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Nat Genet. 2015 Dec;47(12):1471-4. doi: 10.1038/ng.3440. Epub 2015 Nov 9.

Mutations in the transcriptional repressor REST predispose to Wilms tumor.

Author information

1
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
2
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
4
Paediatric and Familial Cancer Research Group, University of Manchester, Manchester, UK.
5
Haematology Oncology-National Paediatric Centre, Our Lady's Children's Hospital, Dublin, Ireland.
6
Cancer Sciences Unit, University of Southampton, Southampton, UK.
7
Department of Paediatric and Adolescent Haematology and Oncology, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK.
8
Department of Haematology and Oncology, Great Ormond Street Hospital, London, UK.
9
Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
10
Yorkshire Clinical Genetics Service, Chapel Allerton Hospital, Leeds, UK.
11
Public Health England, Oxford, UK.
12
Department of Histopathology and Paediatric Laboratory Medicine, Great Ormond Street Hospital, London, UK.
13
Cancer Genetics Unit, Royal Marsden Hospital National Health Service (NHS) Foundation Trust, London, UK.

Abstract

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.

PMID:
26551668
DOI:
10.1038/ng.3440
[Indexed for MEDLINE]

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