EGAGenomicsIllumina HiSeq 2000, Illumina Genome Analyzer IIxhttps://ega-archive.org/datasets/EGAD00001000122206EGA dataset EGAD00001000122EGAMedulloblastoma 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.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.Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.Dissecting the genomic complexity underlying medulloblastoma.Northcott Paul A PA, Lee Catherine C, Zichner Thomas T, Stütz Adrian M AM, Erkek Serap S, Kawauchi Daisuke D, Shih David J H DJ, Hovestadt Volker V, Zapatka Marc M, Sturm Dominik D, Jones David T W DT, Kool Marcel M, Remke Marc M, Cavalli Florence M G FM, Zuyderduyn Scott S, Bader Gary D GD, VandenBerg Scott S, Esparza Lourdes Adriana LA, Ryzhova Marina M, Wang Wei W, Wittmann Andrea A, Stark Sebastian S, Sieber Laura L, Seker-Cin Huriye H, Linke Linda L, Kratochwil Fabian F, Jäger Natalie N, Buchhalter Ivo I, Imbusch Charles D CD, Zipprich Gideon G, Raeder Benjamin B, Schmidt Sabine S, Diessl Nicolle N, Wolf Stephan S, Wiemann Stefan S, Brors Benedikt B, Lawerenz Chris C, Eils Jürgen J, Warnatz Hans-Jörg HJ, Risch Thomas T, Yaspo Marie-Laure ML, Weber Ursula D UD, Bartholomae Cynthia C CC, von Kalle Christof C, Turányi Eszter E, Hauser Peter P, Sanden Emma E, Darabi Anna A, Siesjö Peter P, Sterba Jaroslav J, Zitterbart Karel K, Sumerauer David D, van Sluis Peter P, Versteeg Rogier R, Volckmann Richard R, Koster Jan J, Schuhmann Martin U MU, Ebinger Martin M, Grimes H Leighton HL, Robinson Giles W GW, Gajjar Amar A, Mynarek Martin M, von Hoff Katja K, Rutkowski Stefan S, Pietsch Torsten T, Scheurlen Wolfram W, Felsberg Jörg J, Reifenberger Guido G, Kulozik Andreas E AE, von Deimling Andreas A, Witt Olaf O, Eils Roland R, Gilbertson Richard J RJ, Korshunov Andrey A, Taylor Michael D MD, Lichter Peter P, Korbel Jan O JO, Wechsler-Reya Robert J RJ, Pfister Stefan M SMJones David T W DT, Jäger Natalie N, Kool Marcel M, Zichner Thomas T, Hutter Barbara B, Sultan Marc M, Cho Yoon-Jae YJ, Pugh Trevor J TJ, Hovestadt Volker V, Stütz Adrian M AM, Rausch Tobias T, Warnatz Hans-Jörg HJ, Ryzhova Marina M, Bender Sebastian S, Sturm Dominik D, Pleier Sabrina S, Cin Huriye H, Pfaff Elke E, Sieber Laura L, Wittmann Andrea A, Remke Marc M, Witt Hendrik H, Hutter Sonja S, Tzaridis Theophilos T, Weischenfeldt Joachim J, Raeder Benjamin B, Avci Meryem M, Amstislavskiy Vyacheslav V, Zapatka Marc M, Weber Ursula D UD, Wang Qi Q, Lasitschka Bärbel B, Bartholomae Cynthia C CC, Schmidt Manfred M, von Kalle Christof C, Ast Volker V, Lawerenz Chris C, Eils Jürgen J, Kabbe Rolf R, Benes Vladimir V, van Sluis Peter P, Koster Jan J, Volckmann Richard R, Shih David D, Betts Matthew J MJ, Russell Robert B RB, Russell Robert B RB, Coco Simona S, Tonini Gian Paolo GP, Schüller Ulrich U, Hans Volkmar V, Graf Norbert N, Kim Yoo-Jin YJ, Monoranu Camelia C, Roggendorf Wolfgang W, Unterberg Andreas A, Herold-Mende Christel C, Milde Till T, Kulozik Andreas E AE, von Deimling Andreas A, Witt Olaf O, Maass Eberhard E, Rössler Jochen J, Ebinger Martin M, Schuhmann Martin U MU, Frühwald Michael C MC, Hasselblatt Martin M, Jabado Nada N, Rutkowski Stefan S, von Bueren André O AO, Williamson Dan D, Clifford Steven C SC, McCabe Martin G MG, Collins V Peter VP, Wolf Stephan S, Wiemann Stefan S, Lehrach Hans H, Brors Benedikt B, Scheurlen Wolfram W, Felsberg Jörg J, Reifenberger Guido G, Northcott Paul A PA, Taylor Michael D MD, Meyerson Matthew M, Pomeroy Scott L SL, Yaspo Marie-Laure ML, Korbel Jan O JO, Korshunov Andrey A, Eils Roland R, Pfister Stefan M SM, Lichter Peter Pphapii, IPP2A2, localized primitive neuroectodermal tumor, MDB, Arachnoidal Cerebellar Sarcoma, cerebellar medulloblastoma, igaad, StF-IT-1, desmoplastic, medulloblastoma with extensive nodularity, CNS PNET, Melanocytic, PHAPII, group, 5730420M11Rik, medulloblastoma, CPNET, I-2PP2A, Dm I-2, I2PP2A, Circumscribed Arachnoidal, Medullomyoblastomas, Medulloblastoma, Cerebellar, infratentorial primitive neuroectodermal tumour, Desmoplastic Medulloblastomas, Medulloblastomas, SET, HLA-DR-associated protein II, ensemble, DI-2, TAF-I, Circumscribed, Desmoplastic, I-2Dm, ipp2a2, 2pp2a, CG4299, Childhood, Adult Medulloblastomas, Adult Medulloblastoma, Adult, Melanocytic Medulloblastomas, localised primitive neuroectodermal tumour, CG10574, DmelCG4299, I-2PP1, IGAAD, set, dSET/TAF-Ibeta, Sarcoma, childhood, 2610030F17Rik, infratentorial primitive neuroectodermal tumor, Medullomyoblastoma, TAF-IBETA, 2PP2A, DmelCG10574, taf-ibeta, Childhood Medulloblastoma, dSET, dSet, TAF-Ibeta, AA407739, i2pp2a, Childhood Medulloblastomas, Melanocytic Medulloblastoma, Desmoplastic Medulloblastoma.phapii, IPP2A2, localized primitive neuroectodermal tumor, MDB, Arachnoidal Cerebellar Sarcoma, cerebellar medulloblastoma, igaad, StF-IT-1, desmoplastic, medulloblastoma with extensive nodularity, CNS PNET, Melanocytic, PHAPII, group, 5730420M11Rik, medulloblastoma, CPNET, I-2PP2A, Dm I-2, I2PP2A, Circumscribed Arachnoidal, Medullomyoblastomas, Medulloblastoma, Cerebellar, infratentorial primitive neuroectodermal tumour, Desmoplastic Medulloblastomas, Medulloblastomas, SET, HLA-DR-associated protein II, ensemble, DI-2, TAF-I, Circumscribed, Desmoplastic, I-2Dm, ipp2a2, 2pp2a, CG4299, Childhood, Adult Medulloblastomas, Adult Medulloblastoma, Adult, Melanocytic Medulloblastomas, localised primitive neuroectodermal tumour, CG10574, DmelCG4299, I-2PP1, IGAAD, set, dSET/TAF-Ibeta, Sarcoma, childhood, 2610030F17Rik, infratentorial primitive neuroectodermal tumor, Medullomyoblastoma, TAF-IBETA, 2PP2A, DmelCG10574, taf-ibeta, Childhood Medulloblastoma, dSET, dSet, TAF-Ibeta, AA407739, i2pp2a, Childhood Medulloblastomas, Melanocytic Medulloblastoma, Desmoplastic Medulloblastoma.Networks, AW495828, Family Member, Kinship, Family Research, localized primitive neuroectodermal tumor, MDB, Arachnoidal Cerebellar Sarcoma, cerebellar medulloblastoma, Gene, Network, desmoplastic, medulloblastoma with extensive nodularity, CNS PNET, Melanocytic, Family Members, ZNF163, medulloblastoma, CPNET, Circumscribed Arachnoidal, Medullomyoblastomas, Life Cycle, Pal1, Transforming, Medulloblastoma, Filiation, Cerebellar, infratentorial primitive neuroectodermal tumour, Desmoplastic Medulloblastomas, INSDC_feature:regulatory, Family Life Cycle, Medulloblastomas, Genes, Kinship Network, Transforming Gene, Pal-1, Research, Circumscribed, Desmoplastic, SCN2, Childhood, Adult Medulloblastomas, Adult Medulloblastoma, Adult, Melanocytic Medulloblastomas, localised primitive neuroectodermal tumour, Life Cycles, Sarcoma, childhood, Transforming Genes, Oncogene, infratentorial primitive neuroectodermal tumor, Medullomyoblastoma, GFI-1, Families, Childhood Medulloblastoma, GFI1A, Gfi-1, Kinship Networks, Family Life Cycles, Family, Relatives, Childhood Medulloblastomas, Melanocytic Medulloblastoma, Desmoplastic Medulloblastoma.Structural Variations, Networks, Enhancer, Kinship, Activity, Laboratory, Brain Neoplasms, Mus domesticus, cerebellar medulloblastoma, desmoplastic, pitslre, Tumor, Genetic Enhancer Element, House Mouse, cdc, ZNF163, CPNET, INTRACRANIAL NEOPL, Circumscribed Arachnoidal, l(2)31Eh, Medullomyoblastomas, Life Cycle, Transforming, Medulloblastoma, tumour of brain, preoperative procedures, infratentorial primitive neuroectodermal tumour, Desmoplastic Medulloblastomas, Medulloblastomas, Family Life Cycle, Dmcdc2, Growth, Kinship Network, brain neoplasms, Elements, Comparative Genomics, Genetic Enhancer, Childhood Cancer, Swiss Mice, Brain Tumor, Adult Medulloblastomas, Adult, Melanocytic Medulloblastomas, Peptide Factors, Sarcoma, childhood, Transforming Genes, cdc2Dm, GFI-1, neoplasm of brain, cdk11, CG5363, dCdk1, Recurrent Brain Tumor, Cdc2, CDC2, Therapies, CG4268, Gfi-1, house mouse, Family Life Cycles, Paracrine, Dm cdc2, Tumors, Therapy, Genomics, Intracranial Neoplasm, brain neoplasm, cHILD, localized primitive neuroectodermal tumor, pediatric interstitial lung disease, Comparative, mouse, Functional 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CHILD, Functional, Variant, Paracrine Protein Factors, Mus musculus domesticus, Pal1, Growth Factor, interstitial lung disease of childhood, Medical, Mice, Drug Therapies, Clinical, Genetic, Transforming Gene, tumour of the Brain, Research, Swiss, Medical Coding, Genomic Structural Variant, paediatric interstitial lung disease, chILD, Gfi-1B, juvenile stage, PRIMARY BRAIN NEOPL, CDK1/CDC2, cdk1, Genomic Structural Variants, Enhancer Elements, childhood interstitial lung disease, Proto-Oncogene, toxic potential, operative procedures, Kinship Networks, CDK1, Dcdc2, Cdk1, Family, Childhood Medulloblastomas, Variation, Genome Structural Variants, tumor of brain, NEOPL INTRACRANIAL, AW495828, Genome Structural Variations, Variations, Family Research, MDB, intraoperative procedures, Factor, medulloblastoma with extensive nodularity, Melanocytic, Family Members, Sequences, medulloblastoma, peroperative procedures, Mus, Sequence, group 4, group 3, Neoplasm, Genetic Enhancer Elements, DmCdk1, INSDC_feature:regulatory, Intracranial Neoplasms, Radiations, 5363, Proto Oncogene, brain neoplasm (disease), Genes, Structural Variation, Pal-1, Desmoplastic, operative therapy, Genome Structural, SCN2, operations, chILD syndrome, House Mice, Childhood, Adult Medulloblastoma, localised primitive neuroectodermal tumour, Laboratory Mice, Drug, infratentorial primitive neuroectodermal tumor, Medullomyoblastoma, children's interstitial lung disease, Families, Enhancer Sequences, perioperative procedures, Variants, Structural Genomics, pharmacologic therapy, brain tumour, Genome Structural Variation, Relatives, CDCDm, General activity, Laboratory Mouse, Genome, Melanocytic MedulloblastomafalseDATA_SET_ICGC_PedBrainTumor_Medulloblastoma_Discovery_Cohort - samplesDATA_SET_ICGC_PedBrainTumor_Medulloblastoma2019-10-31 12:52:09EGAD0000100012296062283258325043047EGAC00001000010EGAS00001000215