Thymidylate synthase (TS), a central enzyme in folate metabolism exists as several polymorphisms. Functional polymorphisms in this gene may affect carcinogenesis via effects on nucleotide synthesis, particularly if such genetic variation is combined with low folate or coenzymes of folate metabolism (vitamin B12 and B6).
A repeat polymorphism in the TS promoter enhancer region (2rpt versus 3rpt of 28 bp) is associated with decreased expression, and a 6-bp deletion in the 3'untranslated region may affect RNA stability. This repeat polymorphism has been reported among Japanese individuals (allele frequency 19%), but has not been investigated in previous epidemiologic research.
TS catalyzes the final step in the de novo synthesis of deoxy-thymidine monophosphate (dTMP) using the substrate, dUMP, and a cofactor, 5,10-methylene tetrahydrofolate. Because of its essential role in DNA replication, human TS is an anticancer drug target and TS from infectious pathogens are infectious disease drug targets.
TS is the limiting irreversible step in de novo DNA, catalyzing the conversion of dUMP to dTMP. It is the target for the widely used anticancer agent 5-fluorouracil (5-FU), which is active against solid tumors like breast, head and neck and colon cancers. Increased TS levels in tumors are associated with resistance to chemotherapy with 5-FU. In addition, TS expression has been shown to be an independent prognostic factor in several cancers.
Thymidylate Synthase Promoter Polymorphism, Interaction with Folate Intake, and Risk of Colorectal Adenomas
Cancer Research 62, 3361-3364, June 15, 2002
Cornelia M. Ulrich, Jeannette Bigler, Roberd Bostick, Lisa Fosdick and John D. Potter
- Thymidylate synthase (TS) is a key enzyme in folate metabolism and the primary target of 5-fluorouracil. A repeat polymorphism in the TS promoter enhancer region (2rpt versus 3rpt of 28 bp) is associated with decreased expression, and a 6-bp deletion in the 3'untranslated region may affect RNA stability. We investigated the role of TS polymorphisms in a case control study of adenomatous polyps (510 cases and 604 polyp-free controls). We observed a significant gene-nutrient interaction between the TSER polymorphism and folate intake: among 3rpt/3rpt individuals (greater expression), folate intake > 440 µg/day (highest tertile) versus <=440 µg/day was associated with a 2-fold decreased risk [ORs 1.0 (reference group) versus 0.5 (0.3–0.9)]. However, among 2rpt/2rpt individuals, high folate intake was associated with a 1.5-fold increased risk [ORs 0.6 (0.4–0.9) versus 0.9 (0.5–1.5; P for interaction = 0.03)]. Vitamin B12 showed a similar trend (P = 0.08). No clear pattern was seen with the TS 1494del6 polymorphism. These findings raise questions regarding the molecular pathways linking folate metabolism and colorectal carcinogenesis, including whether high folate is beneficial in the presence of all metabolic genotypes.
Polymorphisms of thymidylate synthase in the 5'- and 3'-untranslated regions associated with risk of gastric cancer in South China: a case–control analysis
Carcinogenesis 2005 26(10):1764-1769;
Zhengdong Zhang, Yaochu Xu, Jianwei Zhou, Xinru Wang, Liwei Wang, Xu Hu, Jiangtao Guo, Qingyi Wei and Hongbing Shen
- Fruits and certain vegetables have a protective effect on gastric cancer (GC) and folate is one of the nutrients in fruits and vegetables. We hypothesized that the polymorphisms of thymidylate synthase (TYMS) gene involved in folate metabolism are associated with GC risk. In a population-based case–control study of 337 GC cases and 326 controls, frequency-matched by age, sex and residential areas in a southern Chinese population, we genotyped the 28 bp tandem repeat in the TYMS 5'-untranslated enhanced region (TSER) and the 6 bp deletion/insertion at bp 1494 in the TYMS 3'-untranslated region (TS3'UTR).We found that although the TSER polymorphism had no main effect on GC risk, the TS3'UTR 6 bp/6 bp genotype was associated with a significantly increased risk of GC [adjusted odds ratio (OR) = 1.96, 95% confidence interval (CI) = 1.18–3.25], especially the non-cardiac gastric cancer (2.16, 1.22–3.82), compared with the 0 bp/0 bp genotype. However, when we evaluated these two polymorphisms together and used the combined genotype with zero variant allele (TSER 2R and TS3'UTR 6 bp variant alleles) as the reference, we found that the combined genotype with three or four variant alleles was associated with a significantly increased risk of GC (2.06, 1.12–3.79), especially the non-cardiac gastric cancer (2.33, 1.19–4.59), and this significant association was more pronounced among older women (>60 years old), non-smokers, and never tea drinkers. In conclusion, the TYMS polymorphisms, especially the TS3'UTR polymorphism, are associated with GC risk, especially the non-cardiac gastric cancer, and the TSER 2R and TS3'UTR 6 bp alleles may jointly play a role in the etiology of GC in the southern Chinese population