Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Paul A. Northcott, Catherine Lee, Thomas Zichner, Adrian M. Stütz, Serap Erkek, Daisuke Kawauchi, David J. H. Shih, Volker Hovestadt, Marc Zapatka, Dominik Sturm, David T. W. Jones, Marcel Kool, Marc Remke, Florence M. G. Cavalli, Scott Zuyderduyn, Gary D. Bader, Scott VandenBerg, Lourdes Adriana Esparza, Marina Ryzhova, Wei Wang, Andrea Wittmann, Sebastian Stark, Laura Sieber, Huriye Seker-Cin, Linda Linke, Fabian Kratochwil, Natalie Jäger, Ivo Buchhalter, Charles D. Imbusch, Gideon Zipprich, Benjamin Raeder, Sabine Schmidt, Nicolle Diessl, Stephan Wolf, Stefan Wiemann, Benedikt Brors, Chris Lawerenz, Jürgen Eils, Hans-Jörg Warnatz, Thomas Risch, Marie-Laure Yaspo, Ursula D. Weber, Cynthia C. Bartholomae, Christof von Kalle, Eszter Turányi, Peter Hauser, Emma Sanden, Anna Darabi, Peter Siesjö, Jaroslav Sterba, Karel Zitterbart, David Sumerauer, Peter van Sluis, Rogier Versteeg, Richard Volckmann, Jan Koster, Martin U. Schuhmann, Martin Ebinger, H. Leighton Grimes, Giles W. Robinson, Amar Gajjar, Martin Mynarek, Katja von Hoff, Stefan Rutkowski, Torsten Pietsch, Wolfram Scheurlen, Jörg Felsberg, Guido Reifenberger, Andreas E. Kulozik, Andreas von Deimling, Olaf Witt, Roland Eils, Richard J. Gilbertson, Andrey Korshunov, Michael D. Taylor, Peter Lichter (), Jan O. Korbel (), Robert J. Wechsler-Reya () and Stefan M. Pfister ()
Additional contact information
Paul A. Northcott: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Catherine Lee: Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0685, USA
Thomas Zichner: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany
Adrian M. Stütz: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany
Serap Erkek: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Daisuke Kawauchi: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
David J. H. Shih: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
Volker Hovestadt: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Marc Zapatka: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Dominik Sturm: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
David T. W. Jones: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Marcel Kool: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Marc Remke: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
Florence M. G. Cavalli: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
Scott Zuyderduyn: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
Gary D. Bader: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
Scott VandenBerg: University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
Lourdes Adriana Esparza: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
Marina Ryzhova: NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia
Wei Wang: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Andrea Wittmann: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Sebastian Stark: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Laura Sieber: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Huriye Seker-Cin: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Linda Linke: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Fabian Kratochwil: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Natalie Jäger: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Ivo Buchhalter: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Charles D. Imbusch: Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Gideon Zipprich: Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Benjamin Raeder: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany
Sabine Schmidt: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Nicolle Diessl: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Stephan Wolf: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Stefan Wiemann: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Benedikt Brors: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Chris Lawerenz: Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Jürgen Eils: Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Hans-Jörg Warnatz: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany
Thomas Risch: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany
Marie-Laure Yaspo: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany
Ursula D. Weber: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Cynthia C. Bartholomae: German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany
Christof von Kalle: German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany
Eszter Turányi: Semmelweis University SE, II.sz. Gyermekklinika, Budapest 1094, Hungary
Peter Hauser: Semmelweis University, SE, II.sz. Gyermekklinika, Budapest 1094, Hungary
Emma Sanden: Glioma Immunotherapy Group, Lund University, Paradisgatan 2, Lund 221 00, Sweden
Anna Darabi: Glioma Immunotherapy Group, Lund University, Paradisgatan 2, Lund 221 00, Sweden
Peter Siesjö: Glioma Immunotherapy Group, Lund University, Paradisgatan 2, Lund 221 00, Sweden
Jaroslav Sterba: Masaryk University and University Hospital, Brno, Cernopolni 9 Brno 613 00, Czech Republic
Karel Zitterbart: Masaryk University and University Hospital, Brno, Cernopolni 9 Brno 613 00, Czech Republic
David Sumerauer: 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, Prague 150 06, Czech Republic
Peter van Sluis: AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands
Rogier Versteeg: AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands
Richard Volckmann: AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands
Jan Koster: AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands
Martin U. Schuhmann: Tübingen University Hospital, Hoppe-Seyler Strasse 3, Tübingen 72076, Germany
Martin Ebinger: Tübingen University Hospital, Hoppe-Seyler Strasse 3, Tübingen 72076, Germany
H. Leighton Grimes: Program in Hematologic Malignancies of the Cancer and Blood Disease Insitute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 452229, USA
Giles W. Robinson: St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA
Amar Gajjar: St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA
Martin Mynarek: University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany
Katja von Hoff: University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany
Stefan Rutkowski: University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany
Torsten Pietsch: University of Bonn, Sigmund-Freud-Str. 25, Bonn 53105, Germany
Wolfram Scheurlen: Cnopf'sche Kinderklinik, Nürnberg Children’s Hospital, St-Johannis-Mühlgasse 19, Nürnberg 90419, Germany
Jörg Felsberg: Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany
Guido Reifenberger: Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany
Andreas E. Kulozik: Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany
Andreas von Deimling: University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany
Olaf Witt: Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany
Roland Eils: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Richard J. Gilbertson: St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA
Andrey Korshunov: University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany
Michael D. Taylor: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
Peter Lichter: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
Jan O. Korbel: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany
Robert J. Wechsler-Reya: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
Stefan M. Pfister: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany

Nature, 2014, vol. 511, issue 7510, 428-434

Abstract: Abstract Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate ‘enhancer hijacking’ as an efficient mechanism driving oncogene activation in a childhood cancer.

Date: 2014
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DOI: 10.1038/nature13379

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