The Association between Genetic Polymorphism of 5,10-Methylenetetrahydrofolate Reductase and Thymidylate Synthase Enhancer Region and Risk of Cholangiocarcinoma

Abstract

Purpose: 5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, plays a major role in the provision of methyl groups for DNA methylation; thymidylate synthase (TS) is a rate limiting enzyme in the synthesis of dTMP and DNA repair. The clinical role of genetic polymorphisms of MTHFR and that of TS enhancer region (TSER) were demonstrated in several clinical studies with colorectal, esophageal, gastric and breast cancer. However, there have never been any studies on the association between cholangiocarcinoma (CCC) and genetic polymorphisms of MTHFR and TSER. Methods: We examined the polymorphism of MTHFR and TSER, that share a common substrate, 5,10-methylenetetrahydrofolate, in the CCC, concurrently.Blood samples were obtained from 85 patients with CCC and 204 healthy control donors. Using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), C to T transition at position 677 of MTHFR and tandem repeat of 28bp in the enhancer region of TS gene were analyzed. Results: Characteristics of 85 CCC cases and 204 controls were as follows. Mean age of CCC was 66.8 year old with 51 males and 34 females. Mean age of control group was 45.9 years with 72 males and 132 females. In 85 CCC patients, 40 had common bile duct cancer, 25 Klatskin tumor, 12 peripheral CCC, and 8 gall bladder cancer. No statistical differences were noted among MTHFR 677CC, CT, TT and TSER 2R2R, 2R3R, 3R3R genotypes. Conclusions: In conclusion, our data from a Korean population suggest that combined polymorphisms of MTHFR C677T and TSER are not associated with risk of cholangiocarcinoma. Large scale clinical study with folate level and other polymorphisms associated with CCC are warranted.