Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism that affects DNA methylation and synthesis. Because germ-line mu tations at nucleotides 677 (C -->T) and 1298 (A -->C) in the MTHFR gene cau se diminished enzyme activity, and aberrant DNA methylation is oncogenic,,v e examined the relationship between these two MTHFR polymorphisms and susce ptibility to esophageal squamous cell carcinoma (ESCC) in 240 ESCC cases an d 360 age- and sex-matched controls in northern China. We found that the al lele frequency of MTHFR 677T was significantly higher among cases than amon g controls (63% versus 41%, P < 0.001). Subjects with the 677TT genotype ha d a more than Q-fold increased risk of developing ESCC [adjusted odds ratio (OR), 6.18; 95% confidence interval (CI), 3.32-11.51] compared with those who had the 677CC genotype. Furthermore, the elevated ESCC risk associated with the 677 polymorphism was in an allele-dose relationship (trend test, P = 0.0001) with ORs of 1.00, 3.14 (95% CT, 1,94-5,08), and 6.18 (95% CI, 3. 32-11.51) for the CC, CT, and TT genotype, respectively, after adjustment f or age, sex, smoking status, and the MTHFR 1298 polymorphism. The allele fr equency for the MTHFR 1298C was 14% among cases and 17% among controls, The 1298CC genotype was extremely rare in both controls (1.4%) and cases (2.9% ) and was also associated with an elevated risk of ESCC (adjusted OR, 4.43; 95% CI, 1.23-16.02) compared with the 1298AA genotype, whereas the 1298AC genotype had no effect on the risk of ESCC, Thus, our findings support the hypothesis that genetic polymorphisms in the MTHFR gene may contribute to s usceptibility to carcinogenesis of the esophagus in the at-risk Chinese pop ulation.