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.

] 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]

] 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

] Division of Molecular Genetics German Cancer Research Center Im Neuenheimer Feld 280 Heidelberg 69120 Germany

] Division of Pediatric Neurooncology German Cancer Research Center Genome Biology Unit Meyerhofstrasse 1 Heidelberg 69117 Germany

] Division of Pediatric Neurooncology German Cancer Research Center Im Neuenheimer Feld 280 Heidelberg 69120 Germany [2]

] Division of Pediatric Neurooncology German Cancer Research Center Im Neuenheimer Feld 280 Heidelberg 69120 Germany [2] Department of Pediatric Oncology Hematology and Immunology Heidelberg University Hospital Im Neuenheimer Feld 430 Heidelberg 69120 Germany

] Division of Theoretical Bioinformatics German Cancer Research Center Im Neuenheimer Feld 280 Heidelberg 69120 Germany

] Division of Translational Oncology German Cancer Research Center Im Neuenheimer Feld 280 Heidelberg 69120 Germany

] European Molecular Biology Laboratory Genome Biology Unit Meyerhofstrasse 1 Heidelberg 69117 Germany [2]

] European Molecular Biology Laboratory Wellcome Trust Genome Campus Hinxton Saffron Walden CB10 1SD UK

] 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

] The Arthur and Sonia Labatt Brain Tumor Research Centre The Hospital for Sick Children 555 University Avenue Toronto Ontario M5G 1X8 Canada [2] Division of Neurosurgery The Hospital for Sick Children 555 University Avenue Toronto Ontario M5G 1X8 Canada

1st Department of Pathology and Experimental Cancer Research Semmelweis University SE 2 sz Gyermekklinika Budapest 1094 Hungary

2nd Department of Pediatrics Semmelweis University SE 2 sz Gyermekklinika Budapest 1094 Hungary

Cnopf'sche Kinderklinik Nürnberg Children's Hospital St Johannis Mühlgasse 19 Nürnberg 90419 Germany

Data Management Facility German Cancer Research Center Im Neuenheimer Feld 280 Heidelberg 69120 Germany

Department of Neuropathology Heinrich Heine University Düsseldorf Moorenstrasse 5 Düsseldorf 40225 Germany

Department of Neuropathology NN Burdenko Neurosurgical Institute 4th Tverskaya Yamskaya 16 Moscow 125047 Russia

Department of Neuropathology University of Bonn Sigmund Freud Str 25 Bonn 53105 Germany

Department of Neuropathology University of Heidelberg Im Neuenheimer Feld 220 Heidelberg 69120 Germany

Department of Neurosurgery Tübingen University Hospital Hoppe Seyler Strasse 3 Tübingen 72076 Germany

Department of Oncogenomics AMC University of Amsterdam Meibergdreef 9 Amsterdam 1105 AZ Netherlands

Department of Oncology St Jude Children's Research Hospital 262 Danny Thomas Place Memphis Tennessee 38105 USA

Department of Paediatric Haematology and Oncology University Medical Center Hamburg Eppendorf Martinistrasse 52 Hamburg 20246 Germany

Department of Pathology University of California San Diego 9500 Gilman Drive La Jolla California 92093 USA

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol 5 Úvalu 84 Prague 150 06 Czech Republic

Department of Pediatric Oncology Hematology and Immunology Heidelberg University Hospital Im Neuenheimer Feld 430 Heidelberg 69120 Germany

Department of Pediatric Oncology Masaryk University and University Hospital Brno Cernopolni 9 Brno 613 00 Czech Republic

Department of Vertebrate Genomics Max Planck Institute for Molecular Genetics Ihnestrasse 63 73 Berlin 14195 Germany

Division of Immunobiology Program in Cancer Pathology of the Divisions of Experimental Hematology and Pathology Program in Hematologic Malignancies of the Cancer and Blood Disease Insitute Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati Ohio 452229 USA

Division of Molecular Genetics German Cancer Research Center Im Neuenheimer Feld 280 Heidelberg 69120 Germany

Division of Pediatric Neurooncology German Cancer Research Center Im Neuenheimer Feld 280 Heidelberg 69120 Germany

Division of Theoretical Bioinformatics German Cancer Research Center Im Neuenheimer Feld 280 Heidelberg 69120 Germany

Division of Translational Oncology German Cancer Research Center Im Neuenheimer Feld 460 Heidelberg 69120 Germany

European Molecular Biology Laboratory Genome Biology Unit Meyerhofstrasse 1 Heidelberg 69117 Germany

Genomics and Proteomics Core Facility German Cancer Research Center Im Neuenheimer Feld 280 Heidelberg 69120 Germany

The Arthur and Sonia Labatt Brain Tumor Research Centre The Hospital for Sick Children 555 University Avenue Toronto Ontario M5G 1X8 Canada

The Donnelly Centre University of Toronto 160 College Street Toronto Ontario M5S 3E1 Canada

Tumor Initiation and Maintenance Program Sanford Burnham Medical Research Institute 10901 North Torrey Pines Road La Jolla California 92037 USA

Cancer Cell. 2014 Aug 11;26(2):160-1. doi: 10.1016/j.ccr.2014.07.021. PubMed

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