Journal Article

Significant increase in risk of gastroesophageal cancer is associated with interaction between promoter polymorphisms in thymidylate synthase and serum folate status

Wen Tan, Xiaoping Miao, Li Wang, Chunyuan Yu, Ping Xiong, Gang Liang, Tong Sun, Yifeng Zhou, Xuemei Zhang, Hui Li and Dongxin Lin

in Carcinogenesis

Volume 26, issue 8, pages 1430-1435
Published in print August 2005 | ISSN: 0143-3334
Published online April 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi090
Significant increase in risk of gastroesophageal cancer is associated with interaction between promoter polymorphisms in thymidylate synthase and serum folate status

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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.

Keywords: CI, confidence interval; ESCC, esophageal squamous cell carcinoma; GCA, gastric cardia adenocarcinoma; MTHFR, methylenetetrahydrofolate reductase; MTRR, methionine synthase reductase; OR, odds ratio; SHMT, serine hydroxymethyltransferase; SNP, single nucleotide polymorphism; THF, tetrahydrofolate; TS, thymidylate synthase; UTR, untranslated region

Journal Article.  5433 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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