3R Variant of Thymidylate Synthase 5'-untranslated Enhanced Region Contributes to Colorectal Cancer Risk: A Meta-analysis

  • Lu, Min (Department of Colorectal Surgery, the First Affiliated Hospital of China Medical University) ;
  • Sun, Luhaoran (Department of Colorectal Surgery, the First Affiliated Hospital of China Medical University) ;
  • Yang, Jing (Department of Colorectal Surgery, the First Affiliated Hospital of China Medical University) ;
  • Li, Yue-Yao (Department of Colorectal Surgery, the First Affiliated Hospital of China Medical University)
  • Published : 2012.06.30


Background: Studies investigating the association of 2R/3R polymorphism in the thymidylate synthase 5'-untranslated enhanced region (TSER) and colorectal cancer (CRC) risk have reported conflicting results. Thus, a meta-analysis was performed to summarize the data on the potential association. Methods: Pubmed, Embase and CBM databases were searched for all available studies. Links between the TSER 2R/3R polymorphism and CRC risk were estimated by odds ratios (ORs) with 95% confidence intervals (CIs). Results: Seven case-control studies with a total of 2723 cases and 4030 controls were included in this meta-analysis. The results showed that the 3R variant of TSER 2R/3R polymorphism contributes to CRC risk in two comparison models (OR 3R vs. 2R =1.10, 95%CI 1.02-1.18, P = 0.015; OR Homozygote comparison model = 1.22 1.04-1.43, 95%CI 1.04-1.43, P = 0.012). Subgroup analyses by ethnicity further demonstrated a contribution in Caucasians with three comparison models (OR 3R vs. 2R = 1.10, 95%CI 1.02-1.19, P = 0.015; OR Homozygote comparison model = 1.21, 95%CI 1.03-1.41, P = 0.019; OR Recessive comparison model = 1.18, 95%CI 1.05-1.33, P = 0.008). However, the association in the Asian population was still uncertain due to the limited data (all P values were more than 0.05). Conclusions: Our meta-analysis suggests that the 3R variant of Thymidylate synthase 5'-untranslated enhanced region 2R/3R polymorphism contributes to gastric cancer risk in the Caucasian population, while any association in Asian populations needs further study.


  1. Adleff V, Hitre E, Koves I, et al (2004). Heterozygote deficiency in thymidylate synthase enhancer region polymorphism genotype distribution in Hungarian colorectal cancer patients. Int J Cancer, 108, 852-6.
  2. Afzal S, Gusella M, Jensen SA, et al (2011). The association of polymorphisms in 5-fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer. Pharmacogenomics, 12, 1257-67.
  3. Arafa MA, Waly MI, Jriesat S, et al (2011). Dietary and lifestyle characteristics of colorectal cancer in Jordan: a case-control study. Asian Pac J Cancer Prev, 12, 1931-6.
  4. Attia J, Thakkinstian A, D'Este C (2003). Meta-analyses of molecular association studies: methodologic lessons for genetic epidemiology. J Clin Epidemiol, 56, 297-303.
  5. Carmona B, Guerreiro C, Cravo M, et al (2008). 5' and 3' UTR thymidylate synthase polymorphisms modulate the risk of colorectal cancer independently of the intake of methyl group donors. Mol Med Report, 1, 747-52.
  6. Chan AT, Giovannucci EL (2010). Primary prevention of colorectal cancer. Gastroenterology, 138, 2029-43 e10.
  7. Chen J, Hunter DJ, Stampfer MJ, et al (2003). Polymorphism in the thymidylate synthase promoter enhancer region modifies the risk and survival of colorectal cancer. Cancer Epidemiol Biomarkers Prev, 12, 958-62.
  8. Chen J, Kyte C, Chan W, et al (2004). Polymorphism in the thymidylate synthase promoter enhancer region and risk of colorectal adenomas. Cancer Epidemiol Biomarkers Prev, 13, 2247-50.
  9. Chen K, Song L, Yu W, et al (2006). Folate, methionine, and polymorphisms methionine synthase and thymidylate synthase with susceptibility to colorectal cancer. Acta Nutrimenta Sinica, 28, 342-9.
  10. Cochran WG (1954). The combination of estimates from different experiments. Biometrics, 10, 101-29.
  11. Costi MP, Ferrari S, Venturelli A, et al (2005). Thymidylate synthase structure, function and implication in drug discovery. Curr Med Chem, 12, 2241-58.
  12. Curtin K, Slattery ML, Ulrich CM, et al (2007). Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet. Carcinogenesis, 28, 1672-9.
  13. Curtin K, Ulrich CM, Samowitz WS, et al (2007). Thymidylate synthase polymorphisms and colon cancer: associations with tumor stage, tumor characteristics and survival. Int J Cancer, 120, 2226-32.
  14. DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Control Clin Trials, 7, 177-88.
  15. Egger M, Davey Smith G, Schneider M, et al (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315, 629-34.
  16. Feng TB, Cai LM, Qian KQ, et al (2012). Reduced telomere length in colorectal carcinomas. Asian Pac J Cancer Prev, 13, 443-6.
  17. Gibson TB (2006). Polymorphisms in the thymidylate synthase gene predict response to 5-fluorouracil therapy in colorectal cancer. Clin Colorectal Cancer, 5, 321-3.
  18. Goode EL, Potter JD, Bigler J, et al (2004). Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev, 13, 157-62.
  19. Goto T, Shinmura K, Yokomizo K, et al (2012). Expression levels of thymidylate synthase, dihydropyrimidine dehydrogenase, and thymidine phosphorylase in patients with colorectal cancer. Anticancer Res, 32, 1757-62.
  20. Higgins JP, Thompson SG, Deeks JJ, et al (2003). Measuring inconsistency in meta-analyses. BMJ, 327, 557-60.
  21. Horie N, Aiba H, Oguro K, et al (1995). Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5'-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct, 20, 191-7.
  22. Ho V, Massey TE, King WD (2011). Thymidylate synthase gene polymorphisms and markers of DNA methylation capacity. Mol Genet Metab, 102, 481-7.
  23. Hubner RA, Liu JF, Sellick GS, et al (2007). Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma. Br J Cancer, 97, 1449-56.
  24. Hubner RA, Muir KR, Liu JF, et al (2006). Folate metabolism polymorphisms influence risk of colorectal adenoma recurrence. Cancer Epidemiol Biomarkers Prev, 15, 1607-13.
  25. Ioannidis JP, Boffetta P, Little J, et al (2008). Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol, 37, 120-32.
  26. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.
  27. Jennings BA, Kwok CS, Willis G, et al (2012). Functional polymorphisms of folate metabolism and response to chemotherapy for colorectal cancer, a systematic review and meta-analysis. Pharmacogenet Genomics, 22, 290-304.
  28. Karpinski P, Myszka A, Ramsey D, et al (2010). Polymorphisms in methyl-group metabolism genes and risk of sporadic colorectal cancer with relation to the CpG island methylator phenotype. Cancer Epidemiol, 34, 338-44.
  29. Mantel N, Haenszel W (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst, 22, 719-48.
  30. Markowitz SD, Bertagnolli MM (2009). Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med, 361, 2449-60.
  31. Marsh S, McKay JA, Cassidy J, et al (2001). Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer. Int J Oncol, 19, 383-6.
  32. Matsuo K, Ito H, Wakai K, et al (2005). One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan. Carcinogenesis, 26, 2164-71.
  33. Park B, Lee HY, Choi KS, et al (2011). Cancer screening in Korea, 2010: results from the Korean National Cancer Screening Survey. Asian Pac J Cancer Prev, 12, 2123-8.
  34. Park CM, Lee WY, Chun HK, et al (2010). Relationship of polymorphism of the tandem repeat sequence in the thymidylate synthase gene and the survival of stage III colorectal cancer patients receiving adjuvant 5-flurouracilbased chemotherapy. J Surg Oncol, 101, 22-7.
  35. Petitti DB. (2000) Meta-analysis, decision analysis, and cost effectiveness analysis: methods for quantitative synthesis in medicine(2nded). New York, NY: Oxford University Press.
  36. Siegel R, Naishadham D, Jemal A (2012). Cancer statistics, 2012. CA Cancer J Clin, 62, 10-29.
  37. Ulrich CM, Bigler J, Bostick R, et al (2002). Thymidylate synthase promoter polymorphism, interaction with folate intake, and risk of colorectal adenomas. Cancer Res, 62, 3361-4.
  38. Ulrich CM, Curtin K, Potter JD, et al (2005). Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer. Cancer Epidemiol Biomarkers Prev, 14, 2509-16.
  39. van den Donk M, Visker MH, Harryvan JL, et al (2007). Dietary intake of B-vitamins, polymorphisms in thymidylate synthase and serine hydroxymethyltransferase 1, and colorectal adenoma risk: a Dutch case-control study. Cancer Lett, 250, 146-53.
  40. Zintzaras E, Lau J (2008). Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches. J Clin Epidemiol, 61, 634-45.

Cited by

  1. Thymidylate Synthase Polymorphisms and Risk of Lung Cancer among the Jordanian Population: a Case Control Study vol.16, pp.18, 2016,
  2. Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood-Based Colorectal Cancer Biomarker vol.16, pp.12, 2015,