The whole-genome landscape of medulloblastoma subtypes

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 () and Peter Lichter ()
Additional contact information
Paul A. Northcott: German Cancer Research Center (DKFZ)
Ivo Buchhalter: German Cancer Research Center (DKFZ)
A. Sorana Morrissy: Developmental & Stem Cell Biology Program, The Hospital for Sick Children
Volker Hovestadt: German Cancer Research Center (DKFZ)
Joachim Weischenfeldt: Biotech Research & Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory
Tobias Ehrenberger: Massachusetts Institute of Technology
Susanne Gröbner: German Cancer Research Center (DKFZ)
Maia Segura-Wang: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Thomas Zichner: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Vasilisa A. Rudneva: St Jude Children’s Research Hospital
Hans-Jörg Warnatz: Max Planck Institute for Molecular Genetics
Nikos Sidiropoulos: Biotech Research & Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory
Aaron H. Phillips: St Jude Children’s Research Hospital
Steven Schumacher: Broad Institute of Harvard and MIT
Kortine Kleinheinz: German Cancer Research Center (DKFZ)
Sebastian M. Waszak: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Serap Erkek: German Cancer Research Center (DKFZ)
David T. W. Jones: German Cancer Research Center (DKFZ)
Barbara C. Worst: German Cancer Research Center (DKFZ)
Marcel Kool: German Cancer Research Center (DKFZ)
Marc Zapatka: German Cancer Research Center (DKFZ)
Natalie Jäger: German Cancer Research Center (DKFZ)
Lukas Chavez: German Cancer Research Center (DKFZ)
Barbara Hutter: German Cancer Research Center (DKFZ)
Matthias Bieg: German Cancer Research Center (DKFZ)
Nagarajan Paramasivam: German Cancer Research Center (DKFZ)
Michael Heinold: German Cancer Research Center (DKFZ)
Zuguang Gu: German Cancer Research Center (DKFZ)
Naveed Ishaque: German Cancer Research Center (DKFZ)
Christina Jäger-Schmidt: German Cancer Research Center (DKFZ)
Charles D. Imbusch: German Cancer Research Center (DKFZ)
Alke Jugold: German Cancer Research Center (DKFZ)
Daniel Hübschmann: German Cancer Research Center (DKFZ)
Thomas Risch: Max Planck Institute for Molecular Genetics
Vyacheslav Amstislavskiy: Max Planck Institute for Molecular Genetics
Francisco German Rodriguez Gonzalez: Biotech Research & Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory
Ursula D. Weber: German Cancer Research Center (DKFZ)
Stephan Wolf: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ)
Giles W. Robinson: St Jude Children’s Research Hospital
Xin Zhou: St Jude Children’s Research Hospital
Gang Wu: St Jude Children’s Research Hospital
David Finkelstein: St Jude Children’s Research Hospital
Yanling Liu: St Jude Children’s Research Hospital
Florence M. G. Cavalli: Developmental & Stem Cell Biology Program, The Hospital for Sick Children
Betty Luu: Developmental & Stem Cell Biology Program, The Hospital for Sick Children
Vijay Ramaswamy: Developmental & Stem Cell Biology Program, The Hospital for Sick Children
Xiaochong Wu: Developmental & Stem Cell Biology Program, The Hospital for Sick Children
Jan Koster: Amsterdam Medical Center
Marina Ryzhova: NN Burdenko Neurosurgical Institute
Yoon-Jae Cho: Papé Family Pediatric Research Institute, Knight Cancer Institute, Oregon Health and Science University
Scott L. Pomeroy: Boston Children's Hospital and Harvard Medical School
Christel Herold-Mende: University Clinic, Heidelberg University, Heidelberg Hospital
Martin Schuhmann: University Hospital Tübingen
Martin Ebinger: Children’s University Hospital Tübingen
Linda M. Liau: David Geffen School of Medicine at UCLA
Jaume Mora: Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu
Roger E. McLendon: Duke University
Nada Jabado: McGill University
Toshihiro Kumabe: Kitasato University School of Medicine
Eric Chuah: Michael Smith Genome Sciences Centre, BC Cancer Agency
Yussanne Ma: Michael Smith Genome Sciences Centre, BC Cancer Agency
Richard A. Moore: Michael Smith Genome Sciences Centre, BC Cancer Agency
Andrew J. Mungall: Michael Smith Genome Sciences Centre, BC Cancer Agency
Karen L. Mungall: Michael Smith Genome Sciences Centre, BC Cancer Agency
Nina Thiessen: Michael Smith Genome Sciences Centre, BC Cancer Agency
Kane Tse: Michael Smith Genome Sciences Centre, BC Cancer Agency
Tina Wong: Michael Smith Genome Sciences Centre, BC Cancer Agency
Steven J. M. Jones: Michael Smith Genome Sciences Centre, BC Cancer Agency
Olaf Witt: Heidelberg University Hospital
Till Milde: Heidelberg University Hospital
Andreas Von Deimling: Heidelberg University Hospital
David Capper: Heidelberg University Hospital
Andrey Korshunov: Heidelberg University Hospital
Marie-Laure Yaspo: Max Planck Institute for Molecular Genetics
Richard Kriwacki: St Jude Children’s Research Hospital
Amar Gajjar: St Jude Children’s Research Hospital
Jinghui Zhang: St Jude Children’s Research Hospital
Rameen Beroukhim: Broad Institute of Harvard and MIT
Ernest Fraenkel: Massachusetts Institute of Technology
Jan O. Korbel: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Benedikt Brors: German Cancer Research Center (DKFZ)
Matthias Schlesner: German Cancer Research Center (DKFZ)
Roland Eils: German Cancer Research Center (DKFZ)
Marco A. Marra: Michael Smith Genome Sciences Centre, BC Cancer Agency
Stefan M. Pfister: German Cancer Research Center (DKFZ)
Michael D. Taylor: Developmental & Stem Cell Biology Program, The Hospital for Sick Children
Peter Lichter: German Cancer Research Center (DKFZ)

Nature, 2017, vol. 547, issue 7663, 311-317

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22973

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