• An Erratum to this article was published on 27 September 2017

This article has been updated

Abstract

Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain as well as end-joining DNA repair and induced structural rearrangements with PSS breakpoints. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.

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  • 24 May 2017

    In the version of this article initially published online, the affiliations for Jiali Zhuang listed an incorrect present address instead of an equal contribution. The error has been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

We are grateful to A. Gutierrez, M. Mansour, D. Bauer, T. Look, H. Zhu, C. Feschotte, M. Kharas, J. Petrini, and M. Gil Mir for critical discussions, and J. Gilbert for editorial advice. We thank T. Westbrook (Baylor College of Medicine) and M. Aldaz (MD Anderson Cancer Center) for materials. This work was supported by funding from NIH K08 CA160660, P30 CA008748, U54 OD020355, UL1 TR000457, P50 CA140146, Spanish Ministerio de Economía y Competitividad SAF2014-60293-R, Cancer Research UK, the Wellcome Trust, the Starr Cancer Consortium, the Burroughs Wellcome Fund, the Sarcoma Foundation of America, the Matthew Larson Foundation, the Josie Robertson Investigator Program, and the Rita Allen Foundation. A.G.H. is supported by the Berliner Krebsgesellschaft e.V. and the Berlin Institute of Health. A.K. is supported as a Damon Runyon–Richard Lumsden Foundation Clinical Investigator.

Author information

Author notes

    • Anton G Henssen

    Present address: Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

    • Anton G Henssen
    • , Richard Koche
    •  & Jiali Zhuang

    These authors contributed equally to this work.

Affiliations

  1. Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Anton G Henssen
    • , Eileen Jiang
    • , Casie Reed
    • , Amy Eisenberg
    • , Eric Still
    • , Ian C MacArthur
    •  & Alex Kentsis
  2. Cancer Biology & Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Richard Koche
    •  & Scott A Armstrong
  3. Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Jiali Zhuang
    •  & Zhiping Weng
  4. Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center (BSC-CNS), Barcelona, Spain.

    • Elias Rodríguez-Fos
    • , Santiago Gonzalez
    • , Montserrat Puiggròs
    •  & David Torrents
  5. The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.

    • Andrew N Blackford
    •  & Stephen P Jackson
  6. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA.

    • Christopher E Mason
  7. Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Elisa de Stanchina
  8. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Mithat Gönen
  9. New York Genome Center, New York, New York, USA.

    • Anne-Katrin Emde
    • , Minita Shah
    • , Kanika Arora
    •  & Catherine Reeves
  10. Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Nicholas D Socci
  11. Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.

    • Elizabeth Perlman
  12. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Cristina R Antonescu
  13. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Charles W M Roberts
  14. Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Hanno Steen
  15. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Elizabeth Mullen
  16. Department of Biochemistry, University of Cambridge, Cambridge, UK.

    • Stephen P Jackson
  17. The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Stephen P Jackson
  18. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

    • David Torrents
  19. Weill Cornell Medical College, Cornell University, New York, New York, USA.

    • Scott A Armstrong
    •  & Alex Kentsis
  20. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Scott A Armstrong
    •  & Alex Kentsis

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Contributions

A.G.H. contributed to the study design and collection and interpretation of the data. R.K. performed ChIP–seq, whole-genome sequencing, and FLEA PCR data analysis. J.Z. analyzed tumor genome-sequencing data with laSV. E.J., C. Reed, A.E., and E.S. performed in vitro transformation assays and vector design and cloning. I.C.M. performed experiments and analyzed data. E.R.-F., S.G., M.P., C.E.M., A.-K.E., M.S., K.A., C. Reeves, N.D.S., D.T., and Z.W. analyzed genome-sequencing data. A.N.B. and S.P.J. contributed to creation of PAXX-deficient cells and study design. E.d.S. contributed to mouse-xenograft study design. M.G. performed statistical analysis of data sets. C.R.A. performed histological analysis of tumor samples. E.P., C.W.M.R., H.S., E.M., and S.A.A. contributed to study design. A.K. contributed to study design, data analysis, and interpretation. A.K. and A.G.H. wrote the manuscript, to which all authors contributed.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Alex Kentsis.

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