Polymorphisms of thymidylate synthase gene 5'- and 3'-untranslated region and risk of gastric cancer in Koreans.

BACKGROUND: Thymidylate synthase (TS) plays an important role in the conversion of dUMP to dTMP. Polymorphisms of the TS gene affect the expression of the gene, which in turn may result in differences in the outcome of cancer chemotherapy and the progression of gastric cancer. PATIENTS AND METHODS: These types of TS polymorphism were investigated in 318 gastric cancer patients and 280 controls. A variable number of tandem repeats (VNTR; 2R or 3R) in the thymidylate synthase enhancer region (TSER), a G/C single nucleotide polymorphism within the second repeat sequence of 3R (3G or 3C), and a 6 bp insertion/deletion polymorphism (6 bp or 0 bp) in the TS 3'-untranslated region (3'-UTR) were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Patients were sub-grouped by the Lauren classification. RESULTS: The TSER 2R/2R genotype had a high odds ratio in gastric cancer and for the intestinal type, but was not statistically significant (adjusted odds ratio, AOR=2.31, 95% confidence interval, CI=0.94-5.65; and AOR=2.53, 95% CI=0.98-6.54, respectively). Among the combined genotypes of TSER VNTR-3'-UTR 6 bp ins/del, 2R2R-6 bp/6 bp having 4 risk alleles conferred a significantly high risk of gastric cancer, particularly of the intestinal type (AOR=8.70, 95% CI=1.09-68.93; and AOR=10.86, 95% CI=1.32-89.09, respectively). CONCLUSION: Our results indicate that the 2R/2R-6 bp/6 bp combined genotype may be related to high gastric cancer susceptibility.

Polymorphisms of 5,10-methylenetetrahydrofolate reductase and thymidylate synthase in squamous cell carcinoma and basal cell carcinoma of the skin.

Genetic instability resulting from mutations in repair genes, defects in folic acid metabolism or DNA synthesis has been reported to contribute significantly to the development of skin cancer. The enzymes 5,10-methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) are essential participants in folic acid metabolism and DNA synthesis. Thus, the present case-control study was conducted to determine whether an association exists between the MTHFR/TS polymorphisms and squamous cell carcinoma (SCC) and/or basal cell carcinoma (BCC) among Korean individuals. The study subjects comprised 95 patients with SCC, 100 patients with BCC and 207 controls with no evidence of malignancy or pre-malignant lesions. Patients with skin cancer and control samples were analyzed for polymorphisms of the MTHFR or TS genes by means of polymerase chain reaction-restriction fragment length polymorphism. The MTHFR 677C>T and MTHFR 1298A>C polymorphisms showed no significance with regard to the development of SCC and BCC. However, within the 6 bp insertion (ins)/deletion (del) polymorphism in the 3'-untranslated region (3'-UTR) of the TS gene, the BCC group showed statistical significance with a 2.8-fold increased risk of cancer development [adjusted odds ratio (AOR)=2.821] in heterozygous mutations (0 bp/6 bp), 7.5-fold (AOR=7.539) in homozygous mutations (6 bp/6 bp) and 3-fold (AOR=3.079) upon combination of heterozygous mutations and homozygous mutations (0 bp/6 bp + 6 bp/6 bp). We thus conclude that the 6 bp ins/del polymorphism in the 3'-UTR is associated with increased risk of the development of skin cancer among Korean individuals with BCC.

Polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR C677T) and thymidylate synthase enhancer region (TSER) as a risk factor of cholangiocarcinoma in a Korean population.

BACKGROUND: 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 the 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. Therefore, the polymorphism of MTHFR and TSER, which share a common substrate, 5,10-methylenetetrahydrofolate, in CCC was examined, concurrently. The influence of these polymorphisms on plasma homocysteine levels was also investigated. PATIENTS AND METHODS: Blood samples were obtained from 47 patients with CCC and 204 healthy control donors. Using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), the C to T transition at position 677 of MTHFR and tandem repeat of 28bp in the enhancer region of TS gene were analyzed. Plasma homocysteine levels were also determined. RESULTS: According to the logistic regression model, a combination of MTHFR 677CC with the TSER 2R(+) genotype had a relative risk of 5.38 (95% CI, 1.23-23.56) of developing CCC compared to MTHFR 677CC with TSER 2R(-) (p = 0.0257). The level of homocysteine was lower in CCC patients than healthy controls without statistical significance (8.27 +/- 4.17 vs. 9.40 +/- 2.57, p = 0.093). CONCLUSION: Our data suggest a role of MTHFR 677CC with the TSER 2R(+) genotype in increasing the risk of CCC. This study is the first to suggest an association between CCC and the polymorphisms of MTHFR and TSER.