Article | Published:

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Nature volume 511, pages 428434 (24 July 2014) | Download Citation



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.

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Data deposits

Short-read sequencing data have been deposited at the European Genome-Phenome Archive (EGA, hosted by the EBI, under accession number EGAS00001000215.


  1. 1.

    et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro-oncol. 15 (Suppl 2). 1–56 (2013)

  2. 2.

    et al. Dissecting the genomic complexity underlying medulloblastoma. Nature 488, 100–105 (2012)

  3. 3.

    et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148, 59–71 (2012)

  4. 4.

    et al. Novel mutations target distinct subgroups of medulloblastoma. Nature 488, 43–48 (2012)

  5. 5.

    et al. Medulloblastomics: the end of the beginning. Nature Rev. Cancer 12, 818–834 (2012)

  6. 6.

    et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J. Clin. Oncol. 29, 1424–1430 (2011)

  7. 7.

    et al. Medulloblastoma comprises four distinct molecular variants. J. Clin. Oncol. 29, 1408–1414 (2011)

  8. 8.

    et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488, 49–56 (2012)

  9. 9.

    , , , & A census of amplified and overexpressed human cancer genes. Nature Rev. Cancer 10, 59–64 (2010)

  10. 10.

    et al. Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes. Genome Res. 23, 217–227 (2013)

  11. 11.

    et al. Tuberous sclerosis complex suppression in cerebellar development and medulloblastoma: separate regulation of mammalian target of rapamycin activity and p27 Kip1 localization. Cancer Res. 69, 7224–7234 (2009)

  12. 12.

    et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011)

  13. 13.

    et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013)

  14. 14.

    et al. Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431, 1002–1007 (2004)

  15. 15.

    et al. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nature Genet. 34, 308–312 (2003)

  16. 16.

    , & The zinc-finger proto-oncogene Gfi-1b is essential for development of the erythroid and megakaryocytic lineages. Genes Dev. 16, 301–306 (2002)

  17. 17.

    , , & Progression of interleukin-2 (IL-2)-dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi-1) encoding a novel zinc finger protein. Mol. Cell. Biol. 13, 1759–1768 (1993)

  18. 18.

    , , & Characterization of pal-1, a common proviral insertion site in murine leukemia virus-induced lymphomas of c-myc and Pim-1 transgenic mice. J. Virol. 71, 9–16 (1997)

  19. 19.

    et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095–1099 (2010)

  20. 20.

    , , & Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997)

  21. 21.

    et al. An animal model of MYC-driven medulloblastoma. Cancer Cell 21, 155–167 (2012)

  22. 22.

    et al. A mouse model of the most aggressive subgroup of human medulloblastoma. Cancer Cell 21, 168–180 (2012)

  23. 23.

    et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J. Clin. Oncol. 31, 2927–2935 (2013)

  24. 24.

    , , , & Zinc finger protein GFI-1 cooperates with myc and pim-1 in T-cell lymphomagenesis by reducing the requirements for IL-2. Oncogene 12, 1789–1801 (1996)

  25. 25.

    et al. Zinc finger protein GFI-1 has low oncogenic potential but cooperates strongly with pim and myc genes in T-cell lymphomagenesis. Oncogene 17, 2661–2667 (1998)

  26. 26.

    et al. Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nature Rev. Genet. 14, 765–780 (2013)

  27. 27.

    & Interplay between the cancer genome and epigenome. Cell 153, 38–55 (2013)

  28. 28.

    et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013)

  29. 29.

    , & Chromosomal translocations in cancer. Biochim. Biophys. Acta 1786, 139–152 (2008)

  30. 30.

    et al. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol. 125, 913–916 (2013)

  31. 31.

    et al. Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathol. 123, 615–626 (2012)

  32. 32.

    et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature (18 May 2014)

  33. 33.

    et al. BayesPeak–an R package for analysing ChIP-seq data. Bioinformatics 27, 713–714 (2011)

  34. 34.

    et al. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nature Genet. 44, 1316–1320 (2012)

  35. 35.

    et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68–73 (2011)

  36. 36.

    et al. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics 28, 333–339 (2012)

  37. 37.

    et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012)

  38. 38.

    & Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009)

  39. 39.

    & BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010)

  40. 40.

    & Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics 27, 1571–1572 (2011)

  41. 41.

    & TopHat-Fusion: an algorithm for discovery of novel fusion transcripts. Genome Biol. 12, R72 (2011)

  42. 42.

    , , , & Model-based clustering and data transformations for gene expression data. Bioinformatics 17, 977–987 (2001)

  43. 43.

    et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)

  44. 44.

    et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc. Natl Acad. Sci. USA 101, 606–6067 (2004)

  45. 45.

    LTR: Linear cross-platform integration of microarray data. Cancer Inform. 9, 197–208 (2010)

  46. 46.

    et al. Isolation of neural stem cells from the postnatal cerebellum. Nature Neurosci. 8, 723–729 (2005)

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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). Additional support came from the German Cancer Research Center–Heidelberg Center 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.

Author information

Author notes

    • Paul A. Northcott
    • , Catherine Lee
    •  & Thomas Zichner

    These authors contributed equally to this work.


  1. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany

    • Paul A. Northcott
    • , Serap Erkek
    • , Daisuke Kawauchi
    • , Dominik Sturm
    • , David T. W. Jones
    • , Marcel Kool
    • , Andrea Wittmann
    • , Sebastian Stark
    • , Laura Sieber
    • , Huriye Seker-Cin
    • , Linda Linke
    • , Fabian Kratochwil
    •  & Stefan M. Pfister
  2. Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0685, USA

    • Catherine Lee
  3. Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA

    • Catherine Lee
    • , Lourdes Adriana Esparza
    •  & Robert J. Wechsler-Reya
  4. European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany

    • Thomas Zichner
    • , Adrian M. Stütz
    • , Serap Erkek
    • , Benjamin Raeder
    •  & Jan O. Korbel
  5. The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada

    • David J. H. Shih
    • , Marc Remke
    • , Florence M. G. Cavalli
    •  & Michael D. Taylor
  6. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany

    • Volker Hovestadt
    • , Marc Zapatka
    • , Wei Wang
    • , Ursula D. Weber
    •  & Peter Lichter
  7. The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada

    • Scott Zuyderduyn
    •  & Gary D. Bader
  8. Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA

    • Scott VandenBerg
  9. Department of Neuropathology, NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia

    • Marina Ryzhova
  10. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany

    • Natalie Jäger
    • , Ivo Buchhalter
    • , Benedikt Brors
    •  & Roland Eils
  11. Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany

    • Charles D. Imbusch
    • , Gideon Zipprich
    • , Chris Lawerenz
    •  & Jürgen Eils
  12. Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany

    • Sabine Schmidt
    • , Nicolle Diessl
    • , Stephan Wolf
    •  & Stefan Wiemann
  13. Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany

    • Hans-Jörg Warnatz
    • , Thomas Risch
    •  & Marie-Laure Yaspo
  14. Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany

    • Cynthia C. Bartholomae
    •  & Christof von Kalle
  15. Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany

    • Christof von Kalle
    • , Roland Eils
    •  & Peter Lichter
  16. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University SE, Gyermekklinika, Budapest 1094, Hungary

    • Eszter Turányi
  17. 2nd Department of Pediatrics, Semmelweis University, SE, Gyermekklinika, Budapest 1094, Hungary

    • Peter Hauser
  18. Glioma Immunotherapy Group, Division of Neurosurgery, Lund University, Paradisgatan 2, Lund 221 00, Sweden

    • Emma Sanden
    • , Anna Darabi
    •  & Peter Siesjö
  19. Department of Clinical Sciences, Lund University, Paradisgatan 2, Lund 221 00, Sweden

    • Emma Sanden
    • , Anna Darabi
    •  & Peter Siesjö
  20. Department of Pediatric Oncology, Masaryk University and University Hospital, Brno, Cernopolni 9 Brno 613 00, Czech Republic

    • Jaroslav Sterba
    •  & Karel Zitterbart
  21. Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, Prague 150 06, Czech Republic

    • David Sumerauer
  22. Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands

    • Peter van Sluis
    • , Rogier Versteeg
    • , Richard Volckmann
    •  & Jan Koster
  23. Department of Neurosurgery, Tübingen University Hospital, Hoppe-Seyler Strasse 3, Tübingen 72076, Germany

    • Martin U. Schuhmann
    •  & Martin Ebinger
  24. Division of Immunobiology, Program in Cancer Pathology of the Divisions of Experimental Hematology and Pathology, Program in Hematologic Malignancies of the Cancer and Blood Disease Insitute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 452229, USA

    • H. Leighton Grimes
  25. Department of Developmental Neurobiology, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA

    • Giles W. Robinson
    •  & Richard J. Gilbertson
  26. Department of Oncology, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA

    • Giles W. Robinson
    • , Amar Gajjar
    •  & Richard J. Gilbertson
  27. Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany

    • Martin Mynarek
    • , Katja von Hoff
    •  & Stefan Rutkowski
  28. Department of Neuropathology, University of Bonn, Sigmund-Freud-Str. 25, Bonn 53105, Germany

    • Torsten Pietsch
  29. Cnopf'sche Kinderklinik, Nürnberg Children’s Hospital, St-Johannis-Mühlgasse 19, Nürnberg 90419, Germany

    • Wolfram Scheurlen
  30. Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany

    • Jörg Felsberg
    •  & Guido Reifenberger
  31. Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany

    • Andreas E. Kulozik
    • , Olaf Witt
    •  & Stefan M. Pfister
  32. Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany

    • Andreas von Deimling
    •  & Andrey Korshunov
  33. Division of Neurosurgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada

    • Michael D. Taylor
  34. EMBL, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1SD, UK

    • Jan O. Korbel


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P.A.N., C.L., T.Z., A.M.S., D.K., L.A.E., W.W., A.W., S.St., L.S., H.S.-C., L.L., F.K., J.F., B.R., S.Sc., N.D., S.Wo., T.R., C.C.B., P.v.S. and A.K. performed and/or coordinated experimental or technical work. P.A.N., T.Z., S.E., D.J.H.S., V.H., M.Z., S.Z., G.D.B., N.J., I.B., C.D.I., G.Z., J.E., R.Vo., J.K. and J.O.K. performed and/or coordinated data analysis. M.Re., F.M.G.C., S.V., M.Ry., E.T., P.H., E.S., A.D., P.S., J.S., K.Z., D.Su., M.U.S., M.E., H.L.G., G.W.R., A.G., M.M., K.v.H., S.R., T.P., W.S., R.J.G., A.K. and M.D.T. contributed data, provided reagents, or patient materials. P.A.N., C.L., T.Z., S.E., D.J.H.S., V.H., D.St., D.T.W.J., M.K., S.Z., H.-J.W., R.J.G., M.D.T., P.Li., J.O.K., R.J.W.-R. and S.M.P. prepared the initial manuscript and display items. P.A.N., G.D.B., S.Wi., B.B., C.L., M-L.Y., U.D.W., C.v.K., R.V., G.R., A.E.K., A.v.D., O.W., R.E., P.Li., J.O.K., R.J.W.-R. and S.M.P. provided project leadership. P.A.N., J.O.K., R.J.W.-R. and S.M.P. co-conceived and led the study. P.Li., J.O.K., R.J.W.-R. and S.M.P are co-senior authors of this study.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Peter Lichter or Jan O. Korbel or Robert J. Wechsler-Reya or Stefan M. Pfister.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This file contains the details on the sequencing cohorts included in the main paper.

  2. 2.

    Supplementary Table 2

    RNA-seq analysis did not disclose evidence for possible GFI1 fusion genes (data not shown), suggesting that the detected rearrangements contribute to GFI1 activation by alternative mechanisms. This table shows that observed translocation partners showed no apparent preference for intragenic or intergenic breakpoints.

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