Thymidylate synthase (TS) catalyzes the 5,10-methylene-tetrahydrofolate-mediated conversion of
deoxyuridine monophosphate to deoxythymydine monophosphate, a
nucleotide required for
DNA synthesis and repair. The impaired TS expression has been shown to be related to 28 bp tandem repeats and a G-->C SNP in the 5'-UTR of TS.
Folate deficiency has been demonstrated to play a role in gastroesophageal
carcinogenesis. This case-control study was to examine the hypothesis that the TS polymorphisms, alone or in combination with serum
folate status, may confer susceptibility of the hosts to gastroesophageal
cancer. We analyzed TS genotype and serum
folate concentration in 324 patients with
esophageal squamous cell carcinoma (ESCC), 231 patients with gastric cardia
adenocarcinoma (GCA) and 492 controls. It was found that compared with the normal expression TS genotype, the low expression TS genotype alone was significantly associated with increased risk of ESCC [adjusted odds ratio (OR) 1.47; 95% confidence interval (CI) 1.03-2.10] but not GCA (OR=0.98, 95% CI=0.68-1.40). More importantly, a significant interaction between the TS polymorphisms and serum
folate status in risk of ESCC and GCA was observed. Among subjects with low serum
folate concentration (<3 ng/ml), the
ORs of ESCC and GCA for the low expression genotype were 22.63 (95% CI=10.44-49.05) and 4.08 (95% CI=1.94-8.59), which were greater than respective 9.97 (95% CI=5.67-17.53) and 1.88 (95% CI=1.18-3.24) for the normal expression genotype (P=0.002 and 0.029). These results suggest an important role for
folate deficiency and impaired TS activity in the etiology of ESCC and GCA.