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Carcinogenesis Advance Access originally published online on April 7, 2005
Carcinogenesis 2005 26(8):1430-1435; doi:10.1093/carcin/bgi090
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Carcinogenesis vol.26 no.8 © Oxford University Press 2005; all rights reserved.

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 1, Chunyuan Yu, Ping Xiong, Gang Liang, Tong Sun, Yifeng Zhou, Xuemei Zhang, Hui Li 1 and Dongxin Lin *

Department of Etiology and Carcinogenesis, Cancer Institute and 1 Department of Epidemiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

* To whom correspondence should be addressed. Tel: +86 10 87788491; Fax: +86 10 677 22460; Email: dlin{at}public.bta.net.cn

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.


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L. Wang, Q. Ke, W. Chen, J. Wang, Y. Tan, Y. Zhou, Z. Hua, W. Ding, J. Niu, J. Shen, et al.
Polymorphisms of MTHFD, Plasma Homocysteine Levels, and Risk of Gastric Cancer in a High-Risk Chinese Population
Clin. Cancer Res., April 15, 2007; 13(8): 2526 - 2532.
[Abstract] [Full Text] [PDF]


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