A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection

Jorge Zeron-Medina, Xuting Wang, Emmanouela Repapi, Michelle R Campbell, Dan Su, Francesc Castro-Giner, Benjamin Davies, Elisabeth F P Peterse, Natalia Sacilotto, Graeme J Walker, Tamara Terzian, Ian P Tomlinson, Neil F Box, Nicolai Meinshausen, Sarah De Val, Douglas A Bell, Gareth L Bond

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)410-22
Number of pages13
Issue number2
Publication statusPublished - 10 Oct 2013

Bibliographical note

Copyright © 2013 Elsevier Inc. All rights reserved.


  • Animals
  • Cell Proliferation
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Male
  • Mice
  • Polymorphism, Single Nucleotide
  • Response Elements
  • Selection, Genetic
  • Stem Cell Factor/genetics
  • Testicular Neoplasms/genetics
  • Transcription, Genetic
  • Tumor Suppressor Protein p53/metabolism


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