Polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase genes and the susceptibility to esophageal and stomach cancer with smoking.

Thymidylate synthetase (TS) and methylenetetrahydrofolate reductase (MTHFR) are major enzymes in the metabolism of folates, involved in DNA 'breaks', instability and hypomethylation. To investigate the possible relations between the TS 3'-UTR and MTHFR C677T polymorphisms and environmental factors impacting on risk of esophageal and stomach cancers, we conducted a case-control study in a high incidence region of China for these cancers. We recruited 138 esophageal and 155 stomach cancer cases, and 223 controls. The TS 3' -UTR and MTHFR C677T genotypes were detected by RFLP assay, using PCR products. The frequency of the -6 bp homozygous TS 3' -UTR genotype was 37.7 % in controls, higher than in Caucasians, although the present distribution was not in Hardy-Weinberg equilibrium. Ever-smoking with the -6 bp/-6 bp TS genotype elevated the ORs (2.61, 1.24-5.49; 3.54, 1.60-7.82) for cases of esophageal and stomach cancers, respectively, when compared with never-smoking with the +6 bp/+6 bp and +6 bp/-6 bp genotypes. No combination between the TS and MTHFR genotypes gave increased ORs. The present results suggest that TS polymorphism may modify the risk of esophageal and stomach cancer with smoking, pointing to the necessity for further investigations with information on folate and methionine intake with a larger population.

[A case-control study on the polymorphisms of methylenetetrahydrofolate reductase 1298A-->C and susceptibility of esophageal cancer].

OBJECTIVE: To investigate the relationship between polymorphisms of methylenetetra-hydrofolate reductase gene 1298A-->C (MTHFR 1298A-->C) and its susceptibility of esophageal cancer (EC). METHODS: We conducted a case-control study with 141 cases of EC and 228 population-based controls in Huaian city of Jiangsu province, China. Epidemiological data were collected, and DNA of peripheral blood leukocytes was obtained from all of the subjects. MTHFR genotypes were identified by polymerase chain reaction. RESULTS: (1) The frequency of MTHFR 1298AA, AC and CC genotype were 63.8%, 34.0% and 2.1% in EC and 71.9%, 28.1% and 0.0% in controls, respectively (chi(2)(MH) = 6.69, P = 0.035). The frequency of the MTHFR 1298C allele was 0.19 for EC and 0.14 for controls. (2) Individuals having MTHFR 1298C allele and smoking habit were at a significantly higher risk of developing EC (adjusted OR = 3.48, 95% CI: 1.57 - 7.71) compared with those who having AA genotype but no smoking habit. Individuals having MTHFR 1298C allele and habit of frequent alcohol drinking were at an increased risk of developing EC (adjusted OR = 2.91, 95% CI: 1.20 - 7.08) compared with those with AA genotype and low consumption of alcohol. Individuals having MTHFR 1298C allele but no habit of tea drinking had a 3.52-fold (95% CI: 1.64 - 7.54) increased risk of developing EC compared with tea drinkers with AA genotype. As compared with subjects having AA genotype, low consumption of alcohol, no smoking habit but having habit of drinking tea, the individuals having 1298C allele, habits of frequent alcohol drinking, smoking but no habit of tea drinking had a 12.64-folds (95% CI: 1.39 - 114.65) increased risk of developing EC. CONCLUSION: Results in the present study suggested that there was a coordinated effect between MTHFR 1298 genotypes and habits of smoking, alcohol drinking and tea consumption in the development of EC.

[Interactions between lifestyle, methylanetetrahydrofolate reductase gene and polymorphisms in thymidylate synthase gene with risk of stomach cancer].

OBJECTIVE: To evaluate interactions between lifestyle, methylanetetrahydrofolate reductase gene (MTHFR) and polymorphisms in the 3'-untranslated region (3'-UTR) of the thymidylate synthase gene (TS) with reference to development of stomach cancer (SC). METHODS: We conducted a case-control study with 107 cases of SC and 200 population-based controls in Huaian city of Jiangsu province, China. TS genotypes were identified by polymerase chain reaction. RESULTS: (1) The frequencies of TS genotypes (+6 bp/+6 bp, +6 bp/-6 bp and -6 bp/-6 bp) among the cases were 5.6%, 47.7% and 46.7% and among the controls were 9.0%, 54.0% and 37.0%, respectively. Individuals identified as -6 bp/-6 bp genotype had a slightly higher risk for SC than those individuals with +6 bp alleles (the crude OR = 1.49, 95% CI: 0.90 - 2.47; adjusted OR = 1.36, 95% CI: 1.00 - 1.78, P = 0.047). (2) Individuals having TS -6 bp/-6 bp genotype and having smoking habit were at a significantly higher risk of developing SC (adjusted OR = 2.79, 95% CI: 1.51 - 5.18) compared with those who had +6 bp alleles with no smoking habit. Individuals having TS -6 bp/-6 bp genotype and habit of frequent alcohol drinking were at an increased risk of developing SC (adjusted OR = 1.76, 95% CI: 1.07 - 2.90) compared with those with +6 bp alleles and low consumption of alcohol. As compared with individuals with +6 bp alleles and who had habit of tea drinking, individuals who had TS -6 bp/-6 bp genotype and but without habit of tea drinking had an increased risk of developing SC (adjusted OR = 2.34, 95% CI: 1.43 - 3.82). (3) Individuals with TS -6 bp/-6 bp genotype and with MTHFR T alleles had an increased risk of developing SC (adjusted OR = 2.67, 95% CI: 1.07 - 6.70) compared with those with +6 bp alleles and with MTHRF C/C genotype. CONCLUSION: Results in the present study suggested that there was a combined effect between lifestyle, MTHFR C/T or T/T genotype and TS -6 bp/-6 bp genotype in the development of SC.