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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma
Open accessAbstract
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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“studies have shown that the ‘hijacking’ of enhancers can lead to overexpression of oncogenes (for example, growth factor independent 1 family oncogenes (GFI1 and GFI1B)) in medulloblastoma13”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [13]
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Metadata
- Authors
- 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., Wang, W., Wittmann, A., Stark, S., Sieber, L., Seker-Cin, H., Linke, L., Kratochwil, F., Jäger, 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., Turányi, E., Hauser, P., Sanden, E., Darabi, A., Siesjö, 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.
- Affiliations
- German Cancer Research Center (DE)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- European Molecular Biology Laboratory (DE)
- Hospital for Sick Children (CA)
- University of Toronto (CA)
- University of California San Diego (US)
- Burdenko Neurosurgery Institute (RU)
- Max Planck Institute for Molecular Genetics (DE)
- Semmelweis University (HU)
- Lund University (SE)
- Masaryk University (CZ)
- Charles University (CZ)
- Amsterdam UMC Location University of Amsterdam (NL)
- Universitätsklinikum Tübingen (DE)
- Cincinnati Children's Hospital Medical Center (US)
- St. Jude Children's Research Hospital (US)
- University Medical Center Hamburg-Eppendorf (DE)
- University of Bonn (DE)
- Cnopf´sche Kinderklinik (DE)
- Heinrich Heine University Düsseldorf (DE)
- University Hospital Heidelberg (DE)
- Heidelberg University (DE)
- European Bioinformatics Institute (GB)
- Corresponding author
- Lichter, Peter
- Korbel, Jan O.
- Pfister, Stefan M.
- ORCID
- 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.
- Bader, Gary D.
- VandenBerg, Scott
- Esparza, Lourdes Adriana
- Ryzhova, Marina
- Wang, Wei
- Linke, Linda
- Jäger, Natalie
- Buchhalter, Ivo
- Imbusch, Charles D.
- Raeder, Benjamin
- Schmidt, Sabine
- Wiemann, Stefan
- Brors, Benedikt
- Warnatz, Hans-Jörg
- Yaspo, Marie-Laure
- Darabi, Anna
- Siesjö, Peter
- Sumerauer, David
- Versteeg, Rogier
- Volckmann, Richard
- Schuhmann, Martin U.
- Ebinger, Martin
- Grimes, H. Leighton
- Robinson, Giles W.
- Gajjar, Amar
- Mynarek, Martin
- Rutkowski, Stefan
- Pietsch, Torsten
- Felsberg, Jörg
- Reifenberger, Guido
- Kulozik, Andreas E.
- Witt, Olaf
- Eils, Roland
- Gilbertson, Richard J.
- Korshunov, Andrey
- Taylor, Michael D.
- Lichter, Peter
- Korbel, Jan O.
- Pfister, Stefan M.
- Venue
- Nature
- Published
- 2014-06-22
- Volume
- 511
- Issue
- 7510
- Pages
- 428-434
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4201514
- OpenAlex
- W2161535481
- Cited by
- 642
- References
- 47
- Citations by year
- 2026: 26 · 2025: 47 · 2024: 51 · 2023: 59 · 2022: 66 · 2021: 75 · 2020: 62 · 2019: 64 · 2018: 51 · 2017: 49 · 2016: 47 · 2015: 36 · 2014: 6
- FWCI
- 23.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Semmelweis University Repository (Semmelweis University) (submittedVersion)
- Funders
- California Institute for Regenerative Medicine (LA1-01747)
- CureSearch for Children's Cancer
- Deutsches Krebsforschungszentrum
- European Commission (260791)
- Bundesministerium für Bildung und Forschung (01KU1201A, 01GS0883)
- Deutsche Krebshilfe (109252)
- Hospital for Sick Children
- Stichting Kinderen Kankervrij
- Nationales Centrum für Tumorerkrankungen Heidelberg
- Partenariat Canadien Contre Le Cancer
- National Institutes of Health (UL1TR001425, GM 103504)
- University of California, San Diego
- Heidelberger Zentrum für Personalisierte Onkologie Deutsches Krebsforschungszentrum In Der Helmholtz-Gemeinschaft
- National Cancer Institute (R01CA129541, CA159859, P30CA030199, R01CA159859, P01CA096832)
- National Institute of General Medical Sciences (P41GM103504)
- National Center for Research Resources
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- medulloblastoma, enhancer hijacking, GFI1, GFI1B, oncogene activation, super-enhancers, structural variants, Group 3 medulloblastoma, Group 4 medulloblastoma, pediatric brain tumors, oncogenic drivers
- MeSH terms
- Animals, Child, Chromosomes, Human, Pair 9, DNA-Binding Proteins, Enhancer Elements, Genetic, Humans, Medulloblastoma, Oncogenes, Proto-Oncogene Proteins, Repressor Proteins, Transcription Factors, Mice, Genomic Structural Variation
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