title: A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.
abstract: 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.
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Zeron-Medina
authors.forename: Xuting
authors.initials: X
authors.lastname: Wang
authors.forename: Emmanouela
authors.initials: E
authors.lastname: Repapi
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Campbell
authors.forename: Dan
authors.initials: D
authors.lastname: Su
authors.forename: Francesc
authors.initials: F
authors.lastname: Castro-Giner
authors.forename: Benjamin
authors.initials: B
authors.lastname: Davies
authors.forename: Elisabeth F P
authors.initials: EF
authors.lastname: Peterse
authors.forename: Natalia
authors.initials: N
authors.lastname: Sacilotto
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Walker
authors.forename: Tamara
authors.initials: T
authors.lastname: Terzian
authors.forename: Ian P
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Neil F
authors.initials: NF
authors.lastname: Box
authors.forename: Nicolai
authors.initials: N
authors.lastname: Meinshausen
authors.forename: Sarah
authors.initials: S
authors.lastname: De Val
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bell
authors.forename: Gareth L
authors.initials: GL
authors.lastname: Bond
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D020218:Response Elements; D012641:Selection, Genetic; D019089:Stem Cell Factor / Q000235:genetics*; D013736:Testicular Neoplasms / Q000235:genetics*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D019089:Stem Cell Factor; D016159:Tumor Suppressor Protein p53