Mutations in the transcriptional repressor REST predispose to Wilms tumour
1Division of Genetics & Epidemiology, Institute of Cancer Research, London, UK,2Verna & Marrs McLean Dept. of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA,3Dept of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA,4Our Ladys Childrens Hospital, Dublin, UK,5Wake Forest University School of Medicine, Winston-Salem, USA,6Public Health England, Oxford, UK,7Dept of Histopathology and Paediatric Laboratory Medicine, Great Ormond Street Hospital, London, UK,8Cancer Genetics Unit, Royal Marsden Hospital NHS Foundation Trust, London, UK
Wilms tumour is the most common childhood renal cancer, affecting 1 in 10,000 children. Whilst Wilms tumour is primarily a non-familial condition, about 2% of cases have one or more relatives that have also had Wilms tumour. Only a small proportion of familial cases are due to WT1 mutations, epigenetic 11p15 defects, or autosomal recessive conditions that include Wilms tumour. In addition, rare germline DICER1 mutations have been identified in Wilms tumours of pleiotropic tumour syndromes, and mutations in CTR9 were recently identified as a rare cause of familial Wilms tumour. Furthermore, two familial Wilms tumour loci have been mapped by genome-wide linkage analysis to chromosomes 17q12-q21 and 19q13, but the causative genes remain elusive. Therefore, additional genetic causes of Wilms tumour remain to be discovered.
To identify genes that predispose to Wilms tumour we conducted exome and Sanger sequencing studies.
We identified 11 different inactivating mutations, in the RE1 Silencing Transcription factor, REST, in four familial Wilms tumour pedigrees and nine non-familial cases. Notably, no similar mutations were identified in the ICR1000 UK control series (13/558 vs 0/993; P<0.0001), nor the ExAC series (13/558 vs 0/61312; P<0.0001). A second mutational event was identified in two tumours, suggesting REST may act as a tumour suppressor gene in Wilms tumour pathogenesis. REST is a zinc finger transcription factor that functions in cellular differentiation and embryonic development. 10 of 11 mutations clustered within the DNA binding domain of REST and functional analyses revealed that they compromise REST transcriptional repression.
We demonstrate that germline REST mutations account for ~8% familial (4/52) and ~2% non-familial (9/519) Wilms tumour, the largest contribution to familial Wilms tumour known to date and are equivalent in contribution to non-familial Wilms tumour to WT1. This study will allow clinical genetic testing and targeted screening to at-risk children.