The p53 R72P and MDM2 -309 polymorphisms and risk of breast cancer in the Nurses' Health Studies.

A175

Candidate gene association studies to detect breast cancer susceptibility loci have yielded few positive associations. Therefore, a hypothesis in which variants in multiple genes along related biological pathways combine to influence breast cancer risk is more likely. A strong candidate pathway is that of p53-mediated cell cycle control, DNA repair, and apoptosis. The two major proteins along this pathway are p53 and its negative regulator MDM2. Functional polymorphisms in both genes have been identified. The -309 SNP in MDM2 is associated with increased transcription. The Pro72Arg polymorphism of p53 alters the transcription of p53 target genes and modifies the apoptotic potential of cells. Both polymorphisms have been studied with respect to breast cancer risk, with inconclusive results. We hypothesize that both SNPs in combination alter breast cancer risk. To test this hypothesis, we genotyped both the -309 SNP in MDM2 and Pro72Arg in p53 among breast cancer cases and controls from the Nurses' Health Study and Nurses' Health Study II. While neither SNP is independently associated with breast cancer risk, an interaction between MDM2 -309 and p53 Pro72Arg is detected (p-interaction = 0.01). Women carrying one copy of the G allele of MDM2 -309 and homozygous for Pro72 of p53 are at a 21 percent decreased risk of breast cancer (OR 0.79, 95% CI 0.65 - 0.97).