Journal
CELL
Volume 155, Issue 2, Pages 410-422Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.09.017
Keywords
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Categories
Funding
- Ludwig Institute for Cancer Research
- Development Fund-Oxford Cancer Research Centre-University of Oxford
- Nuffield Department of Medicine
- Clarendon Fund
- Wellcome Trust [090532/Z/09/Z]
- Oxford NIHR Comprehensive Biomedical Research Centre
- Intramural Research Program of the National Institute of Environmental Health Sciences-National Institutes of Health [Z01ES100475, Z01ES046008]
- Australian NHMRC
- NIAMS [1P30AR057212, 5K01AR063203]
- Cancer Council of Queensland
- British Heart Foundation [PG/10/83/28610] Funding Source: researchfish
- Medical Research Council [MR/J007765/1] Funding Source: researchfish
- MRC [MR/J007765/1] Funding Source: UKRI
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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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