Introduction: Oxidative stress has been associated with the carcinogenesis of colorectal cancer. Cigarette smoking is a major source of oxidative stress, but vegetables and fruits exert as antioxidants and genetic polymorphisms of glutathione S-transferase (GSTs) also modulate the elimination of free radical. Increased levels of carbonyl groups have been found in serum proteins of smokers compared to nonsmokers. However, the interaction between oxidative stress, genes and cigarette smoke on colorectal cancer risk has not been studied. Hence, we conducted a hospital-base case-control study to examine the three-way interaction for protein carbonyl, genes and oxidative-related factors on the risk of colorectal cancer. Methods: Subjects who had received colonoscopies examinations were eligible for this study. A total of 1463 participants (727 cases and 736 controls) completed a socio-demographic and lifestyle questionnaire and provided blood samples for the biomarker study. Protein oxidation as a parameter of oxidative stress was measured by derivatization of the carbonyl groups with 2,4-dinitrophenylhydrazine (DNPH) and ELISA (Enzyme-Linked Immunosorbent Assay) quantitation of the DNPH group. Genotypes of the GSTM1, GSTT1, and GSTP1 genes were determined by PCR methods. Multivariate logistic regressions were use to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: The protein carbonyl levels were significantly higher in cases of colorectal adenocarcinoma compared to healthy controls (p<0.001). This association was also significant among participants carrying the GSTM1 null, GSTT1 present and null, and GSTP1 A/A genotypes (p<0.05), while protein carbonyls did not differ significantly by GSTM1, GSTT1 and GSTP1 genotypes in case or control groups. The risk of colorectal caner increased from 1.5 folds at the 2nd and 3rd quartiles of carbonyl levels to 2.0 folds for the 4th quartile (p for trend<0.001). We found a significantly modifying effect of GSTM1 genotype on the association between carbonyl levels and colorectal cancer risk (p=0.036). This risk was enhanced for individuals at the highest quartile carbonyl levels with GSTM1 null genotype (OR=2.54, 95%CI=1.69-3.81) and GSTT1 present genotype with (OR=2.35, 95%CI=1.49-3.69). The strongest impact of oxidative stress on colorectal cancer was more prominent among ever smokers with GSTM1 null genotype (OR=3.40, 95%CI=1.69-6.84) and GSTT1 present genotype (OR=3.57, 95%CI=1.76-7.25). Conclusions: Plasma protein carbonyl level is significantly associated with colorectal cancer, particularly among ever-smokers, which indicates that oxidative stress may play an important role in the etiology of colorectal cancer.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA