Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA, gaudetm@mail.nih.gov
BACKGROUND: p53 participates in cell cycle control, programmed cell death/apoptosis, and DNA repair, all pathways involved in carcinogenesis. TP53 variants may influence p53 function. OBJECTIVES: We evaluated whether three well-characterized TP53 variants -- Ex4 + 119 C > G (rs#1042522, Arg72Pro), IVS6 + 62 A > G (rs#1625895), and an IVS3 16 bp insertion/ deletion (INDEL; rs#17878362) -- were associated with breast cancer risk in a population-based case-control study. METHODS: Genotypes and haplotypes were determined using long-range PCR in a sample of 578 cases and 390 controls. RESULTS: For the Ex4 + 19 C > G SNP (rs1042522), women with the heterozygous genotype (G/C) had a 32% increase in breast cancer risk. Other variants were not associated with risk. We further examined whether these associations were modified by cigarette smoking status and detection of PAH-DNA adducts in circulating lymphocytes. Among current smokers, each copy of the minor alleles for the IVS6 + 62 A > G SNP (rs1625895) and the IVS3 INDEL polymorphism (rs17878362) was associated with lower breast cancer risk (OR = 0.49, 95% CI 0.27-0.90; OR = 0.42, 95% CI 0.22-0.78, respectively). However, among former smokers, the homozygous variant genotype for these 2 SNPs was observed among cases (4.1 and 3.2%, respectively) and not controls. Genotype associations were not modified by the presence or absence of DNA adducts in circulating lymphocytes. Three-loci haplotypes were not significantly associated with breast cancer risk. CONCLUSIONS: These results should be confirmed in larger studies, but suggest that cigarette smoking may influence breast cancer risk through interaction with p53.