Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

• Authors: 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.; KALLE Christof von; TURÁNYI Eszter; HAUSER Peter; SANDEN Emma; DARABI Anna; SIESJÖ Peter; ŠTĚRBA Jaroslav; ZITTERBART Karel; SUMERAUER David; SLUIS Peter van; VERSTEEG Rogier; VOLCKMANN Richard; KOSTER Jan; SCHUHMANN Martin U.; EBINGER Martin; GRIMES H. Leighton; ROBINSON Giles W.; GAJJAR Amar; MYNAREK Martin; HOFF Katja von; RUTKOWSKI Stefan; PIETSCH Torsten; SCHEURLEN Wolfram; FELSBERG Jörg; REIFENBERGER Guido; KULOZIK Andreas E.; DEIMLING Andreas von; WITT Olaf; EILS Roland; GILBERTSON Richard J.; KORSHUNOV Andrey; TAYLOR Michael D.; LICHTER Peter; KORBEL Jan O.; WECHSLER-REYA Robert J.; PFISTER Stefan M.
• Year of publication: 2014
• Type: Article in Periodical
• Magazine / Source: Nature
• MU Faculty or unit: Faculty of Medicine
• Doi: http://dx.doi.org/10.1038/nature13379
• Field: Oncology and hematology
• Keywords: ZINC-FINGER PROTEIN; T-CELL LYMPHOMAGENESIS; STEM-CELLS; SUPER-ENHANCERS; CANCER; MUTATIONS; GENOME; GENE; MYC; SUBGROUP
• Description: 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.