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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Author

Listed:
  • Paul A. Northcott

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Catherine Lee

    (Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0685, USA
    Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Thomas Zichner

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany)

  • Adrian M. Stütz

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany)

  • Serap Erkek

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
    European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany)

  • Daisuke Kawauchi

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • David J. H. Shih

    (The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada)

  • Volker Hovestadt

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Marc Zapatka

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Dominik Sturm

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • David T. W. Jones

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Marcel Kool

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Marc Remke

    (The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada)

  • Florence M. G. Cavalli

    (The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada)

  • Scott Zuyderduyn

    (The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada)

  • Gary D. Bader

    (The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada)

  • Scott VandenBerg

    (University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Lourdes Adriana Esparza

    (Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Marina Ryzhova

    (NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia)

  • Wei Wang

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Andrea Wittmann

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Sebastian Stark

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Laura Sieber

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Huriye Seker-Cin

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Linda Linke

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Fabian Kratochwil

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Natalie Jäger

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Ivo Buchhalter

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Charles D. Imbusch

    (Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Gideon Zipprich

    (Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Benjamin Raeder

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany)

  • Sabine Schmidt

    (Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Nicolle Diessl

    (Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Stephan Wolf

    (Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Stefan Wiemann

    (Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Benedikt Brors

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Chris Lawerenz

    (Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Jürgen Eils

    (Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Hans-Jörg Warnatz

    (Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany)

  • Thomas Risch

    (Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany)

  • Marie-Laure Yaspo

    (Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany)

  • Ursula D. Weber

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Cynthia C. Bartholomae

    (German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany)

  • Christof von Kalle

    (German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany
    Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Eszter Turányi

    (Semmelweis University SE, II.sz. Gyermekklinika, Budapest 1094, Hungary)

  • Peter Hauser

    (Semmelweis University, SE, II.sz. Gyermekklinika, Budapest 1094, Hungary)

  • Emma Sanden

    (Glioma Immunotherapy Group, Lund University, Paradisgatan 2, Lund 221 00, Sweden
    Lund University, Paradisgatan 2, Lund 221 00, Sweden)

  • Anna Darabi

    (Glioma Immunotherapy Group, Lund University, Paradisgatan 2, Lund 221 00, Sweden
    Lund University, Paradisgatan 2, Lund 221 00, Sweden)

  • Peter Siesjö

    (Glioma Immunotherapy Group, Lund University, Paradisgatan 2, Lund 221 00, Sweden
    Lund University, Paradisgatan 2, Lund 221 00, Sweden)

  • Jaroslav Sterba

    (Masaryk University and University Hospital, Brno, Cernopolni 9 Brno 613 00, Czech Republic)

  • Karel Zitterbart

    (Masaryk University and University Hospital, Brno, Cernopolni 9 Brno 613 00, Czech Republic)

  • David Sumerauer

    (2nd Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, Prague 150 06, Czech Republic)

  • Peter van Sluis

    (AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands)

  • Rogier Versteeg

    (AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands)

  • Richard Volckmann

    (AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands)

  • Jan Koster

    (AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands)

  • Martin U. Schuhmann

    (Tübingen University Hospital, Hoppe-Seyler Strasse 3, Tübingen 72076, Germany)

  • Martin Ebinger

    (Tübingen University Hospital, Hoppe-Seyler Strasse 3, Tübingen 72076, Germany)

  • H. Leighton Grimes

    (Program in Hematologic Malignancies of the Cancer and Blood Disease Insitute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 452229, USA)

  • Giles W. Robinson

    (St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA
    St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA)

  • Amar Gajjar

    (St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA)

  • Martin Mynarek

    (University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany)

  • Katja von Hoff

    (University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany)

  • Stefan Rutkowski

    (University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany)

  • Torsten Pietsch

    (University of Bonn, Sigmund-Freud-Str. 25, Bonn 53105, Germany)

  • Wolfram Scheurlen

    (Cnopf'sche Kinderklinik, Nürnberg Children’s Hospital, St-Johannis-Mühlgasse 19, Nürnberg 90419, Germany)

  • Jörg Felsberg

    (Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany)

  • Guido Reifenberger

    (Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany)

  • Andreas E. Kulozik

    (Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany)

  • Andreas von Deimling

    (University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany)

  • Olaf Witt

    (Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany)

  • Roland Eils

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
    Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Richard J. Gilbertson

    (St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA
    St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA)

  • Andrey Korshunov

    (University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany)

  • Michael D. Taylor

    (The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
    The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada)

  • Peter Lichter

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
    Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany)

  • Jan O. Korbel

    (European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany
    EMBL, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1SD, UK)

  • Robert J. Wechsler-Reya

    (Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Stefan M. Pfister

    (German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
    Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany)

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.

Suggested Citation

  • 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 , 2014. "Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma," Nature, Nature, vol. 511(7510), pages 428-434, July.
    • Handle: RePEc:nat:nature:v:511:y:2014:i:7510:d:10.1038_nature13379
    DOI: 10.1038/nature13379
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    Citations

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    Cited by:

    1. Michael R. Kelly & Kamila Wisniewska & Matthew J. Regner & Michael W. Lewis & Andrea A. Perreault & Eric S. Davis & Douglas H. Phanstiel & Joel S. Parker & Hector L. Franco, 2022. "A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    2. Fengju Chen & Yiqun Zhang & Darshan S. Chandrashekar & Sooryanarayana Varambally & Chad J. Creighton, 2023. "Global impact of somatic structural variation on the cancer proteome," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Katelyn L. Mortenson & Courtney Dawes & Emily R. Wilson & Nathan E. Patchen & Hailey E. Johnson & Jason Gertz & Swneke D. Bailey & Yang Liu & Katherine E. Varley & Xiaoyang Zhang, 2024. "3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Zaili Luo & Dazhuan Xin & Yunfei Liao & Kalen Berry & Sean Ogurek & Feng Zhang & Liguo Zhang & Chuntao Zhao & Rohit Rao & Xinran Dong & Hao Li & Jianzhong Yu & Yifeng Lin & Guoying Huang & Lingli Xu &, 2023. "Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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