A High-Frequency Regulatory Polymorphism in the p53 Pathway Accelerates Tumor Development

SummaryMDM2, a negative regulator of p53, is elevated in many cancers that retain wild-type p53. A single nucleotide polymorphism (SNP) in the human MDM2 promoter increases the affinity of Sp1 resulting in elevated MDM2 levels. We generated mice carrying either the MDM2SNP309T or the MDM2SNP309G allele to address the impact of MDM2SNP309G on tumorigenesis. Mdm2SNP309G/G cells exhibit elevated Mdm2 levels, reduced p53 levels, and decreased apoptosis. Importantly, some Mdm2SNP309G/G mice succumbed to tumors before 1 year of age, suggesting that this allele increases tumor risk. Additionally, the Mdm2SNP309G allele potentiates the tumor phenotype and alters tumor spectrum in mice inheriting a p53 hot-spot mutation. These data provide causal evidence for increased cancer risk in carriers of the Mdm2SNP309G allele