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Mutations in the transcriptional repressor REST predispose to Wilms tumor

Mutations in the transcriptional repressor REST predispose to Wilms tumor
Mutations in the transcriptional repressor REST predispose to Wilms tumor
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.
1061-4036
1471-1474
Mahamdallie, Shazia S.
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Hanks, Sandra
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Karlin, Kristen L.
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Zachariou, Anna
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Perdeaux, Elizabeth R.
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Ruark, Elise
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Shaw, Chad A.
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Renwick, Alexander
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Ramsay, Emma
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Yost, Shawn
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Elliott, Anna
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Birch, Jillian
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Capra, Michael
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Gray, Juliet
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Hale, Juliet
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Kingston, Judith
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Levitt, Gill
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Mclean, Thomas
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Sheridan, Eamonn
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Renwick, Anthony
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Seal, Sheila
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Stiller, Charles
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Sebire, Neil
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Westbrook, Thomas F.
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Rahman, Nazneen
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Mahamdallie, Shazia S.
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Hanks, Sandra
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Karlin, Kristen L.
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Zachariou, Anna
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Perdeaux, Elizabeth R.
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Ruark, Elise
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Shaw, Chad A.
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Renwick, Alexander
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Ramsay, Emma
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Yost, Shawn
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Elliott, Anna
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Birch, Jillian
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Capra, Michael
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Gray, Juliet
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Hale, Juliet
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Kingston, Judith
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Levitt, Gill
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Mclean, Thomas
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Sheridan, Eamonn
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Renwick, Anthony
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Seal, Sheila
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Stiller, Charles
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Sebire, Neil
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Westbrook, Thomas F.
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Rahman, Nazneen
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Mahamdallie, Shazia S., Hanks, Sandra, Karlin, Kristen L., Zachariou, Anna, Perdeaux, Elizabeth R., Ruark, Elise, Shaw, Chad A., Renwick, Alexander, Ramsay, Emma, Yost, Shawn, Elliott, Anna, Birch, Jillian, Capra, Michael, Gray, Juliet, Hale, Juliet, Kingston, Judith, Levitt, Gill, Mclean, Thomas, Sheridan, Eamonn, Renwick, Anthony, Seal, Sheila, Stiller, Charles, Sebire, Neil, Westbrook, Thomas F. and Rahman, Nazneen (2015) Mutations in the transcriptional repressor REST predispose to Wilms tumor. Nature Genetics, 47 (12), 1471-1474. (doi:10.1038/ng.3440).

Record type: Article

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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More information

Accepted/In Press date: 14 October 2015
e-pub ahead of print date: 9 November 2015
Published date: 1 December 2015

Identifiers

Local EPrints ID: 418098
URI: http://eprints.soton.ac.uk/id/eprint/418098
ISSN: 1061-4036
PURE UUID: 79db282c-781d-47b1-bac2-6d80296c94c6
ORCID for Juliet Gray: ORCID iD orcid.org/0000-0002-5652-4722

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Date deposited: 22 Feb 2018 17:30
Last modified: 16 Mar 2024 03:33

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Contributors

Author: Shazia S. Mahamdallie
Author: Sandra Hanks
Author: Kristen L. Karlin
Author: Anna Zachariou
Author: Elizabeth R. Perdeaux
Author: Elise Ruark
Author: Chad A. Shaw
Author: Alexander Renwick
Author: Emma Ramsay
Author: Shawn Yost
Author: Anna Elliott
Author: Jillian Birch
Author: Michael Capra
Author: Juliet Gray ORCID iD
Author: Juliet Hale
Author: Judith Kingston
Author: Gill Levitt
Author: Thomas Mclean
Author: Eamonn Sheridan
Author: Anthony Renwick
Author: Sheila Seal
Author: Charles Stiller
Author: Neil Sebire
Author: Thomas F. Westbrook
Author: Nazneen Rahman

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