TY - JOUR
T1 - XA polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection
AU - Zeron-Medina, Jorge
AU - Wang, Xuting
AU - Repapi, Emmanouela
AU - Campbell, Michelle R.
AU - Su, Dan
AU - Castro-Giner, Francesc
AU - Davies, Benjamin
AU - Peterse, Elisabeth F.P.
AU - Sacilotto, Natalia
AU - Walker, Graeme J.
AU - Terzian, Tamara
AU - Tomlinson, Ian P.
AU - Box, Neil F.
AU - Meinshausen, Nicolai
AU - De Val, Sarah
AU - Bell, Douglas A.
AU - Bond, Gareth L.
N1 - Funding Information:
This work was funded in part by the Ludwig Institute for Cancer Research, the Development Fund-Oxford Cancer Research Centre-University of Oxford, the Nuffield Department of Medicine, the Clarendon Fund, the Wellcome Trust (090532/Z/09/Z), the Oxford NIHR Comprehensive Biomedical Research Centre, the Intramural Research Program of the National Institute of Environmental Health Sciences-National Institutes of Health (projects: Z01ES100475 and Z01ES046008), the Australian NHMRC, Cancer Council of Queensland and the NIAMS (projects: 1P30AR057212 and 5K01AR063203). The authors would like to acknowledge Daniel Biggs and Nicole Hortin for assistance with ES cell culture; Shuangshuang Dai for Linux computing support; Colin Goding and Will Fairbrother for helpful discussions; and Suzanne Christen, Claire Beveridge, Elisabeth Bond, and Mark Shipman for help with the preparation of this manuscript.
PY - 2013/10/10
Y1 - 2013/10/10
N2 - The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.
AB - The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.
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U2 - 10.1016/j.cell.2013.09.017
DO - 10.1016/j.cell.2013.09.017
M3 - Article
C2 - 24120139
AN - SCOPUS:84885651314
SN - 0092-8674
VL - 155
SP - 410
JO - Cell
JF - Cell
IS - 2
ER -