Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma
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NORTHCOTT, Paul A.; Catherine LEE; Thomas ZICHNER; Adrian M. STÜTZ; Serap ERKEK; Daisuke KAWAUCHI; David J.H. SHIH; Volker HOVESTADT; Marc ZAPATKA; Dominik STURM; David T.W. JONES; Marcel KOOL; Marc REMKE; Florence M.G. CAVALLI; Scott ZUYDERDUYN; Gary D. BADER; Scott VANDENBERG; Lourdes Adriana ESPARZA; Marina RYZHOVA; Wei WANG; Andrea WITTMANN; Sebastian STARK; Laura SIEBER; Huriye SEKER-CIN; Linda LINKE; Fabian KRATOCHWIL; Natalie JÄGER; Ivo BUCHHALTER; Charles D. IMBUSCH; Gideon ZIPPRICH; Benjamin RAEDER; Sabine SCHMIDT; Nicolle DIESSL; Stephan WOLF; Stefan WIEMANN; Benedikt BRORS; Chris LAWERENZ; Jürgen EILS; Hans-Jörg WARNATZ; Thomas RISCH; Marie-Laure YASPO; Ursula D. WEBER; Cynthia C. BARTHOLOMAE; Christof von KALLE; Eszter TURÁNYI; Peter HAUSER; Emma SANDEN; Anna DARABI; Peter SIESJÖ; Jaroslav ŠTĚRBA; Karel ZITTERBART; David SUMERAUER; Peter van SLUIS; Rogier VERSTEEG; Richard VOLCKMANN; Jan KOSTER; Martin U. SCHUHMANN; Martin EBINGER; H. Leighton GRIMES; Giles W. ROBINSON; Amar GAJJAR; Martin MYNAREK; Katja von HOFF; Stefan RUTKOWSKI; Torsten PIETSCH; Wolfram SCHEURLEN; Jörg FELSBERG; Guido REIFENBERGER; Andreas E. KULOZIK; Andreas von DEIMLING; Olaf WITT; Roland EILS; Richard J. GILBERTSON; Andrey KORSHUNOV; Michael D. TAYLOR; Peter LICHTER; Jan O. KORBEL; Robert J. WECHSLER-REYA a Stefan M. PFISTER
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.
NORTHCOTT, Paul A.; Catherine LEE; Thomas ZICHNER; Adrian M. STÜTZ; Serap ERKEK; Daisuke KAWAUCHI; David J.H. SHIH; Volker HOVESTADT; Marc ZAPATKA; Dominik STURM; David T.W. JONES; Marcel KOOL; Marc REMKE; Florence M.G. CAVALLI; Scott ZUYDERDUYN; Gary D. BADER; Scott VANDENBERG; Lourdes Adriana ESPARZA; Marina RYZHOVA; Wei WANG; Andrea WITTMANN; Sebastian STARK; Laura SIEBER; Huriye SEKER-CIN; Linda LINKE; Fabian KRATOCHWIL; Natalie JÄGER; Ivo BUCHHALTER; Charles D. IMBUSCH; Gideon ZIPPRICH; Benjamin RAEDER; Sabine SCHMIDT; Nicolle DIESSL; Stephan WOLF; Stefan WIEMANN; Benedikt BRORS; Chris LAWERENZ; Jürgen EILS; Hans-Jörg WARNATZ; Thomas RISCH; Marie-Laure YASPO; Ursula D. WEBER; Cynthia C. BARTHOLOMAE; Christof von KALLE; Eszter TURÁNYI; Peter HAUSER; Emma SANDEN; Anna DARABI; Peter SIESJÖ; Jaroslav ŠTĚRBA; Karel ZITTERBART; David SUMERAUER; Peter van SLUIS; Rogier VERSTEEG; Richard VOLCKMANN; Jan KOSTER; Martin U. SCHUHMANN; Martin EBINGER; H. Leighton GRIMES; Giles W. ROBINSON; Amar GAJJAR; Martin MYNAREK; Katja von HOFF; Stefan RUTKOWSKI; Torsten PIETSCH; Wolfram SCHEURLEN; Jörg FELSBERG; Guido REIFENBERGER; Andreas E. KULOZIK; Andreas von DEIMLING; Olaf WITT; Roland EILS; Richard J. GILBERTSON; Andrey KORSHUNOV; Michael D. TAYLOR; Peter LICHTER; Jan O. KORBEL; Robert J. WECHSLER-REYA a Stefan M. PFISTER. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature. LONDON: NATURE PUBLISHING GROUP, 2014, roč. 511, č. 7510, s. "428"-"+", 19 s. ISSN 0028-0836. Dostupné z: https://doi.org/10.1038/nature13379.
@article{1194769, 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 SekerandCin, 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, HansandJörg and Risch, Thomas and Yaspo, MarieandLaure and Weber, Ursula D. and Bartholomae, Cynthia C. and Kalle, Christof von and Turányi, Eszter and Hauser, Peter and Sanden, Emma and Darabi, Anna and Siesjö, Peter and Štěrba, Jaroslav and Zitterbart, Karel and Sumerauer, David and Sluis, Peter van 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 Hoff, Katja von and Rutkowski, Stefan and Pietsch, Torsten and Scheurlen, Wolfram and Felsberg, Jörg and Reifenberger, Guido and Kulozik, Andreas E. and Deimling, Andreas von 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 WechslerandReya, Robert J. and Pfister, Stefan M.}, article_location = {LONDON}, article_number = {7510}, doi = {https://doi.org/10.1038/nature13379}, keywords = {ZINC-FINGER PROTEIN; T-CELL LYMPHOMAGENESIS; STEM-CELLS; SUPER-ENHANCERS; CANCER; MUTATIONS; GENOME; GENE; MYC; SUBGROUP}, language = {eng}, issn = {0028-0836}, journal = {Nature}, title = {Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma}, volume = {511}, year = {2014} }
TY - JOUR ID - 1194769 AU - 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. - Kalle, Christof von - Turányi, Eszter - Hauser, Peter - Sanden, Emma - Darabi, Anna - Siesjö, Peter - Štěrba, Jaroslav - Zitterbart, Karel - Sumerauer, David - Sluis, Peter van - Versteeg, Rogier - Volckmann, Richard - Koster, Jan - Schuhmann, Martin U. - Ebinger, Martin - Grimes, H. Leighton - Robinson, Giles W. - Gajjar, Amar - Mynarek, Martin - Hoff, Katja von - Rutkowski, Stefan - Pietsch, Torsten - Scheurlen, Wolfram - Felsberg, Jörg - Reifenberger, Guido - Kulozik, Andreas E. - Deimling, Andreas von - Witt, Olaf - Eils, Roland - Gilbertson, Richard J. - Korshunov, Andrey - Taylor, Michael D. - Lichter, Peter - Korbel, Jan O. - Wechsler-Reya, Robert J. - Pfister, Stefan M. PY - 2014 TI - Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma JF - Nature VL - 511 IS - 7510 SP - "428"-"+" EP - "428"-"+" PB - NATURE PUBLISHING GROUP SN - 00280836 KW - ZINC-FINGER PROTEIN KW - T-CELL LYMPHOMAGENESIS KW - STEM-CELLS KW - SUPER-ENHANCERS KW - CANCER KW - MUTATIONS KW - GENOME KW - GENE KW - MYC KW - SUBGROUP 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. ER -
NORTHCOTT, Paul A.; Catherine LEE; Thomas ZICHNER; Adrian M. STÜTZ; Serap ERKEK; Daisuke KAWAUCHI; David J.H. SHIH; Volker HOVESTADT; Marc ZAPATKA; Dominik STURM; David T.W. JONES; Marcel KOOL; Marc REMKE; Florence M.G. CAVALLI; Scott ZUYDERDUYN; Gary D. BADER; Scott VANDENBERG; Lourdes Adriana ESPARZA; Marina RYZHOVA; Wei WANG; Andrea WITTMANN; Sebastian STARK; Laura SIEBER; Huriye SEKER-CIN; Linda LINKE; Fabian KRATOCHWIL; Natalie JÄGER; Ivo BUCHHALTER; Charles D. IMBUSCH; Gideon ZIPPRICH; Benjamin RAEDER; Sabine SCHMIDT; Nicolle DIESSL; Stephan WOLF; Stefan WIEMANN; Benedikt BRORS; Chris LAWERENZ; Jürgen EILS; Hans-Jörg WARNATZ; Thomas RISCH; Marie-Laure YASPO; Ursula D. WEBER; Cynthia C. BARTHOLOMAE; Christof von KALLE; Eszter TURÁNYI; Peter HAUSER; Emma SANDEN; Anna DARABI; Peter SIESJÖ; Jaroslav ŠTĚRBA; Karel ZITTERBART; David SUMERAUER; Peter van SLUIS; Rogier VERSTEEG; Richard VOLCKMANN; Jan KOSTER; Martin U. SCHUHMANN; Martin EBINGER; H. Leighton GRIMES; Giles W. ROBINSON; Amar GAJJAR; Martin MYNAREK; Katja von HOFF; Stefan RUTKOWSKI; Torsten PIETSCH; Wolfram SCHEURLEN; Jörg FELSBERG; Guido REIFENBERGER; Andreas E. KULOZIK; Andreas von DEIMLING; Olaf WITT; Roland EILS; Richard J. GILBERTSON; Andrey KORSHUNOV; Michael D. TAYLOR; Peter LICHTER; Jan O. KORBEL; Robert J. WECHSLER-REYA a Stefan M. PFISTER. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. \textit{Nature}. LONDON: NATURE PUBLISHING GROUP, 2014, roč.~511, č.~7510, s.~''428''-''+'', 19 s. ISSN~0028-0836. Dostupné z: https://doi.org/10.1038/nature13379.