Polymorphisms in the thymidylate synthase gene and risk of colorectal cancer

To evaluate the relationship between polymorphisms (28 bp repeated sequences in 5'-UTR and 6-bp ins/ del in 3'-UTR) in then thymidylate synthetase gene (TS) and risk of colorectal, colon and rectal cancers, we conducted a case-control study with 315 cases of colorectal cancer and 439 population-based controls in Jiangsu province, China. TS genotypes were identified using PCR-RFLP (restriction fragment length polymorphism) methods. Odds ratios (ORs) were estimated with an unconditional logistic regression model. We found that the distributions of 5'-UTR genotypes in TS were significantly different between controls and male colon cases (χ2 =8.25, P = 0.016). Compared with 3R/3R genotype, individuals with the 2R allele were at an increased risk of colon cancer (age-, BMI-, smoking- and alcohol drinking-adjusted OR=1.98, 95%CI: 1.11-3.53) among men. In contrast, the 6-bp ins/del polymorphism at the TS 3'- UTR did not influence risk of the colorectal, colon and rectal cancers. When combined genotypes for both TS 5'-UTR and 3'-UTR polymorphisms were evaluated, individuals with the 5'-UTR 2R allele had a OR of 3.61 (95%CI: 1.38-9.49) for colon cancer among men with the 3'-UTR -6bp/-6bp genotype. These results show that the polymorphism of the 28 bp repeated sequences in TS 5'-UTR could influence susceptibility to colon cancer and that there was a coordinated effect between TS 3'-UTR and 5'-UTR polymorphisms in increasing risk of colon cancer among Chinese men.