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

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.

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Creators:
Northcott, P. A., Author
Lee, C., Author
Zichner, T., Author
Stütz, A. M., Author
Erkek, S., Author
Kawauchi, D., Author
Shih, D. J., Author
Hovestadt, V., Author
Zapatka, M., Author
Sturm, D., Author
Jones, D. T., Author
Kool, M., Author
Remke, M., Author
Cavalli, F. M., Author
Zuyderduyn, S., Author
Bader, G. D., Author
VandenBerg, S., Author
Esparza, L. A., Author
Ryzhova, M., Author
Wang, W., Author
Wittmann, A., AuthorStark, S., AuthorSieber, L., AuthorSeker-Cin, H., AuthorLinke, L., AuthorKratochwil, F., AuthorJager, N., AuthorBuchhalter, I., AuthorImbusch, C. D., AuthorZipprich, G., AuthorRaeder, B., AuthorSchmidt, S., AuthorDiessl, N., AuthorWolf, S., AuthorWiemann, S., AuthorBrors, B., AuthorLawerenz, C., AuthorEils, J., AuthorWarnatz, H.-J.¹, Author Risch, T.¹, Author Yaspo, M. L.², Author Weber, U. D., AuthorBartholomae, C. C., Authorvon Kalle, C., AuthorTuranyi, E., AuthorHauser, P., AuthorSanden, E., AuthorDarabi, A., AuthorSiesjo, P., AuthorSterba, J., AuthorZitterbart, K., AuthorSumerauer, D., Authorvan Sluis, P., AuthorVersteeg, R., AuthorVolckmann, R., AuthorKoster, J., AuthorSchuhmann, M. U., AuthorEbinger, M., AuthorGrimes, H. L., AuthorRobinson, G. W., AuthorGajjar, A., AuthorMynarek, M., Authorvon Hoff, K., AuthorRutkowski, S., AuthorPietsch, T., AuthorScheurlen, W., AuthorFelsberg, J., AuthorReifenberger, G., AuthorKulozik, A. E., Authorvon Deimling, A., AuthorWitt, O., AuthorEils, R., AuthorGilbertson, R. J., AuthorKorshunov, A., AuthorTaylor, M. D., AuthorLichter, P., AuthorKorbel, J. O., AuthorWechsler-Reya, R. J., AuthorPfister, S. M., Author more..

Affiliations:
1Human Chromosome 21 (Marie-Laure Yaspo), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479652
2Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2117287

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Free keywords: Animals Child Chromosomes, Human, Pair 9/genetics DNA-Binding Proteins/*genetics/metabolism Enhancer Elements, Genetic/*genetics Genomic Structural Variation/*genetics Humans Medulloblastoma/classification/*genetics/pathology Mice Oncogenes/*genetics Proto-Oncogene Proteins/*genetics/metabolism Repressor Proteins/*genetics/metabolism Transcription Factors/*genetics/metabolism

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.

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Language(s): eng - English

Dates: Published Online: 2014-06-22Date issued: 2014-07-24

Publication Status: Issued

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Rev. Type: Peer

Identifiers: DOI: 10.1038/nature13379
ISSN: 1476-4687 (Electronic)0028-0836 (Print)

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Title: Nature

Source Genre: Journal

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Publ. Info: London : Nature Publishing Group

Pages: - Volume / Issue: 511 (7510) Sequence Number: - Start / End Page: 428 - 434 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238