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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.

Northcott, Paul A; Lee, Catherine; Zichner, Thomas; Stütz, Adrian M; Erkek, Serap; Kawauchi, Daisuke; Shih, David J H; Hovestadt, Volker; Zapatka, Marc and Sturm, Dominik, et al. (2014) In Nature 511(7510). p.428-428
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... (More)
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. (Less)
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Nature
volume
511
issue
7510
pages
428 - 428
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Nature Publishing Group
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  • pmid:25043047
  • wos:000339335700038
  • scopus:84904816744
ISSN
0028-0836
DOI
10.1038/nature13379
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English
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yes
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c6ef0dc4-cc87-41d1-bbc2-a077c8f660ad (old id 4581678)
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http://www.ncbi.nlm.nih.gov/pubmed/25043047?dopt=Abstract
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2014-08-08 21:12:41
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@article{c6ef0dc4-cc87-41d1-bbc2-a077c8f660ad,
  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.},
  author       = {Northcott, Paul A and Lee, Catherine and Zichner, Thomas and Stütz, Adrian M and Erkek, Serap and Kawauchi, Daisuke and Shih, David J H and Hovestadt, Volker and Zapatka, Marc and Sturm, Dominik and Jones, David T W and Kool, Marcel and Remke, Marc and Cavalli, Florence M G and Zuyderduyn, Scott and Bader, Gary D and VandenBerg, Scott and Esparza, Lourdes Adriana and Ryzhova, Marina and Wang, Wei and Wittmann, Andrea and Stark, Sebastian and Sieber, Laura and Seker-Cin, Huriye and Linke, Linda and Kratochwil, Fabian and Jäger, Natalie and Buchhalter, Ivo and Imbusch, Charles D and Zipprich, Gideon and Raeder, Benjamin and Schmidt, Sabine and Diessl, Nicolle and Wolf, Stephan and Wiemann, Stefan and Brors, Benedikt and Lawerenz, Chris and Eils, Jürgen and Warnatz, Hans-Jörg and Risch, Thomas and Yaspo, Marie-Laure and Weber, Ursula D and Bartholomae, Cynthia C and von Kalle, Christof and Turányi, Eszter and Hauser, Peter and Sandén, Emma and Darabi, Anna and Siesjö, Peter and Sterba, Jaroslav and Zitterbart, Karel and Sumerauer, David and van Sluis, Peter and Versteeg, Rogier and Volckmann, Richard and Koster, Jan and Schuhmann, Martin U and Ebinger, Martin and Grimes, H Leighton and Robinson, Giles W and Gajjar, Amar and Mynarek, Martin and von Hoff, Katja and Rutkowski, Stefan and Pietsch, Torsten and Scheurlen, Wolfram and Felsberg, Jörg and Reifenberger, Guido and Kulozik, Andreas E and von Deimling, Andreas and Witt, Olaf and Eils, Roland and Gilbertson, Richard J and Korshunov, Andrey and Taylor, Michael D and Lichter, Peter and Korbel, Jan O and Wechsler-Reya, Robert J and Pfister, Stefan M},
  issn         = {0028-0836},
  language     = {eng},
  number       = {7510},
  pages        = {428--428},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.},
  url          = {http://dx.doi.org/10.1038/nature13379},
  volume       = {511},
  year         = {2014},
}