A p53 Response Element Polymorphism Affects Cancer Risk

An increasing number of single-nucleotide polymorphisms (SNP) have been implicated in cancer susceptibility through genome-wide association studies (GWAS), but it is often difficult to determine which SNPs are pathogenic. Given that p53 exerts its tumor-suppressive activity by binding to p53-response element (p53-RE) consensus motifs throughout the genome and regulating transcription of target genes, Zeron-Medina and colleagues hypothesized that cancer-associated SNPs might affect key nucleotides in p53-REs. A list of cancer GWAS SNPs and SNPs in strong linkage disequilibrium with the GWAS SNPs was integrated with published p53 chromatin immunoprecipitation sequencing data to determine which SNPs mapped to p53-occupied loci. Of 62,657 SNPs evaluated, only 86 resided in a p53-occupied region, and only one, in the gene encoding the KIT receptor ligand (KITLG), affected a key nucleotide of a strong p53 response element. Surprisingly, the G allele of the KITLG p53-RE SNP, which is in linkage disequilibrium with SNPs that are associated with an increased risk of testicular cancer in Caucasians, strengthened the KITLG p53-RE, leading to greater p53 occupancy and greater p53-dependent transactivation of KITLG. Consistent with these findings, p53 activity is often robust in testicular cancers, raising the possibility that increased p53-dependent KITLG expression may drive male germ cell proliferation. Despite this increased cancer risk, the KITLG p53-RE G allele appeared to have undergone greater positive selection among Caucasians than Africans, potentially due to a role of KIT signaling in UV responses in light-skinned individuals. Interestingly, the KITLG p53-RE SNP was the only SNP in the entire genome that affected a core nucleotide of a strong, frequently occupied p53-RE. Polymorphisms in functional, frequently occupied p53-REs were exceedingly rare, suggesting that such variants have undergone negative selection and that polymorphisms in p53 binding sites are usually detrimental.

Zeron-Medina J, Wang X, Repapi E, Campbell MR, Su D, Castro-Giner F, et al. A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection. Cell 2013;155:410–22.