Wilms tumor is the most common childhood renal cancer. 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 series (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 development. 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.
Bibliographical noteFunding Information:
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.