Abstract

Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor. Constitutional mosaic aneuploidies, microcephaly, developmental delay and seizures, which are features of mosaic variegated aneuploidy (MVA) syndrome1,2, were more variably present. Through functional studies, we show that TRIP13-mutant patient cells have no detectable TRIP13 and have substantial impairment of the spindle assembly checkpoint (SAC), leading to a high rate of chromosome missegregation. Accurate segregation, as well as SAC proficiency, is rescued by restoring TRIP13 function. Individuals with biallelic TRIP13 or BUB1B mutations have a high risk of embryonal tumors3, and here we show that their cells display severe SAC impairment. MVA due to biallelic CEP57 mutations4, or of unknown cause, is not associated with embryonal tumors and cells from these individuals show minimal SAC deficiency. These data provide insights into the complex relationships between aneuploidy and carcinogenesis.

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Acknowledgements

We thank the families for their participation and the researchers who recruited them, including K. Asakura-Hay, S. Bernardo de Sousa, P. Callier, D. Chitayat, J. Clayton-Smith, S. Fernandes, D. FitzPatrick, L. Florentin, J. Hurst, B. Isidor, S. Jacquemont, R. Marin Iglesias, M. Micale and J. Tolmie. We thank H.J. Snippert (UMC Utrecht) for providing the lentiviral H2B plasmid. We thank A. Renwick, S. Mahamdallie, C. Loveday and members of the Kops laboratory for helpful discussions and A. Strydom and B. Rex for assistance in preparing the manuscript. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. This research was supported by the Wellcome Trust (100210/Z/12/Z), by the Netherlands Organisation for Scientific Research (NWO-ALW 823.02.004 to G.J.P.L.K.) and by the Dutch Cancer Society (KWF Kankerbestrijding to R.M.d.V., KUN2014-6666).

Author information

Author notes

    • Shawn Yost
    • , Bas de Wolf
    •  & Sandra Hanks

    These authors contributed equally to this work.

    • Geert J P L Kops
    •  & Nazneen Rahman

    These authors jointly directed this work.

Affiliations

  1. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

    • Shawn Yost
    • , Sandra Hanks
    • , Anna Zachariou
    • , Matthew Clarke
    • , Emma Ramsay
    • , Harriet Wylie
    • , Anna Elliott
    • , Sheila Seal
    • , Elise Ruark
    •  & Nazneen Rahman
  2. Hubrecht Institute–KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, the Netherlands.

    • Bas de Wolf
    • , Richarda M de Voer
    • , Banafsheh Etemad
    • , Esther Uijttewaal
    •  & Geert J P L Kops
  3. Division of Cancer Biology, The Institute of Cancer Research, London, UK.

    • Chiara Marcozzi
    •  & Jonathon Pines
  4. Gurdon Institute and Department of Zoology, University of Cambridge, Cambridge, UK.

    • Chiara Marcozzi
    •  & Jonathon Pines
  5. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Richarda M de Voer
  6. Children's and Adolescent Oncology and Haematology Unit, Leeds General Infirmary, Leeds, UK.

    • Susan Picton
  7. Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Leeds, UK.

    • Audrey Smith
  8. Clinical Genetics Service, St Michael's Hospital, Bristol, UK.

    • Sarah Smithson
  9. Center for Medical Genetics, Haukeland University Hospital, Bergen, Norway.

    • Gunnar Houge
  10. Cancer Genomics Netherlands, Utrecht, the Netherlands.

    • Geert J P L Kops
  11. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Geert J P L Kops
  12. Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK.

    • Nazneen Rahman

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Contributions

N.R. designed and oversaw the study. G.J.P.L.K. designed and oversaw the functional experiments. E. Ramsay undertook the exome sequencing. S.H., H.W. and S. Seal performed the molecular analyses. S.Y., M.C. and E. Ruark performed bioinformatic analyses. B.d.W., E.U., R.M.d.V., B.E. and C.M. undertook functional analyses under the supervision of G.J.P.L.K., and J.P., S.P., A.S., S. Smithson and G.H. provided samples and data, coordinated by A.Z. and A.E. S.Y., S.H., B.d.W., A.Z., G.J.P.L.K. and N.R. wrote the manuscript with input from the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Geert J P L Kops or Nazneen Rahman.

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DOI

https://doi.org/10.1038/ng.3883

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