Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Paul A. Northcott, Catherine Lee, Thomas Zichner, Adrian M. Stütz, Serap Erkek, Daisuke Kawauchi, David J.H. Shih, Volker Hovestadt, Marc Zapatka, Dominik Sturm, David T.W. Jones, Marcel Kool, Marc Remke, Florence M.G. Cavalli, Scott Zuyderduyn, Gary D. Bader, Scott Vandenberg, Lourdes Adriana Esparza, Marina Ryzhova, Wei WangAndrea Wittmann, Sebastian Stark, Laura Sieber, Huriye Seker-Cin, Linda Linke, Fabian Kratochwil, Natalie Jäger, Ivo Buchhalter, Charles D. Imbusch, Gideon Zipprich, Benjamin Raeder, Sabine Schmidt, Nicolle Diessl, Stephan Wolf, Stefan Wiemann, Benedikt Brors, Chris Lawerenz, Jürgen Eils, Hans Jörg Warnatz, Thomas Risch, Marie Laure Yaspo, Ursula D. Weber, Cynthia C. Bartholomae, Christof Von Kalle, Eszter Turányi, Peter Hauser, Emma Sanden, Anna Darabi, Peter Siesjö, Jaroslav Sterba, Karel Zitterbart, David Sumerauer, Peter Van Sluis, Rogier Versteeg, Richard Volckmann, Jan Koster, Martin U. Schuhmann, Martin Ebinger, H. Leighton Grimes, Giles W. Robinson, Amar Gajjar, Martin Mynarek, Katja Von Hoff, Stefan Rutkowski, Torsten Pietsch, Wolfram Scheurlen, Jörg Felsberg, Guido Reifenberger, Andreas E. Kulozik, Andreas Von Deimling, Olaf Witt, Roland Eils, Richard J. Gilbertson, Andrey Korshunov, Michael D. Taylor, Peter Lichter, Jan O. Korbel, Robert J. Wechsler-Reya, Stefan M. Pfister

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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.

Original languageEnglish
Pages (from-to)428-434
Number of pages7
JournalNature
Volume511
Issue number7510
DOIs
Publication statusPublished - Jan 1 2014

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Northcott, P. A., Lee, C., Zichner, T., Stütz, A. M., Erkek, S., Kawauchi, D., Shih, D. J. H., Hovestadt, V., Zapatka, M., Sturm, D., Jones, D. T. W., Kool, M., Remke, M., Cavalli, F. M. G., Zuyderduyn, S., Bader, G. D., Vandenberg, S., Esparza, L. A., Ryzhova, M., ... Pfister, S. M. (2014). Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature, 511(7510), 428-434. https://doi.org/10.1038/nature13379