Dissecting the genomic complexity underlying medulloblastoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-08

AUTHORS

David T. W. Jones, Natalie Jäger, Marcel Kool, Thomas Zichner, Barbara Hutter, Marc Sultan, Yoon-Jae Cho, Trevor J. Pugh, Volker Hovestadt, Adrian M. Stütz, Tobias Rausch, Hans-Jörg Warnatz, Marina Ryzhova, Sebastian Bender, Dominik Sturm, Sabrina Pleier, Huriye Cin, Elke Pfaff, Laura Sieber, Andrea Wittmann, Marc Remke, Hendrik Witt, Sonja Hutter, Theophilos Tzaridis, Joachim Weischenfeldt, Benjamin Raeder, Meryem Avci, Vyacheslav Amstislavskiy, Marc Zapatka, Ursula D. Weber, Qi Wang, Bärbel Lasitschka, Cynthia C. Bartholomae, Manfred Schmidt, Christof von Kalle, Volker Ast, Chris Lawerenz, Jürgen Eils, Rolf Kabbe, Vladimir Benes, Peter van Sluis, Jan Koster, Richard Volckmann, David Shih, Matthew J. Betts, Robert B. Russell, Simona Coco, Gian Paolo Tonini, Ulrich Schüller, Volkmar Hans, Norbert Graf, Yoo-Jin Kim, Camelia Monoranu, Wolfgang Roggendorf, Andreas Unterberg, Christel Herold-Mende, Till Milde, Andreas E. Kulozik, Andreas von Deimling, Olaf Witt, Eberhard Maass, Jochen Rössler, Martin Ebinger, Martin U. Schuhmann, Michael C. Frühwald, Martin Hasselblatt, Nada Jabado, Stefan Rutkowski, André O. von Bueren, Dan Williamson, Steven C. Clifford, Martin G. McCabe, V. Peter Collins, Stephan Wolf, Stefan Wiemann, Hans Lehrach, Benedikt Brors, Wolfram Scheurlen, Jörg Felsberg, Guido Reifenberger, Paul A. Northcott, Michael D. Taylor, Matthew Meyerson, Scott L. Pomeroy, Marie-Laure Yaspo, Jan O. Korbel, Andrey Korshunov, Roland Eils, Stefan M. Pfister, Peter Lichter

ABSTRACT

Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients. More... »

PAGES

100

Journal

TITLE

Nature

ISSUE

7409

VOLUME

488

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature11284

DOI

http://dx.doi.org/10.1038/nature11284

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1039302414

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22832583


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943 schema:name Division of Neurosurgery and The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
944 The Arthur and Sonia Labbatt Brain Tumor Research Centre, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
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947 schema:name Department of Pediatric Oncology, Hematology & Immunology, Klinikum Stuttgart Olgahospital, Bismarckstrasse 8, Stuttgart 70176, Germany.
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950 schema:name European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, Heidelberg 69117, Germany.
951 Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, Heidelberg 69117, Germany.
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954 schema:name Cnopf’sche Kinderklinik, Nürnberg Children’s Hospital, St-Johannis-Mühlgasse 19, Nürnberg 90419, Germany.
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957 schema:name Center for Neuropathology and Prion Research, University of Munich, Feodor-Lynen-Strasse 23, Munich 81377, Germany.
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960 schema:name Department of Neurosurgery, Heidelberg University Hospital, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
961 Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany.
962 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
963