Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Northcott, P. A.; Lee, C.; Zichner, T.; Stütz, A. M.; Erkek, S.; Kawauchi, D.; Shih, D. J.; Hovestadt, V.; Zapatka, M.; Sturm, D.; Jones, D. T.; Kool, M.; Remke, M.; Cavalli, F. M.; Zuyderduyn, S.; Bader, G. D.; VandenBerg, S.; Esparza, L. A.; Ryzhova, M.; Wang, W.; Wittmann, A.; Stark, S.; Sieber, L.; Seker-Cin, H.; Linke, L.; Kratochwil, F.; Jager, N.; Buchhalter, I.; Imbusch, C. D.; Zipprich, G.; Raeder, B.; Schmidt, S.; Diessl, N.; Wolf, S.; Wiemann, S.; Brors, B.; Lawerenz, C.; Eils, J.; Warnatz, H.-J.; Risch, T.; Yaspo, M. L.; Weber, U. D.; Bartholomae, C. C.; von Kalle, C.; Turanyi, E.; Hauser, P.; Sanden, E.; Darabi, A.; Siesjo, P.; Sterba, J.; Zitterbart, K.; Sumerauer, D.; van Sluis, P.; Versteeg, R.; Volckmann, R.; Koster, J.; Schuhmann, M. U.; Ebinger, M.; Grimes, H. L.; Robinson, G. W.; Gajjar, A.; Mynarek, M.; von Hoff, K.; Rutkowski, S.; Pietsch, T.; Scheurlen, W.; Felsberg, J.; Reifenberger, G.; Kulozik, A. E.; von Deimling, A.; Witt, O.; Eils, R.; Gilbertson, R. J.; Korshunov, A.; Taylor, M. D.; Lichter, P.; Korbel, J. O.; Wechsler-Reya, R. J.; Pfister, S. M.

doi:10.1038/nature13379

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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

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Warnatz, H.-J.
Human Chromosome 21 (Marie-Laure Yaspo), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Risch, T.
Human Chromosome 21 (Marie-Laure Yaspo), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Yaspo, M. L.
Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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http://www.ncbi.nlm.nih.gov/pubmed/25043047
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Zitation

Northcott, P. A., Lee, C., Zichner, T., Stütz, A. M., Erkek, S., Kawauchi, D., et al. (2014). Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature, 511(7510), 428-434. doi:10.1038/nature13379.

Zitierlink: https://hdl.handle.net/11858/00-001M-0000-0025-B56E-2

Zusammenfassung

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.