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

This article has been updated


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    , & The yin and yang of kidney development and Wilms' tumors. Genes Dev. 29, 467–482 (2015).

  2. 2.

    et al. The ICR1000 UK exome series: a resource of gene variation in an outbred population. F1000 Res. 4, 883 (2015).

  3. 3.

    REST: transcriptional and epigenetic regulator. Epigenomics 3, 47–58 (2011).

  4. 4.

    & Chromatin crosstalk in development and disease: lessons from REST. Nat. Rev. Genet. 8, 544–554 (2007).

  5. 5.

    , , & Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J. Med. Genet. 43, 705–715 (2006).

  6. 6.

    et al. Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour. Nat. Commun. 5, 4398 (2014).

  7. 7.

    et al. Evidence for a familial Wilms' tumour gene (FWT1) on chromosome 17q12-q21. Nat. Genet. 13, 461–463 (1996).

  8. 8.

    et al. Linkage of familial Wilms' tumor predisposition to chromosome 19 and a two-locus model for the etiology of familial tumors. Cancer Res. 58, 1387–1390 (1998).

  9. 9.

    et al. Evidence for susceptibility genes to familial Wilms tumour in addition to WT1, FWT1 and FWT2. Br. J. Cancer 83, 177–183 (2000).

  10. 10.

    et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 493, 406–410 (2013).

  11. 11.

    et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 39, D945–D950 (2011).

  12. 12.

    et al. REST and stress resistance in ageing and Alzheimer's disease. Nature 507, 448–454 (2014).

  13. 13.

    , , , & The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease. Neurobiol. Dis. 39, 28–39 (2010).

  14. 14.

    et al. DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome. Am. J. Hum. Genet. 83, 388–400 (2008).

  15. 15.

    et al. The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor. Cell Rep. 9, 1318–1332 (2014).

  16. 16.

    , , , & Reduced expression of the neuron restrictive silencer factor permits transcription of glycine receptor α1 subunit in small-cell lung cancer cells. Oncogene 22, 5636–5645 (2003).

  17. 17.

    et al. Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer. Oncogene 29, 5828–5838 (2010).

  18. 18.

    et al. IB1/JIP-1 controls JNK activation and increased during prostatic LNCaP cells neuroendocrine differentiation. Cell. Signal. 17, 929–939 (2005).

  19. 19.

    , , , & REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121, 645–657 (2005).

  20. 20.

    et al. Frequency and heritability of WT1 mutations in nonsyndromic Wilms' tumor patients: a UK Children's Cancer Study Group Study. J. Clin. Oncol. 22, 4140–4146 (2004).

  21. 21.

    et al. Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice. Arch. Dis. Child. 91, 995–999 (2006).

  22. 22.

    & Stampy: a statistical algorithm for sensitive and fast mapping of Illumina sequence reads. Genome Res. 21, 936–939 (2011).

  23. 23.

    et al. Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat. Genet. 46, 912–918 (2014).

Download references


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


  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


  1. Search for Shazia S Mahamdallie in:

  2. Search for Sandra Hanks in:

  3. Search for Kristen L Karlin in:

  4. Search for Anna Zachariou in:

  5. Search for Elizabeth R Perdeaux in:

  6. Search for Elise Ruark in:

  7. Search for Chad A Shaw in:

  8. Search for Alexander Renwick in:

  9. Search for Emma Ramsay in:

  10. Search for Shawn Yost in:

  11. Search for Anna Elliott in:

  12. Search for Jillian Birch in:

  13. Search for Michael Capra in:

  14. Search for Juliet Gray in:

  15. Search for Juliet Hale in:

  16. Search for Judith Kingston in:

  17. Search for Gill Levitt in:

  18. Search for Thomas McLean in:

  19. Search for Eamonn Sheridan in:

  20. Search for Anthony Renwick in:

  21. Search for Sheila Seal in:

  22. Search for Charles Stiller in:

  23. Search for Neil Sebire in:

  24. Search for Thomas F Westbrook in:

  25. Search for Nazneen Rahman in:


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.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–3, Supplementary Tables 1–3 and Supplementary Note.

About this article

Publication history






Further reading