title: Mutations in the transcriptional repressor REST predispose to Wilms tumor.
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.
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Shazia S
authors.initials: SS
authors.lastname: Mahamdallie
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hanks
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Karlin
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Zachariou
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Perdeaux
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Elise
authors.identifier: http://orcid.org/0000-0002-9373-4059
authors.initials: E
authors.lastname: Ruark
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Renwick
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Ramsay
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Shawn
authors.initials: S
authors.lastname: Yost
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Elliott
authors.affiliation: Paediatric and Familial Cancer Research Group, University of Manchester, Manchester, UK.
authors.forename: Jillian
authors.initials: J
authors.lastname: Birch
authors.affiliation: Haematology Oncology-National Paediatric Centre, Our Lady's Children's Hospital, Dublin, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Capra
authors.affiliation: Cancer Sciences Unit, University of Southampton, Southampton, UK.
authors.forename: Juliet
authors.initials: J
authors.lastname: Gray
authors.affiliation: Department of Paediatric and Adolescent Haematology and Oncology, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK.
authors.forename: Juliet
authors.initials: J
authors.lastname: Hale
authors.affiliation: Department of Haematology and Oncology, Great Ormond Street Hospital, London, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Kingston
authors.affiliation: Department of Haematology and Oncology, Great Ormond Street Hospital, London, UK.
authors.forename: Gill
authors.initials: G
authors.lastname: Levitt
authors.affiliation: Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: McLean
authors.affiliation: Yorkshire Clinical Genetics Service, Chapel Allerton Hospital, Leeds, UK.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Renwick
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Sheila
authors.initials: S
authors.lastname: Seal
authors.affiliation: Public Health England, Oxford, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Stiller
authors.affiliation: Department of Histopathology and Paediatric Laboratory Medicine, Great Ormond Street Hospital, London, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Sebire
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Westbrook
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.|Cancer Genetics Unit, Royal Marsden Hospital National Health Service (NHS) Foundation Trust, London, UK.
authors.forename: Nazneen
authors.identifier: http://orcid.org/0000-0003-4376-0440
authors.initials: N
authors.lastname: Rahman
mesh_terms: D016022:Case-Control Studies; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D009396:Wilms Tumor / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D005819:Genetic Markers; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor