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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
Northcott, Paul A; Lee, Catherine; Zichner, Thomas; Stütz, Adrian M; Erkek, Serap; Kawauchi, Daisuke; Shih, David J H; Hovestadt, Volker; Zapatka, Marc; Sturm, Dominik; Jones, David T W; Kool, Marcel; Remke, Marc; Cavalli, Florence M G; Zuyderduyn, Scott; Bader, Gary D; VandenBerg, Scott; Esparza, Lourdes Adriana; Ryzhova, Marina; Wang, Wei; Wittmann, Andrea; Stark, Sebastian; Sieber, Laura; Seker-Cin, Huriye; Linke, Linda; Kratochwil, Fabian; Jäger, Natalie; Buchhalter, Ivo; Imbusch, Charles D; Zipprich, Gideon; Raeder, Benjamin; Schmidt, Sabine; Diessl, Nicolle; Wolf, Stephan; Wiemann, Stefan; Brors, Benedikt; Lawerenz, Chris; Eils, Jürgen; Warnatz, Hans-Jörg; Risch, Thomas; Yaspo, Marie-Laure; Weber, Ursula D; Bartholomae, Cynthia C; von Kalle, Christof; Turányi, Eszter; Hauser, Peter; Sanden, Emma; Darabi, Anna; Siesjö, Peter; Sterba, Jaroslav.
Affiliation
  • Northcott PA; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2].
  • Lee C; 1] Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0685, USA [2] Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA [3].
  • Zichner T; 1] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany [2].
  • Stütz AM; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
  • Erkek S; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
  • Kawauchi D; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Shih DJ; The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
  • Hovestadt V; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Zapatka M; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Sturm D; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Jones DT; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Kool M; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Remke M; The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
  • Cavalli FM; The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
  • Zuyderduyn S; The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
  • Bader GD; The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
  • VandenBerg S; Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
  • Esparza LA; Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
  • Ryzhova M; Department of Neuropathology, NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia.
  • Wang W; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Wittmann A; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Stark S; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Sieber L; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Seker-Cin H; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Linke L; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Kratochwil F; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Jäger N; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Buchhalter I; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Imbusch CD; Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Zipprich G; Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Raeder B; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
  • Schmidt S; Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Diessl N; Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Wolf S; Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Wiemann S; Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Brors B; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Lawerenz C; Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Eils J; Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Warnatz HJ; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany.
  • Risch T; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany.
  • Yaspo ML; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany.
  • Weber UD; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Bartholomae CC; Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
  • von Kalle C; 1] Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • Turányi E; 1st Department of Pathology and Experimental Cancer Research, Semmelweis University SE, II.sz. Gyermekklinika, Budapest 1094, Hungary.
  • Hauser P; 2nd Department of Pediatrics, Semmelweis University, SE, II.sz. Gyermekklinika, Budapest 1094, Hungary.
  • Sanden E; 1] Glioma Immunotherapy Group, Division of Neurosurgery, Lund University, Paradisgatan 2, Lund 221 00, Sweden [2] Department of Clinical Sciences, Lund University, Paradisgatan 2, Lund 221 00, Sweden.
  • Darabi A; 1] Glioma Immunotherapy Group, Division of Neurosurgery, Lund University, Paradisgatan 2, Lund 221 00, Sweden [2] Department of Clinical Sciences, Lund University, Paradisgatan 2, Lund 221 00, Sweden.
  • Siesjö P; 1] Glioma Immunotherapy Group, Division of Neurosurgery, Lund University, Paradisgatan 2, Lund 221 00, Sweden [2] Department of Clinical Sciences, Lund University, Paradisgatan 2, Lund 221 00, Sweden.
  • Sterba J; Department of Pediatric Oncology, Masaryk University and University Hospital, Brno, Cernopolni 9 Brno 613 00, Czech Republic.
Nature ; 511(7510): 428-34, 2014 Jul 24.
Article in En | MEDLINE | ID: mdl-25043047
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oncogenes / Repressor Proteins / Transcription Factors / Proto-Oncogene Proteins / Enhancer Elements, Genetic / DNA-Binding Proteins / Genomic Structural Variation / Medulloblastoma Type of study: Prognostic_studies Limits: Animals / Child / Humans Language: En Journal: Nature Year: 2014 Document type: Article Country of publication: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oncogenes / Repressor Proteins / Transcription Factors / Proto-Oncogene Proteins / Enhancer Elements, Genetic / DNA-Binding Proteins / Genomic Structural Variation / Medulloblastoma Type of study: Prognostic_studies Limits: Animals / Child / Humans Language: En Journal: Nature Year: 2014 Document type: Article Country of publication: United kingdom