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Abnormalities of the tumor suppressor TP53 pathway are critical in the development of many cancers since it regulates cell cycle components and apoptosis. Murine double minute-2 (MDM2) protein is a central node in the p53 pathway and a direct negative regulator of p53. TheMDM2 SNP309(rs2279744) polymorphism increases MDM2 RNA and protein levels, attenuating the p53 pathway. TheMDM2 SNP309polymorphism was investigated in 1,787 Caucasian nonsmall cell lung cancer (NSCLC) patients and 1,360 healthy controls. Cases and controls were analyzed for associations with genotype and adjusted for age, gender, histology and smoking history. There were no overall associations between theMDM2genotypes and risk of lung cancer (adjusted odds ratios [AORs] = 0.82 [95% confidence interval [CI] = 0.6–1.1] for theT/Ggenotype and AOR = 1.32 [95% CI = 0.9–2.0] for theG/Ggenotype). A statistically significant interaction (p= 0.01) was found between smoking andMDM2genotypes. Consistent with this interaction, stratified analysis by pack-years of smoking demonstrated that the AORs ofG/G vs. T/Twere 1.56 (1.0–2.7), 1.46 (1.0–2.2), 0.80 (0.5–1.3) and 0.63 (0.4–1.1), respectively, for never, mild (<30 pack-years), moderate (30–57 pack-years) and heavy smokers (≥58 pack-years). In conclusion, a strong gene-smoking interaction was observed between theMDM2 SNP309and NSCLC risk.