Patil & Prisni Rath & Bharati Mehani & Pardeep Heir & Severa Bunda & German L. Velez-Reyes & Olivia Singh &, 2023. "Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. N. Shukla & M. F. Levine & G. Gundem & D. Domenico & B. Spitzer & N. Bouvier & J. E. Arango-Ossa & D. Glodzik & J. S. Medina-Martínez & U. Bhanot & J. Gutiérrez-Abril & Y. Zhou & E. Fiala & E. Stockfi, 2022. "Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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