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Polymorphisms in the Thymidylate Synthase Gene and Risk of Colorectal Cancer

  • Gao, Chang-Ming (Department of Epidemiology, Jiangsu Province Institute of Cancer Research) ;
  • Ding, Jian-Hua (Department of Epidemiology, Jiangsu Province Institute of Cancer Research) ;
  • Li, Su-Ping (Department of Epidemiology, Jiangsu Province Institute of Cancer Research) ;
  • Liu, Yan-Ting (Department of Epidemiology, Jiangsu Province Institute of Cancer Research) ;
  • Cao, Hai-Xia (Department of Epidemiology, Jiangsu Province Institute of Cancer Research) ;
  • Wu, Jian-Zhong (Department of Epidemiology, Jiangsu Province Institute of Cancer Research) ;
  • Tajima, Kazuo (Division of Epidemiology and Prevention, Aich Cancer Center Research Institute)
  • Published : 2012.08.31

Abstract

To evaluate the relationship between polymorphisms (28 bp repeated sequences in 5'-UTR and 6-bp ins/del in 3'-UTR) in then thymidylate synthetase gene (TS) and risk of colorectal, colon and rectal cancers, we conducted a case-control study with 315 cases of colorectal cancer and 439 population-based controls in Jiangsu province, China. TS genotypes were identified using PCR.RFLP (restriction fragment length polymorphism) methods. Odds ratios (ORs) were estimated with an unconditional logistic regression model. We found that the distributions of 5'-UTR genotypes in TS were significantly different between controls and male colon cases (${\chi}^2$=8.25, P = 0.016). Compared with 3R/3R genotype, individuals with the 2R allele were at an increased risk of colon cancer (age-, BMI-, smoking- and alcohol drinking-adjusted OR=1.98, 95%CI: 1.11-3.53) among men. In ccontrast, the 6-bp ins/del polymorphism at the TS 3'- UTR did not influence risk of the colorectal, colon and rectal cancers. When combined genotypes for both TS 5'-UTR and 3'-UTR polymorphisms were evaluated, individuals with the 5'-UTR 2R allele had a OR of 3.61 (95%CI: 1.38-9.49) for colon cancer among men with the 3'-UTR .6bp/-6bp genotype. These results show that the polymorphism of the 28 bp repeated sequences in TS 5'-UTR could influence susceptibility to colon cancer and that there was a coordinated effect between TS 3'-UTR and 5'-UTR polymorphisms in increasing risk of colon cancer among Chinese men.

Keywords

Colorectal cancer;thymidylate synthetase;genetic polymorphism

References

  1. 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
  2. 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.
  3. Choi SW, Mason JB (2000). Folate and carcinogenesis: an integrated scheme. J Nutr, 130, 129-32. https://doi.org/10.1093/jn/130.2.129
  4. Curtin K, Ulrich CM, Samowitz WS, et al (2007). Slattery ML.Thymidylate synthase polymorphisms and colon cancer: associations with tumor stage, tumor characteristics and survival. Int J Cancer, 120, 2226-32. https://doi.org/10.1002/ijc.22603
  5. Gao CM, Gong JP, Wu JZ, et al (2010). Relationship between growth hormone 1 genetic polymorphism and susceptibility to colorectal cancer. J Human Genetics, 55, 163-6. https://doi.org/10.1038/jhg.2010.3
  6. Gao CM, Takezaki T, Wu JZ, et al (2004). Polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase genes and the susceptibility to esophageal and stomach cancer with smoking. Asian Pac J Cancer Prev,. 5,133-8.
  7. Giovannucci E, Rimm EB, Ascherio A, et al (1995). Alcohol, low-methionine-low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst, 87, 265-73. https://doi.org/10.1093/jnci/87.4.265
  8. 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. https://doi.org/10.1247/csf.20.191
  9. 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. https://doi.org/10.1038/sj.bjc.6604056
  10. Kato I, Dnistrian AM, Schwartz M, et al (1999). Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study. Br J Cancer, 79, 1917-22. https://doi.org/10.1038/sj.bjc.6690305
  11. Mandola MV, Stoehlmacher J, Zhang W, et al (2004). A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics, 14, 319-27. https://doi.org/10.1097/00008571-200405000-00007
  12. Marsh S, Collie-Duguid ESR, Li T, et al (1999). Ethnic variation in the thymidylate synthase enhancer region polymorphism among Caucasian and Asian population. Genomics, 58, 310-2. https://doi.org/10.1006/geno.1999.5833
  13. 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. https://doi.org/10.1093/carcin/bgi196
  14. Pullarkat S T, Stoehlmacher J, Ghaderi V, et al (2001). Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J, 1, 65-70. https://doi.org/10.1038/sj.tpj.6500012
  15. Trinh BN, Ong CN, Coetzee GA, et al (2002). Thymidylate synthase: a novel genetic determinant of plasma homocysteine and folate levels. Hum Genet, 111, 299-302. https://doi.org/10.1007/s00439-002-0779-2
  16. 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.
  17. Ulrich CM, Bigler J, Velicer CM, et al (2000). Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomark Prev, 9, 1381-5.
  18. 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. https://doi.org/10.1158/1055-9965.EPI-05-0261
  19. 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. https://doi.org/10.1016/j.canlet.2006.10.002
  20. Villafranca E, Okruzhnov Y, Dominguez MA, et al (2001). Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol, 19, 1779-86. https://doi.org/10.1200/JCO.2001.19.6.1779

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