• A Corrigendum to this article was published on 29 March 2016

This article has been updated

Abstract

Wilms tumor is the most common childhood renal cancer1. To identify mutations that predispose to Wilms tumor, we are conducting exome sequencing studies. Here we describe 11 different inactivating mutations in the REST gene (encoding RE1-silencing transcription factor) in four familial Wilms tumor pedigrees and nine non-familial cases. Notably, no similar mutations were identified in the ICR1000 control series2 (13/558 versus 0/993; P < 0.0001) or in the ExAC series (13/558 versus 0/61,312; P < 0.0001). We identified a second mutational event in two tumors, suggesting that REST may act as a tumor-suppressor gene in Wilms tumor pathogenesis. REST is a zinc-finger transcription factor that functions in cellular differentiation and embryonic development3,4. Notably, ten of 11 mutations clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these mutations compromise REST transcriptional repression. These data establish REST as a Wilms tumor predisposition gene accounting for 2% of Wilms tumor.

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Change history

  • 08 February 2016

    In the version of this article initially published, the authors failed to acknowledge funding from the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London to Neil Sebire. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank the families for their participation in our research and the physicians and nurses who recruited them. Samples were collected through the Factors Associated with Childhood Tumours (FACT) study, which is a Children's Cancer and Leukaemia (CCLG) Study (UK National Research Ethics Service reference 05/MRE02/17). The individuals who recruited patients with Wilms tumor for this study are listed in the Supplementary Note. We thank M. Warren-Perry and J. Bull for assistance in recruitment and A. Strydom for assistance in preparing the manuscript. We acknowledge NHS funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research (NIHR) Biomedical Research Centre. The authors acknowledge joint participation by the Adrienne Helis Melvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with Baylor College of Medicine for cancer research. T.F.W. and K.L.K. were supported by the Cancer Prevention Research Institute of Texas (CPRIT; RP120583), the US National Institutes of Health (1R01CA178039-01) and the US Department of Defense Breast Cancer Research Program (BC120604). This research was supported by the Wellcome Trust (088804/Z/09/Z) and the Rosetrees Trust. This research was supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (to N.S.).

Author information

Affiliations

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

    • Shazia S Mahamdallie
    • , Sandra Hanks
    • , Anna Zachariou
    • , Elizabeth R Perdeaux
    • , Elise Ruark
    • , Emma Ramsay
    • , Shawn Yost
    • , Anna Elliott
    • , Anthony Renwick
    • , Sheila Seal
    •  & Nazneen Rahman
  2. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.

    • Kristen L Karlin
    •  & Thomas F Westbrook
  3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • Kristen L Karlin
    • , Chad A Shaw
    • , Alexander Renwick
    •  & Thomas F Westbrook
  4. Paediatric and Familial Cancer Research Group, University of Manchester, Manchester, UK.

    • Jillian Birch
  5. Haematology Oncology–National Paediatric Centre, Our Lady's Children's Hospital, Dublin, Ireland.

    • Michael Capra
  6. Cancer Sciences Unit, University of Southampton, Southampton, UK.

    • Juliet Gray
  7. Department of Paediatric and Adolescent Haematology and Oncology, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK.

    • Juliet Hale
  8. Department of Haematology and Oncology, Great Ormond Street Hospital, London, UK.

    • Judith Kingston
    •  & Gill Levitt
  9. Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • Thomas McLean
  10. Yorkshire Clinical Genetics Service, Chapel Allerton Hospital, Leeds, UK.

    • Eamonn Sheridan
  11. Public Health England, Oxford, UK.

    • Charles Stiller
  12. Department of Histopathology and Paediatric Laboratory Medicine, Great Ormond Street Hospital, London, UK.

    • Neil Sebire
  13. Cancer Genetics Unit, Royal Marsden Hospital National Health Service (NHS) Foundation Trust, London, UK.

    • Nazneen Rahman

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Contributions

N.R. designed and oversaw the study. S.S.M., S.H., E.R.P., Anthony Renwick, E. Ramsay and S.S. performed the molecular analyses. E. Ruark, A.E., S.Y., C.A.S. and Alexander Renwick performed bioinformatics analyses. J.B., M.C., J.G., J.H., J.K., G.L., T.M., E.S. and C.S. provided samples and data, coordinated by A.Z. K.L.K. and T.F.W. undertook functional analyses. N.S. undertook pathology review. S.S.M., S.H., K.L.K., T.F.W. and N.R. wrote the manuscript with input from the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nazneen Rahman.

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DOI

https://doi.org/10.1038/ng.3440

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