The whole-genome landscape of medulloblastoma subtypes View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-07-20

AUTHORS

Paul A. Northcott, Ivo Buchhalter, A. Sorana Morrissy, Volker Hovestadt, Joachim Weischenfeldt, Tobias Ehrenberger, Susanne Gröbner, Maia Segura-Wang, Thomas Zichner, Vasilisa A. Rudneva, Hans-Jörg Warnatz, Nikos Sidiropoulos, Aaron H. Phillips, Steven Schumacher, Kortine Kleinheinz, Sebastian M. Waszak, Serap Erkek, David T. W. Jones, Barbara C. Worst, Marcel Kool, Marc Zapatka, Natalie Jäger, Lukas Chavez, Barbara Hutter, Matthias Bieg, Nagarajan Paramasivam, Michael Heinold, Zuguang Gu, Naveed Ishaque, Christina Jäger-Schmidt, Charles D. Imbusch, Alke Jugold, Daniel Hübschmann, Thomas Risch, Vyacheslav Amstislavskiy, Francisco German Rodriguez Gonzalez, Ursula D. Weber, Stephan Wolf, Giles W. Robinson, Xin Zhou, Gang Wu, David Finkelstein, Yanling Liu, Florence M. G. Cavalli, Betty Luu, Vijay Ramaswamy, Xiaochong Wu, Jan Koster, Marina Ryzhova, Yoon-Jae Cho, Scott L. Pomeroy, Christel Herold-Mende, Martin Schuhmann, Martin Ebinger, Linda M. Liau, Jaume Mora, Roger E. McLendon, Nada Jabado, Toshihiro Kumabe, Eric Chuah, Yussanne Ma, Richard A. Moore, Andrew J. Mungall, Karen L. Mungall, Nina Thiessen, Kane Tse, Tina Wong, Steven J. M. Jones, Olaf Witt, Till Milde, Andreas Von Deimling, David Capper, Andrey Korshunov, Marie-Laure Yaspo, Richard Kriwacki, Amar Gajjar, Jinghui Zhang, Rameen Beroukhim, Ernest Fraenkel, Jan O. Korbel, Benedikt Brors, Matthias Schlesner, Roland Eils, Marco A. Marra, Stefan M. Pfister, Michael D. Taylor, Peter Lichter

ABSTRACT

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and ‘enhancer hijacking’ events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma. More... »

PAGES

311-317

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  • Journal

    TITLE

    Nature

    ISSUE

    7663

    VOLUME

    547

    Author Affiliations

  • Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA
  • Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany
  • Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario
  • Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • Biotech Research & Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory, Rigshospitalet, Denmark
  • Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  • German Cancer Consortium (DKTK), Heidelberg, Germany
  • Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
  • Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
  • Department of Structural Biology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA
  • Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
  • Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany
  • Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
  • Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
  • Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA
  • Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA
  • Department of Oncogenomics, Amsterdam Medical Center, Amsterdam, Netherlands
  • Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia
  • Department of Pediatrics, Papé Family Pediatric Research Institute, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA
  • Department of Neurology, Boston Children's Hospital and Harvard Medical School, BostonMassachusetts, USA
  • Department of Neurosurgery, University Clinic, Heidelberg University, Heidelberg Hospital, Germany
  • Department of Neurosurgery, University Hospital Tübingen, Tübingen, Germany
  • Department of Hematology and Oncology, Children’s University Hospital Tübingen, Tübingen, Germany
  • Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  • Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Barcelona, Spain
  • Department of Pathology, Duke University, Durham, North County, USA
  • Department of Pediatrics, McGill University, Montreal, Quebec, Canada
  • Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Japan
  • Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
  • Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
  • Division of Neurosurgery, Hospital for Sick Children, Toronto, Ontario, Canada
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature22973

    DOI

    http://dx.doi.org/10.1038/nature22973

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1090777008

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28726821


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