Background: Aberrant arachidonic acid metabolism by 12-lipoxygenase (12-LOX) and cyclooxygenase-2 (COX-2) has been implicated in human carcinogenesis. Inherited polymorphisms in 12-LOX and COX-2 contributed to differential expression or activity of these enzymes might confer interindividual susceptibility to cancer.
Objective: To examine the functional significance of 12-LOX 261 Arg> Gln polymorphism and its association, alone and in combination with COX-2 -1195G > A and -765G > C polymorphisms, with risk of developing esophageal squamous cell carcinoma (ESCC).
Methods: The platelet 12-LOX activity was measured by quantifying 12-HETE in the lipoxygenation reaction. Genotypes of 12-LOX261Arg>Gln and COX-2 -1195G>A and -765G>C polymorphisms were determined in a case-control study consisting of 1026 patients and 1270 controls. Associations with the risk of ESCC were estimated by logistic regression.
Results: Subjects with the 12-LOX Gln/Gln genotype had higher platelet 12-LOX activity (mean+/-SEM nmol/mg/min) than those with the Arg/Arg genotype (0.405+/-0.047 [n=10] versus 0.136+/-0.022 [n=6]; P=0.001). Genotyping data showed that the 12-LOX Gln/Gln genotype was associated with increased risk of developing ESCC (odds ratio [OR]=1.42, 95% confidence interval [CI]=1.12-1.81), compared with the Arg/Arg genotype adjusted for sex, age, and smoking. An increased risk of ESCC was also associated with the COX-2 -1195GA (OR=1.34, 95% CI=1.08-1.68; P=0.008), -1195AA (OR=1.72, 95% CI=1.35-2.20; P=<0.001), and -765GC (OR=2.24, 95% CI=1.59-3.16; P<0.001) genotypes. Furthermore, a multiplicative interaction between the 12-LOX Gln/Gln and COX-2 -1195AA or -765GC genotype in intensifying risk of ESCC was observed, with the ORs for the presence of both 12-LOX Gln/Gln and COX-2 -1195AA or -765GC genotypes being 3.21 (95% CI=1.93-5.34) and 3.33 (95% CI=1.59-6.98). A multiplicative interaction between the -765GC genotype and smoking was also evident (OR=4.45, 95% CI=2.71-7.29).
Conclusion: These observations suggest that inherited polymorphisms in arachidonic acid-metabolizing enzymes, which result in heightened gene expression or enzymatic activity, may confer host susceptibility to ESCC.