Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
Northcott, Paul A. 1,*; Lee, Catherine 2,3,*; Zichner, Thomas 4,*; Stutz, Adrian M. 4; Erkek, Serap 1,4; Kawauchi, Daisuke 1; Shih, David J. H. 5; Hovestadt, Volker 6; Zapatka, Marc 6; Sturm, Dominik 1; Jones, David T. W. 1; Kool, Marcel 1; Remke, Marc 5; Cavalli, Florence M. G. 5; Zuyderduyn, Scott 7; Bader, Gary D. 7; VandenBerg, Scott 8; Esparza, Lourdes Adriana 3; Ryzhova, Marina 9; Wang, Wei 6; Wittmann, Andrea 1; Stark, Sebastian 1; Sieber, Laura 1; Seker-Cin, Huriye 1; Linke, Linda 1; Kratochwil, Fabian 1; Jager, Natalie 10; Buchhalter, Ivo 10; Imbusch, Charles D. 11; Zipprich, Gideon 11; Raeder, Benjamin 4; Schmidt, Sabine 12; Diessl, Nicolle 12; Wolf, Stephan 12; Wiemann, Stefan 12; Brors, Benedikt 10; Lawerenz, Chris 11; Eils, Jurgen 11; Warnatz, Hans-Jorg 13; Risch, Thomas 13; Yaspo, Marie-Laure 13; Weber, Ursula D. 6; Bartholomae, Cynthia C. 14; von Kalle, Christof 14,15; Turanyi, Eszter 16; Hauser, Peter 17; Sanden, Emma 18,19; Darabi, Anna 18,19; Siesjo, Peter 18,19; Sterba, Jaroslav 20; Zitterbart, Karel 20; Sumerauer, David 21; van Sluis, Peter 22; Versteeg, Rogier 22; Volckmann, Richard 22; Koster, Jan 22; Schuhmann, Martin U. 23; Ebinger, Martin 23; Grimes, Leighton H. 24; Robinson, Giles W. 25,26; Gajjar, Amar 26; Mynarek, Martin 27; von Hoff, Katja 27; Rutkowski, Stefan 27; Pietsch, Torsten 28; Scheurlen, Wolfram 29; Felsberg, Jorg 30; Reifenberger, Guido 30; Kulozik, Andreas E. 31; von Deimling, Andreas 32; Witt, Olaf 31; Eils, Roland 10,15; Gilbertson, Richard J. 25,26; Korshunov, Andrey 32; Taylor, Michael D. 5,33; Lichter, Peter 6,15; Korbel, Jan O. 4,34; Wechsler-Reya, Robert J. 3; Pfister, Stefan M. 1,31
[Article]
Nature.
511(7510):428-434, July 24, 2014.
(Format: HTML, PDF)
: 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.
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