Subgroup-specific structural variation across 1,000 medulloblastoma genomes View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-07-25

AUTHORS

Paul A. Northcott, David J. H. Shih, John Peacock, Livia Garzia, A. Sorana Morrissy, Thomas Zichner, Adrian M. Stütz, Andrey Korshunov, Jüri Reimand, Steven E. Schumacher, Rameen Beroukhim, David W. Ellison, Christian R. Marshall, Anath C. Lionel, Stephen Mack, Adrian Dubuc, Yuan Yao, Vijay Ramaswamy, Betty Luu, Adi Rolider, Florence M. G. Cavalli, Xin Wang, Marc Remke, Xiaochong Wu, Readman Y. B. Chiu, Andy Chu, Eric Chuah, Richard D. Corbett, Gemma R. Hoad, Shaun D. Jackman, Yisu Li, Allan Lo, Karen L. Mungall, Ka Ming Nip, Jenny Q. Qian, Anthony G. J. Raymond, Nina Thiessen, Richard J. Varhol, Inanc Birol, Richard A. Moore, Andrew J. Mungall, Robert Holt, Daisuke Kawauchi, Martine F. Roussel, Marcel Kool, David T. W. Jones, Hendrick Witt, Africa Fernandez-L, Anna M. Kenney, Robert J. Wechsler-Reya, Peter Dirks, Tzvi Aviv, Wieslawa A. Grajkowska, Marta Perek-Polnik, Christine C. Haberler, Olivier Delattre, Stéphanie S. Reynaud, François F. Doz, Sarah S. Pernet-Fattet, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Wolfram Scheurlen, Charles G. Eberhart, Michelle Fèvre-Montange, Anne Jouvet, Ian F. Pollack, Xing Fan, Karin M. Muraszko, G. Yancey Gillespie, Concezio Di Rocco, Luca Massimi, Erna M. C. Michiels, Nanne K. Kloosterhof, Pim J. French, Johan M. Kros, James M. Olson, Richard G. Ellenbogen, Karel Zitterbart, Leos Kren, Reid C. Thompson, Michael K. Cooper, Boleslaw Lach, Roger E. McLendon, Darell D. Bigner, Adam Fontebasso, Steffen Albrecht, Nada Jabado, Janet C. Lindsey, Simon Bailey, Nalin Gupta, William A. Weiss, László Bognár, Almos Klekner, Timothy E. Van Meter, Toshihiro Kumabe, Teiji Tominaga, Samer K. Elbabaa, Jeffrey R. Leonard, Joshua B. Rubin, Linda M. Liau, Erwin G. Van Meir, Maryam Fouladi, Hideo Nakamura, Giuseppe Cinalli, Miklós Garami, Peter Hauser, Ali G. Saad, Achille Iolascon, Shin Jung, Carlos G. Carlotti, Rajeev Vibhakar, Young Shin Ra, Shenandoah Robinson, Massimo Zollo, Claudia C. Faria, Jennifer A. Chan, Michael L. Levy, Poul H. B. Sorensen, Matthew Meyerson, Scott L. Pomeroy, Yoon-Jae Cho, Gary D. Bader, Uri Tabori, Cynthia E. Hawkins, Eric Bouffet, Stephen W. Scherer, James T. Rutka, David Malkin, Steven C. Clifford, Steven J. M. Jones, Jan O. Korbel, Stefan M. Pfister, Marco A. Marra, Michael D. Taylor

ABSTRACT

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy. More... »

PAGES

49-56

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  • Journal

    TITLE

    Nature

    ISSUE

    7409

    VOLUME

    488

    Author Affiliations

  • Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
  • Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Buildings, 1 King’s College Circle, 6th Floor, Toronto, Ontario M5S 1A8, Canada.
  • Developmental & Stem Cell Biology Program, The Hospital for Sick Children, 101 College Street, TMDT-11-401M, Toronto, Ontario M5G 1L7, Canada.
  • Genome Biology, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
  • Department of Neuropathology, CCU Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 220-221, University of Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
  • The Donnelly Centre, University of Toronto, 160 College Street, Room 602, Toronto, Ontario M5S 3E1, Canada.
  • Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
  • Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
  • Pathology, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
  • McLaughlin Centre and Department of Molecular Genetics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
  • The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, 101 College Street, TMDT-14-701, Toronto, Ontario M5G 1L7, Canada.
  • Michael Smith Genome Sciences Centre, BC Cancer Agency, 100-570 West 7th Avenue, Vancouver, British Columbia V5Z 4S6, Canada.
  • Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
  • Tumour Cell Biology, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
  • Departments of Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
  • Pediatric Clinical Trials Office, Memorial Sloan-Kettering Cancer Center, 405 Lexington Avenue, New York, New York 10174, USA.
  • Cancer Biology, Vanderbilt Medical Center, 465 21st Avenue South, MRB III 6160, Nashville, Tennessee 37232-8550, USA.
  • Sanford-Burnham Medical Research Institute, 92037, La Jolla, California, USA
  • Department of Surgery, Division of Neurosurgery and Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Hill 1503, Toronto, Ontario M5G 1X8, Canada.
  • Developmental & Stem Cell Biology Program, The Hospital for Sick Children, 101 College Street, TMDT-13-601, Toronto, Ontario M5G 1L7, Canada.
  • Department of Pathology, The Children’s Memorial Health Institute, Aleja Dzieci Polskich 20, 04-730 Warsaw, Poland.
  • Department of Oncology, The Children’s Memorial Health Institute, Aleja Dzieci Polskich 20, 04-730 Warsaw, Poland.
  • Institute of Neurology, Medical University of Vienna, AKH 4J, Waehringer Gürtel 18-20, A-1097 Vienna, Austria.
  • INSERM U 830, Institut Curie, 26 rue d’Ulm, 75238 Paris Cedex 5, France.
  • Unit of Somatic Genetics, Institut Curie, 26 rue d’Ulm, 75238 Paris Cedex 5, France.
  • Department of Pediatric Oncology, Institut Curie, 26 rue d’Ulm, 75248 Paris Cedex 5, France.
  • Pediatric Hematology and Oncology, CHUV University Hospital, 1011 Lausanne, Switzerland.
  • Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, 101 Daehak-Ro Jongno-Gu, Seoul 110-744, South Korea.
  • Head of Pediatrics, Cnopfsche Kinderklinik, Theodor-Kutzer-Ufer 1-3, 90419 Nuremberg, Germany.
  • Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building 558, Baltimore, Maryland 21205, USA.
  • INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences, Université de Lyon, 69336 Lyon, France.
  • Centre de Pathologie EST, Groupement Hospitalier EST, Université de Lyon, 69500 Bron, France.
  • Department of Neurological Surgery, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, Pennsylvania 15224, USA.
  • Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Place, 5018 BSRB, Ann Arbor, Michigan 48109, USA.
  • Department of Neurosurgery, University of Michigan Medical School, 1500 E. Medical Center Drive, Taubman Center, Room 3552, Ann Arbor, Michigan 48109, USA.
  • Department of Surgery, Division of Neurosurgery, University of Alabama at Birmingham, 1900 University Boulevard, THT 1052, Birmingham, Alabama 35294-0006, USA.
  • Pediatric Neurosurgery, Catholic University Medical School, 00186 Rome, Italy.
  • Department of Pediatric Oncology and Hematology, Erasmus Medical Center, Dr. Molewaterplein 50, 3000 Rotterdam, The Netherlands.
  • Department of Neurology, Erasmus Medical Center, Dr. Molewaterplein 50, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
  • Department of Pathology, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
  • Seattle Children’s Hospital, 98104, Seattle, Washington, USA
  • Neurological Surgery, University of Washington School of Medicine, Harborview Medical Center, 325 Ninth Avenue, Seattle, Washington 98104, USA.
  • Department of Pediatric Oncology, University Hospital Brno, 625 00 Brno, Czech Republic.
  • Department of Pathology, University Hospital Brno, Jihlavska 20, 625 00 Brno, Czech Republic.
  • Neurological Surgery, Vanderbilt Medical Center, T-4224 MCN, Nashville, Tennessee 37232-2380, USA.
  • Department of Neurology, Vanderbilt Medical Center, 465 21st Avenue South, MRB III 6160, Nashville, Tennessee 37232-8550, USA.
  • Department of Pathology and Laboratory Medicine, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
  • Department of Pathology, Duke University, DUMC 3712, Durham, North Carolina 27710, USA.
  • Division of Experimental Medicine, McGill University, 4060 Ste Catherine West, Montreal, Quebec H3Z 2Z3, Canada.
  • Department of Pathology, Montreal Children’s Hospital, 2300 Tupper, Montreal, Quebec H3H 1P3, Canada.
  • Department of Pediatrics, Division of Hemato-Oncology, McGill University, Montreal, Quebec H3H 1P3, Canada.
  • Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, United Kingdom.
  • Departments of Neurological Surgery and Pediatrics, University of California San Francisco, 505 Parnassus Avenue, Room M779, San Francisco, California 94143-0112, USA.
  • Departments of Neurology, Pediatrics, and Neurosurgery, University of California San Francisco, The Helen Diller Family Cancer Research Building 1450 3rd Street, Room HD-220, MC 0520, San Francisco, California 94158, USA.
  • Department of Neurosurgery, University of Debrecen, Medical and Health Science Centre, Móricz Zs. Krt. 22., 4032 Debrecen, Hungary.
  • Pediatrics, Virginia Commonwealthy University, School of Medicine, Box 980646, Pediatric Hematology-Oncology, 1101 East Marshall Street, Richmond, Virginia 23298-0646, USA.
  • Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
  • Department of Neurosurgery, Division of Pediatric Neurosurgery, St Louis University School of Medicine, 1465 South Grand Boulevard, Suite 3707, St Louis, Missouri 63104, USA.
  • Department of Neurosurgery, Division of Pediatric Neurosurgery, Washington University School of Medicine and St Louis Children’s Hospital, Campus Box 8057, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
  • Departments of Pediatrics, Anatomy and Neurobiology, Washington University School of Medicine and St Louis Children’s Hospital, Campus Box 8208, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
  • Department of Neurosurgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Campus 690118, Los Angeles, California 90095, USA.
  • Departments of Neurosurgery and Hematology & Medical Oncology, Laboratory of Molecular Neuro-Oncology, School of Medicine and Winship Cancer Institute, Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
  • Division of Oncology, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, 45229, Cincinnati, Ohio, USA
  • Department of Neurosurgery, Kumamoto University Graduate School of Medical Science, 1-1-1, Honjo, Kumamoto 860-8556, Japan.
  • Paediatric Neurosurgery, Ospedale Santobono-Pausilipon, 80145 Naples, Italy.
  • 2nd Department of Pediatrics, Semmelweis University, 1085 Budapest, Hungary.
  • Pathology, University of Arkansas for Medical Sciences, 1 Children’s Way, lot 820, Little Rock, Arkansas 72202, USA.
  • CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145 Naples, Italy.
  • Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, 322 Seoyang-ro, Hwasun-eup, Hwasun-gun, Chonnam 519-763, South Korea.
  • Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, Universidade de São Paulo, Brazil, Avenida Bandeirantes, 3900, Monte Alegre, 14049-900, Rebeirao Preto, São Paulo, Brazil.
  • Pediatrics, University of Colorado Denver, 12800 19th Avenue, Aurora, Colorado 80045, USA.
  • Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul, 138-736, South Korea.
  • Rainbow Babies & Children’s, 44106, Cleveland, Ohio, USA
  • Cell Biology Program, The Hospital for Sick Children, 101 College Street, TMDT-401-J, Toronto, Ontario M5G 1L7, Canada.
  • Department of Pathology and Laboratory Medicine, University of Calgary, 3330 Hospital Drive NW, HRIC 2A25A, Calgary, Alberta T2N 4N1, Canada.
  • UCSD Division of Neurosurgery, Rady Children’s Hospital San Diego, 8010 Frost Street, Suite 502, San Diego, California 92123, USA.
  • Department of Molecular Oncology, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
  • Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
  • Department of Neurology, Harvard Medical School, Children’s Hospital Boston, Fegan 11, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
  • Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 1201 Welch Road, MSLS Building, Rm P213, Stanford, California 94305, USA.
  • Samuel Lunenfeld Research Institute at Mount Sinai Hospital, University of Toronto, Toronto M5G 1X5, Ontario, Canada.
  • Department of Haematology & Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
  • Department of Pathology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
  • Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
  • Department of Pediatric Oncology, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
  • Department of Medical Genetics, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature11327

    DOI

    http://dx.doi.org/10.1038/nature11327

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1039022488

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/22832581


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