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.).
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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.
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Integrated supplementary information
Supplementary Figure 2 Pedigrees of Wilms tumor cases with germline REST mutations.
Individuals with Wilms tumor (WT) are represented by shaded symbols, with age at diagnosis in years given below. Circles depict females, and squares depict males.
Supplementary Figure 3 REST mutants identified in Wilms tumor cases are deficient in transcriptional repression relative to the normalizing control GAPDH.
(a) Expression of REST target genes was assessed in REST-deficient breast cancer cells (SUM149) expressing the indicated cDNAs by qRT-PCR. Relative expression of the REST target complexin 1 is not shown, as it is not expressed in the SUM149 cell line. (b) Expression of REST target genes was assessed in REST-deficient colon cancer cells (SW1417) expressing the indicated cDNAs by qRT-PCR. GFP, green fluorescent protein control; WT, wild-type REST. REST mutations within the DNA-binding domain and/or truncating mutations are shown in bold.
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Supplementary Figures 1–3, Supplementary Tables 1–3 and Supplementary Note. (PDF 2507 kb)
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Mahamdallie, S., Hanks, S., Karlin, K. et al. Mutations in the transcriptional repressor REST predispose to Wilms tumor. Nat Genet 47, 1471–1474 (2015). https://doi.org/10.1038/ng.3440
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DOI: https://doi.org/10.1038/ng.3440
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