title: Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
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.
authors.affiliation: 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2].
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authors.initials: PA
authors.lastname: Northcott
authors.affiliation: 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].
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authors.affiliation: 1] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany [2].
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authors.lastname: Zichner
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Stütz
authors.affiliation: 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.
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authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Daisuke
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authors.lastname: Kawauchi
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
authors.forename: David J H
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authors.lastname: Shih
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Volker
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authors.lastname: Hovestadt
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Marc
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authors.lastname: Zapatka
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Dominik
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authors.lastname: Sturm
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
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authors.lastname: Jones
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Marcel
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authors.lastname: Kool
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
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authors.lastname: Remke
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Florence M G
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authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
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authors.lastname: Zuyderduyn
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
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authors.affiliation: Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
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authors.affiliation: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Lourdes Adriana
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authors.lastname: Esparza
authors.affiliation: Department of Neuropathology, NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia.
authors.forename: Marina
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authors.lastname: Ryzhova
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Wei
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authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Andrea
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authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Sebastian
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authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Laura
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authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Huriye
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authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Linda
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authors.lastname: Linke
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Fabian
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authors.lastname: Kratochwil
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Natalie
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authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Ivo
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authors.affiliation: Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Charles D
authors.initials: CD
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authors.affiliation: Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
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authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
authors.forename: Benjamin
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authors.lastname: Raeder
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Sabine
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authors.lastname: Schmidt
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Nicolle
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authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
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authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
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authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
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authors.affiliation: Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
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authors.affiliation: Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
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authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany.
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Warnatz
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany.
authors.forename: Thomas
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authors.lastname: Risch
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Yaspo
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
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authors.affiliation: Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
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authors.affiliation: 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.
authors.forename: Christof
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authors.affiliation: Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands.
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authors.affiliation: Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands.
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authors.affiliation: Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands.
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authors.affiliation: Department of Neurosurgery, Tübingen University Hospital, Hoppe-Seyler Strasse 3, Tübingen 72076, Germany.
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authors.affiliation: 1] Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA [2] Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
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authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
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authors.affiliation: Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany.
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authors.affiliation: Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany.
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authors.affiliation: Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany.
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authors.affiliation: Department of Neuropathology, University of Bonn, Sigmund-Freud-Str. 25, Bonn 53105, Germany.
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authors.affiliation: Cnopf'sche Kinderklinik, Nürnberg Children's Hospital, St-Johannis-Mühlgasse 19, Nürnberg 90419, Germany.
authors.forename: Wolfram
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authors.affiliation: Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany.
authors.forename: Jörg
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authors.lastname: Felsberg
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authors.affiliation: Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany.
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authors.affiliation: Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany.
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authors.affiliation: Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany.
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authors.affiliation: Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany.
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authors.lastname: Korshunov
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authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: 1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: 1] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany [2] EMBL, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1SD, UK.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
authors.affiliation: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
authors.affiliation: 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
mesh_terms: D000818:Animals; D002648:Child; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D056914:Genomic Structural Variation / Q000235:genetics*; D006801:Humans; D008527:Medulloblastoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009857:Oncogenes / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; C111977:GFI1B protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors