Journal Article

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Ebinger, Martin, Mynarek, Martin, Siesjö, Peter, Weber, Ursula D., Sturm, Dominik, Kawauchi, Daisuke, Zuyderduyn, Scott, Diessl, Nicolle, Koster, Jan, Buchhalter, Ivo, Warnatz, Hans-Jörg, Northcott, Paul A., Wolf, Stephan, Rutkowski, Stefan, Kratochwil, Fabian, Korshunov, Andrey, Sterba, Jaroslav, Witt, Olaf, Schuhmann, Martin U., Eils, Roland, Sanden, Emma, Shih, David J. H., Grimes, H. Leighton, Pietsch, Torsten, Lawerenz, Chris, Ryzhova, Marina, Wiemann, Stefan, Bartholomae, Cynthia C., Sumerauer, David, Versteeg, Rogier, Hauser, Peter, Pfister, Stefan M., Esparza, Lourdes Adriana, Schmidt, Sabine, Yaspo, Marie-Laure, Zapatka, Marc, Zitterbart, Karel, Gilbertson, Richard J., Volckmann, Richard, von Deimling, Andreas, Taylor, Michael D., Imbusch, Charles D., Turányi, Eszter, Scheurlen, Wolfram, VandenBerg, Scott, Jäger, Natalie, Korbel, Jan O., Wang, Wei, Sieber, Laura, Stütz, Adrian M., Reifenberger, Guido, Bader, Gary D., Darabi, Anna, Zichner, Thomas, Wechsler-Reya, Robert J., Linke, Linda, Zipprich, Gideon, Cavalli, Florence M. G., von Hoff, Katja, Erkek, Serap, Remke, Marc, van Sluis, Peter, Jones, D

2014

Overview

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. Focusing on two ill-characterized subtypes of medulloblastoma (group 3 and group 4), this study identifies prevalent genomic structural variants that are restricted to these two subtypes and independently bring together coding regions of GFI1 family proto-oncogenes with active enhancer elements, leading to their mutually exclusive oncogenic activation. Oncogenesis through enhancer hijacking Medulloblastoma is a highly malignant paediatric brain tumour. Here the authors focus on two ill-characterized subtypes — group 3 and group 4 — which account for the majority of paediatric cases. They identify prevalent genomic structural variants, which are restricted to these two subtypes, and bring together coding regions of proto-oncogenes, GFI1 and GFI1B , and active enhancer elements leading to oncogene activation. This work identifies 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/100 / 45 / 45/15 / 45/23 / 45/61 / 59/5 / 631/67/69 / 64/60 / Analysis / Animals / Brain tumors / Cancer / Child / Chromosomes, Human, Pair 9 - genetics / Clinical Medicine / Deoxyribonucleic acid / DNA / DNA methylation / DNA sequencing / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Enhancer Elements, Genetic - genetics / Epigenetics / Gene expression / Genomes / Genomic Structural Variation - genetics / Growth factor receptors / Health aspects / Heterogeneity / Humanities and Social Sciences / Humans / Kirurgi / Klinisk medicin / Medical and Health Sciences / Medical research / Medicin och hälsovetenskap / Medulloblastoma / Medulloblastoma - classification / Medulloblastoma - genetics / Medulloblastoma - pathology / Mice / multidisciplinary / Neurologi / Neurology / Nucleotide sequencing / Oncogenes - genetics / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Repressor Proteins - genetics / Repressor Proteins - metabolism / Science / Surgery / Transcription Factors - genetics / Transcription Factors - metabolism