Mutations in the transcriptional repressor REST predispose to Wilms tumor

Nature Genetics 47, 1471 (2015). doi:10.1038/ng.3440 Authors: Shazia S Mahamdallie, Sandra Hanks, Kristen L Karlin, Anna Zachariou, Elizabeth R Perdeaux, Elise Ruark, Chad A Shaw, Alexander Renwick, Emma Ramsay, Shawn Yost, Anna Elliott, Jillian Birch, Michael Capra, Juliet Gray, Juliet Hale, Judith Kingston, Gill Levitt, Thomas McLean, Eamonn Sheridan, Anthony Renwick, Sheila Seal, Charles Stiller, Neil Sebire, Thomas F Westbrook & Nazneen Rahman 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 accou...
Source: Nature Genetics - Category: Genetics & Stem Cells Authors: Tags: Letter Source Type: research