Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma
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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; Sturm, Dominik; Jones, David T W; Kool, Marcel; Remke, Marc; Cavalli, Florence M G; Zuyderduyn, Scott; Bader, Gary D; VandenBerg, Scott; Esparza, Lourdes Adriana; Ryzhova, Marina; Wang, Wei; Wittmann, Andrea; Stark, Sebastian; Sieber, Laura; Seker-Cin, Huriye; Linke, Linda; Kratochwil, Fabian; Jäger, Natalie; Buchhalter, Ivo; Imbusch, Charles D; Zipprich, Gideon; Raeder, Benjamin; Schmidt, Sabine; Diessl, Nicolle; Wolf, Stephan; Wiemann, Stefan; Brors, Benedikt; Lawerenz, Chris; Eils, Jürgen; Warnatz, Hans-Jörg; Risch, Thomas; Yaspo, Marie-Laure; Weber, Ursula D; Bartholomae, Cynthia C; von Kalle, Christof; Turányi, Eszter; Hauser, Peter; Sanden, Emma; Darabi, Anna; Siesjö, Peter; Sterba, Jaroslav; Zitterbart, Karel; Sumerauer, David; van Sluis, Peter; Versteeg, Rogier; Volckmann, Richard; Koster, Jan; Schuhmann, Martin U; Ebinger, Martin; Grimes, H Leighton; Robinson, Giles W; Gajjar, Amar; Mynarek, Martin; von Hoff, Katja; Rutkowski, Stefan; Pietsch, Torsten; Scheurlen, Wolfram; Felsberg, Jörg; Reifenberger, Guido; Kulozik, Andreas E; von Deimling, Andreas; Witt, Olaf; Eils, Roland; Gilbertson, Richard J; Korshunov, Andrey; Taylor, Michael D; Lichter, Peter; Korbel, Jan O; Wechsler-Reya, Robert J; Pfister, Stefan M.
in: NATURE, Jahrgang 511, Nr. 7510, 24.07.2014, S. 428-434.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma
AU - Northcott, Paul A
AU - Lee, Catherine
AU - Zichner, Thomas
AU - Stütz, Adrian M
AU - Erkek, Serap
AU - Kawauchi, Daisuke
AU - Shih, David J H
AU - Hovestadt, Volker
AU - Zapatka, Marc
AU - Sturm, Dominik
AU - Jones, David T W
AU - Kool, Marcel
AU - Remke, Marc
AU - Cavalli, Florence M G
AU - Zuyderduyn, Scott
AU - Bader, Gary D
AU - VandenBerg, Scott
AU - Esparza, Lourdes Adriana
AU - Ryzhova, Marina
AU - Wang, Wei
AU - Wittmann, Andrea
AU - Stark, Sebastian
AU - Sieber, Laura
AU - Seker-Cin, Huriye
AU - Linke, Linda
AU - Kratochwil, Fabian
AU - Jäger, Natalie
AU - Buchhalter, Ivo
AU - Imbusch, Charles D
AU - Zipprich, Gideon
AU - Raeder, Benjamin
AU - Schmidt, Sabine
AU - Diessl, Nicolle
AU - Wolf, Stephan
AU - Wiemann, Stefan
AU - Brors, Benedikt
AU - Lawerenz, Chris
AU - Eils, Jürgen
AU - Warnatz, Hans-Jörg
AU - Risch, Thomas
AU - Yaspo, Marie-Laure
AU - Weber, Ursula D
AU - Bartholomae, Cynthia C
AU - von Kalle, Christof
AU - Turányi, Eszter
AU - Hauser, Peter
AU - Sanden, Emma
AU - Darabi, Anna
AU - Siesjö, Peter
AU - Sterba, Jaroslav
AU - Zitterbart, Karel
AU - Sumerauer, David
AU - van Sluis, Peter
AU - Versteeg, Rogier
AU - Volckmann, Richard
AU - Koster, Jan
AU - Schuhmann, Martin U
AU - Ebinger, Martin
AU - Grimes, H Leighton
AU - Robinson, Giles W
AU - Gajjar, Amar
AU - Mynarek, Martin
AU - von Hoff, Katja
AU - Rutkowski, Stefan
AU - Pietsch, Torsten
AU - Scheurlen, Wolfram
AU - Felsberg, Jörg
AU - Reifenberger, Guido
AU - Kulozik, Andreas E
AU - von Deimling, Andreas
AU - Witt, Olaf
AU - Eils, Roland
AU - Gilbertson, Richard J
AU - Korshunov, Andrey
AU - Taylor, Michael D
AU - Lichter, Peter
AU - Korbel, Jan O
AU - Wechsler-Reya, Robert J
AU - Pfister, Stefan M
PY - 2014/7/24
Y1 - 2014/7/24
N2 - 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.
AB - 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.
KW - Animals
KW - Child
KW - Chromosomes, Human, Pair 9
KW - DNA-Binding Proteins
KW - Enhancer Elements, Genetic
KW - Genomic Structural Variation
KW - Humans
KW - Medulloblastoma
KW - Mice
KW - Oncogenes
KW - Proto-Oncogene Proteins
KW - Repressor Proteins
KW - Transcription Factors
U2 - 10.1038/nature13379
DO - 10.1038/nature13379
M3 - SCORING: Journal article
C2 - 25043047
VL - 511
SP - 428
EP - 434
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 7510
ER -