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Background  Accumulative evidence suggests that low folate intake is associated with increased risk of breast cancer. Polymorphisms in genes involved in folate metabolism may influence DNA methylation, nucleotide synthesis, and thus individual susceptibility to cancer. Thymidylate synthase (TYMS) is a key enzyme that participates in folate metabolism and catalyzes the conversion of dUMP to dTMP in the process of DNA synthesis. Two potentially functional polymorphisms [a 28-bp tandem repeat in the  TYMS  5'-untranslated enhanced region ( TSER ) and a 6-bp deletion/insertion in the  TYMS  3'-untranslated region ( TS 3'-UTR )] were suggested to be correlated with alteration of thymidylate synthase expression and associated with cancer risk.    Methods  To test the hypothesis that polymorphisms of the  TYMS  gene are associated with risk of breast cancer, we genotyped these two polymorphisms in a case-control study of 432 incident cases with invasive breast cancer and 473 cancer-free controls in a Chinese population.    Results  We found that the distribution of  TS3'-UTR  (1494del6) genotype frequencies were significantly different between the cases and controls ( P  = 0.026). Compared with the  TS3'-UTR del6/del6  wild-type genotype, a significantly reduced risk was associated with the  ins6/ins6  homozygous variant genotype (adjusted OR = 0.58, 95% CI = 0.35–0.97) but not the  del6/ins6  genotype (OR = 1.09, 95% CI = 0.82–1.46). Furthermore, breast cancer risks associated with the  TS3'-UTR del6/del6  genotype were more evident in older women, postmenopausal subjects, individuals with a younger age at first-live birth and individuals with an older age at menarche. However, there was no evidence for an association between the  TSER  polymorphism and breast cancer risks.    Conclusion  These findings suggest that the  TS3'-UTR del6  polymorphism may play a role in the etiology of breast cancer. Further larger population-based studies as well as functional evaluation of the variants are warranted to confirm our findings.

Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case-control analysis