Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Paul A. Northcott; 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 Sterba; 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; Stefan M. Pfister

doi:10.1038/nature13379

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Paul A. Northcott, 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 WangAndrea 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 Sterba, 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, Stefan M. Pfister

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

500 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	428-434
Aantal pagina's	7
Tijdschrift	Nature
Volume	511
Nummer van het tijdschrift	7510
DOI's	https://doi.org/10.1038/nature13379
Status	Gepubliceerd - 2014
Extern gepubliceerd	Ja

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10.1038/nature13379

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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., ... Pfister, S. M. (2014). Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature, 511(7510), 428-434. https://doi.org/10.1038/nature13379

@article{e2d09240270b4fc091b437dc915eec17,

title = "Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma",

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 Catherine Lee and Thomas Zichner and St{\"u}tz, {Adrian M.} and Serap Erkek and Daisuke Kawauchi and Shih, {David J.H.} and Volker Hovestadt and Marc Zapatka and Dominik Sturm and Jones, {David T.W.} and Marcel Kool and Marc Remke and Cavalli, {Florence M.G.} and Scott Zuyderduyn and Bader, {Gary D.} and Scott Vandenberg and Esparza, {Lourdes Adriana} and Marina Ryzhova and Wei Wang and Andrea Wittmann and Sebastian Stark and Laura Sieber and Huriye Seker-Cin and Linda Linke and Fabian Kratochwil and Natalie J{\"a}ger and Ivo Buchhalter and Imbusch, {Charles D.} and Gideon Zipprich and Benjamin Raeder and Sabine Schmidt and Nicolle Diessl and Stephan Wolf and Stefan Wiemann and Benedikt Brors and Chris Lawerenz and J{\"u}rgen Eils and Warnatz, {Hans J{\"o}rg} and Thomas Risch and Yaspo, {Marie Laure} and Weber, {Ursula D.} and Bartholomae, {Cynthia C.} and {Von Kalle}, Christof and Eszter Tur{\'a}nyi and Peter Hauser and Emma Sanden and Anna Darabi and Peter Siesj{\"o} and Jaroslav Sterba and Karel Zitterbart and David Sumerauer and {Van Sluis}, Peter and Rogier Versteeg and Richard Volckmann and Jan Koster and Schuhmann, {Martin U.} and Martin Ebinger and Grimes, {H. Leighton} and Robinson, {Giles W.} and Amar Gajjar and Martin Mynarek and {Von Hoff}, Katja and Stefan Rutkowski and Torsten Pietsch and Wolfram Scheurlen and J{\"o}rg Felsberg and Guido Reifenberger and Kulozik, {Andreas E.} and {Von Deimling}, Andreas and Olaf Witt and Roland Eils and Gilbertson, {Richard J.} and Andrey Korshunov and Taylor, {Michael D.} and Peter Lichter and Korbel, {Jan O.} and Wechsler-Reya, {Robert J.} and Pfister, {Stefan M.}",

note = "Funding Information: Acknowledgements For technical support and expertise we thank: the DKFZ Genomics and Proteomics Core Facility; B. Haase, D. Pavlinic and B. Baying (EMBL Genomics Core Facility); M. Knopf (NCT Heidelberg); the Sanford-Burnham Animal Facility and Cell Imaging, Tissue & Histopathology Shared Resource; and the UCSD Flow Cytometry Core Facility. We also thank Active Motif for the preparation of histone ChIP libraries. This work was principally supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by the German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). Additionalsupportcame fromthe German Cancer ResearchCenter–HeidelbergCenter for Personalized Oncology (DKFZ-HIPO), the EMBL International PhD Programme (T.Z.), Dutch Cancer Foundations KWF (2010-4713) and KIKA (M.Ko.), the US National Institutes of Health, National Center for Research Resources (P41 GM103504; G.D.B.), the CancerSys grant MYC-NET (German Federal Ministry of Education and Research, BMBF, 0316076A), the European Commission (Health-F2-2010-260791), and the Helmholtz Alliance PCCC (grant number HA-305). PAN is a Roman Herzog Postdoctoral Fellow funded by the Hertie Foundation and the DKFZ. R.J.W.-R. is the recipient of a Research Leadership Award from the California Institute for Regenerative Medicine (CIRM LA1-01747) and obtained additional support from the National Cancer Institute (5P30CA030199 and R01 CA159859), and the CureSearch for Children{\textquoteright}s Cancer Foundation.",

year = "2014",

doi = "10.1038/nature13379",

language = "English",

volume = "511",

pages = "428--434",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7510",

}

Northcott, PA, Lee, C, Zichner, T, Stütz, AM, Erkek, S, Kawauchi, D, Shih, DJH, Hovestadt, V, Zapatka, M, Sturm, D, Jones, DTW, Kool, M, Remke, M, Cavalli, FMG, Zuyderduyn, S, Bader, GD, Vandenberg, S, Esparza, LA, Ryzhova, M, Wang, W, Wittmann, A, Stark, S, Sieber, L, Seker-Cin, H, Linke, L, Kratochwil, F, Jäger, N, Buchhalter, I, Imbusch, CD, Zipprich, G, Raeder, B, Schmidt, S, Diessl, N, Wolf, S, Wiemann, S, Brors, B, Lawerenz, C, Eils, J, Warnatz, HJ, Risch, T, Yaspo, ML, Weber, UD, Bartholomae, CC, 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, MU, Ebinger, M, Grimes, HL, Robinson, GW, Gajjar, A, Mynarek, M, Von Hoff, K, Rutkowski, S, Pietsch, T, Scheurlen, W, Felsberg, J, Reifenberger, G, Kulozik, AE, Von Deimling, A, Witt, O, Eils, R, Gilbertson, RJ, Korshunov, A, Taylor, MD, Lichter, P, Korbel, JO, Wechsler-Reya, RJ & Pfister, SM 2014, 'Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma', Nature, vol. 511, nr. 7510, blz. 428-434. https://doi.org/10.1038/nature13379

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.

N1 - Funding Information: Acknowledgements For technical support and expertise we thank: the DKFZ Genomics and Proteomics Core Facility; B. Haase, D. Pavlinic and B. Baying (EMBL Genomics Core Facility); M. Knopf (NCT Heidelberg); the Sanford-Burnham Animal Facility and Cell Imaging, Tissue & Histopathology Shared Resource; and the UCSD Flow Cytometry Core Facility. We also thank Active Motif for the preparation of histone ChIP libraries. This work was principally supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by the German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). Additionalsupportcame fromthe German Cancer ResearchCenter–HeidelbergCenter for Personalized Oncology (DKFZ-HIPO), the EMBL International PhD Programme (T.Z.), Dutch Cancer Foundations KWF (2010-4713) and KIKA (M.Ko.), the US National Institutes of Health, National Center for Research Resources (P41 GM103504; G.D.B.), the CancerSys grant MYC-NET (German Federal Ministry of Education and Research, BMBF, 0316076A), the European Commission (Health-F2-2010-260791), and the Helmholtz Alliance PCCC (grant number HA-305). PAN is a Roman Herzog Postdoctoral Fellow funded by the Hertie Foundation and the DKFZ. R.J.W.-R. is the recipient of a Research Leadership Award from the California Institute for Regenerative Medicine (CIRM LA1-01747) and obtained additional support from the National Cancer Institute (5P30CA030199 and R01 CA159859), and the CureSearch for Children’s Cancer Foundation.

PY - 2014

Y1 - 2014

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.

UR - http://www.scopus.com/inward/record.url?scp=84904816744&partnerID=8YFLogxK

U2 - 10.1038/nature13379

DO - 10.1038/nature13379

M3 - Article

C2 - 25043047

AN - SCOPUS:84904816744

SN - 0028-0836

VL - 511

SP - 428

EP - 434

JO - Nature

JF - Nature

IS - 7510

ER -

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

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