Abstract
3443
Background: The p53 tumor suppressor protein regulates the cellular response to DNA damage by coordinating the expression of select genes through its binding to specific p53 response elements in the promoter region of target genes. Functional polymorphisms in p53 response elements could lead to inter-individual differences in response to genotoxic stress and susceptibility to neoplasia. Methods: We investigated the association between functional polymorphisms in p53 response elements in four p53-regulated genes and colorectal adenoma risk in a case-control study of 757 advanced adenoma cases and 766 controls from the baseline screening exam of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cases included participants diagnosed with advanced left-sided adenoma (>1 cm in size, high-grade dysplasia, or villous characteristics). Controls consisted of subjects without evidence of a left-sided polyp by sigmoidoscopy, matched to cases on race (94% white) and sex. Using DNA extracted from blood specimens, four single nucleotide polymorphisms in p53 response elements (ADARB1 -62440G>A, DCC -2296C>G, EOMES -837C>T, RRM1 -1703A>G) were genotyped. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between each polymorphism and colorectal adenoma, adjusted for age. Results: The strongly responsive EOMES -837T variant was found to be associated with a reduced risk of colorectal adenoma compared to the wildtype (OR = 0.76, 95% CI: 0.60-0.96 and OR = 0.68, 95% CI: 0.50-0.91 for the CT and TT genotypes, respectively, Ptrend = 0.007). Similarly, carriers of the more responsive RRM1 -1703G variant were found to have a reduced risk of adenoma (OR = 0.74, 95% CI: 0.56-0.97). Smoking was related to adenoma risk in this population, and the protective association observed with RRM1 -1703G variant was stronger among ever smokers (OR = 0.59, 95% CI: 0.42-0.83) compared to never smokers (OR = 1.06, 95% CI: 0.67-1.69, Pinteraction = 0.04), suggesting that the more responsive variant may protect against tobacco-induced genotoxic stress. No associations were observed with the other two polymorphisms. Conclusion: This study indicates that functional genetic variants in EOMES and RRM1, associatedwith enhanced responsiveness to p53-induced transactivation, are associated with a reduced risk of colorectal adenoma.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA