A Polymorphic p53 Response Element in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection

• Published in: Cell Vol. 155; no. 2; pp. 410 - 422
• Main Authors: Zeron-Medina, Jorge, Wang, Xuting, Repapi, Emmanouela, Campbell, Michelle R., Su, Dan, Castro-Giner, Francesc, Davies, Benjamin, Peterse, Elisabeth F.P., Sacilotto, Natalia, Walker, Graeme J., Terzian, Tamara, Tomlinson, Ian P., Box, Neil F., Meinshausen, Nicolai, De Val, Sarah, Bell, Douglas A., Bond, Gareth L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.10.2013
• Subjects: 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
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.09.017

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. [Display omitted] •A common SNP can influence p53’s regulation of a key target gene, the KITLG gene•The SNP in the p53-binding site can significantly influence human cancer risk•The SNP in the p53-binding site has undergone positive natural selection in humans•Similar SNPs in p53-binding sites are rare in the genome due to negative selection The polymorphism in the KITLG regulatory region associates with differential testicular cancer risk (higher with the G allele, which is more prevalent in Caucasians than in African American males) but also shows signs of positive natural selection, perhaps due to the role of KIT in UV protection in light skinned Caucasians.