- Volume 16 Issue 18
Background: Thymidylate synthase (TS) catalyzes the methylation of deoxyuridylate to deoxythymidylate and is involved in DNA methylation, synthesis and repair. Two common polymorphisms have been reported, tandem repeats in the promoter-enhancer region (TSER), and 6bp ins/del in the 5'UTR, that are implicated in a number of human diseases, including cancer. The association between the two polymorphisms in risk for lung cancer (LC) was here investigated in the Jordanian population. Materials and Methods: An age, gender, and smoking-matched case-control study involving 84 lung cancer cases and 71 controls was conducted. The polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) technique was used to detect the polymorphism of interest. Results: Individuals bearing the ins/ins genotype were 2.5 times more likely to have lung cancer [(95%CI: 0.98-6.37), p=0.051]. Individuals who were less than or equal to 57 years and carrying ins/ins genotype were 4.6 times more susceptible to lung cancer [OR<57 vs >57years: 4.6 (95%CI: 0.93-22.5), p=0.059)]. Genotypes and alleles of TSER were distributed similarly between cases and controls. Weak linkage disequilibrium existed between the two loci of interest (Lewontin's coefficient [D']) (LC: D' =0.03, r2: 0. 001, p=0.8; Controls: D' =0.29, r2: 0.08, p=0.02). Carriers of the "3 tandem repeats_insertion" haplotype (3R_ins) were 2 times more likely to have lung cancer [2 (95%CI: 1.13-3.48), p=0.061]. Conclusions: Genetic polymorphism of TS at 3 'UTR and its haplotype analysis may modulate the risk of lung cancer in Jordanians. The 6bp ins/del polymorphism of TS at 3 'UTR is more informative than TSER polymorphism in predicting increased risk.
Jordan;TS;polymorphism;lung cancer;3 'UTR;6 bp ins/del
- Al-Matubsi HY, Kanaan RA, Hamdan F, et al (2011). Smoking practices in Jordanian people and their impact on semen quality and hormonal levels among adult men. Central European Journal Of Public Health, 19, 54-9.
- Al-Motassem Y, Shomaf M, Said I, et al (2015). Allele and Genotype Frequencies of the Polymorphic Methylenetetrahydrofolate Reductase and Lung Cancer in ther Jordanian Population: a Case Control Study. Asian Pac J Cancer Prev, 16, 3101-9. https://doi.org/10.7314/APJCP.2015.16.8.3101
- Alberg AJ, Samet JM (2003). Epidemiology of lung cancer. Chest, 123, 21-49. https://doi.org/10.1378/chest.123.1_suppl.21S
- Awwad N, Yousef AM, Abuhaliema A, et al (2015). Relationship between Genetic Polymorphisms in MTHFR (C677T, A1298C and their Haplotypes) and the Incidence Of Breast Cancer among Jordanian Females-Case-Control Study. Asian Pac J Cancer Prev, 16, 5007-11. https://doi.org/10.7314/APJCP.2015.16.12.5007
- Baroudi O, Baroudi T, Omrane I, et al (2014). Thymidylate synthase polymorphism in sporadic colorectal and gastric cancer in Tunisian population: a predictive role in 5-fluorouracil based chemotherapy treatment. Med Oncol, 31, 825. https://doi.org/10.1007/s12032-013-0825-z
Cochran G (1954). Some Methods for Strengthening the Common
$\chi$Tests. Biometrics, 10, 417-51. https://doi.org/10.2307/3001616
- Dajani R, Fathallah R, Arafat A, et al (2013). Prevalence of MTHFR C677T single nucleotide polymorphism in genetically isolated populations in Jordan. Biochem Genet, 51, 780-8. https://doi.org/10.1007/s10528-013-9606-9
- Galbiatti AL, Castro R, Caldas HC, et al (2013). Alterations in the expression pattern of MTHFR, DHFR, TYMS, and SLC19A1 genes after treatment of laryngeal cancer cells with high and low doses of methotrexate. Tumour Biol, 34, 3765-71. https://doi.org/10.1007/s13277-013-0960-3
- Gao CM, Ding JH, Li SP, et al (2012). Polymorphisms in the thymidylate synthase gene and risk of colorectal cancer. Asian Pac J Cancer Prev, 13, 4087-91. https://doi.org/10.7314/APJCP.2012.13.8.4087
- Gaunt TR, Rodriguez S, Zapata C, et al (2006). MIDAS: software for analysis and visualisation of interallelic disequilibrium between multiallelic markers. BMC Bioinformatics, 7, 227. https://doi.org/10.1186/1471-2105-7-227
- Graziano F, Ruzzo A, Loupakis F, et al (2008). Liver-only metastatic colorectal cancer patients and thymidylate synthase polymorphisms for predicting response to 5-fluorouracil-based chemotherapy. Br J Cancer, 99, 716-21. https://doi.org/10.1038/sj.bjc.6604555
- Hensing T, Chawla A, Batra R, et al (2014). A personalized treatment for lung cancer: molecular pathways, targeted therapies, and genomic characterization. Adv Exp Med Biol, 799, 85-117. https://doi.org/10.1007/978-1-4614-8778-4_5
- 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
- Horn L, Pao W, Johnson DH (2012). Chapter 89. Neoplasms of the Lung. In 'Harrison's Principles of Internal Medicine, 18e', Eds The McGraw-Hill Companies, New York, NY,
- Hu HB, Kuang L, Zeng XM, et al (2012). Predictive value of thymidylate synthase expression in gastric cancer: a systematic review with meta-analysis. Asian Pac J Cancer Prev, 13, 261-7. https://doi.org/10.7314/APJCP.2012.13.1.261
- Islami F, Ward EM, Jacobs EJ, et al (2015). Potentially preventable premature lung cancer deaths in the USA if overall population rates were reduced to those of educated whites in lower-risk states. Cancer Causes Control, 26, 409-18. https://doi.org/10.1007/s10552-014-0517-9
- Jang MJ, Kim JW, Jeon YJ, et al (2014). Polymorphisms of folate metabolism-related genes and survival of patients with colorectal cancer in the Korean population. Gene, 533, 558-64. https://doi.org/10.1016/j.gene.2013.09.056
- Jung M, Lee CH, Park HS, et al (2013). Pharmacogenomic assessment of outcomes of pemetrexed-treated patients with adenocarcinoma of the lung. Yonsei Med J, 54, 854-64. https://doi.org/10.3349/ymj.2013.54.4.854
- Kumagai K, Hiyama K, Oyama T, et al (2003). Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. Int J Mol Med, 11, 593-600.
- Longley DB, Harkin DP, Johnston PG (2003). 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer, 3, 330-8. https://doi.org/10.1038/nrc1074
- Lu M, Sun L, Yang J, et al (2012). 3R variant of thymidylate synthase 5'-untranslated enhanced region contributes to colorectal cancer risk: a meta-analysis. Asian Pac J Cancer Prev, 13, 2605-10. https://doi.org/10.7314/APJCP.2012.13.6.2605
- Lv YT, Du PJ, Wang QY, et al (2013). A novel approach to cloning and expression of human thymidylate synthase. Asian Pac J Cancer Prev, 14, 7523-7. https://doi.org/10.7314/APJCP.2013.14.12.7523
- 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
- Morita M, Yin G, Yoshimitsu S, et al (2013). Folate-related nutrients, genetic polymorphisms, and colorectal cancer risk: the fukuoka colorectal cancer study. Asian Pac J Cancer Prev, 14, 6249-56. https://doi.org/10.7314/APJCP.2013.14.11.6249
- Pullarkat ST, 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
- Rai V (2014). Folate pathway gene MTHFR C677T polymorphism and risk of lung cancer in Asian populations. Asian Pac J Cancer Prev, 15, 9259-64. https://doi.org/10.7314/APJCP.2014.15.21.9259
- Shi Q, Zhang Z, Neumann AS, et al (2005). Case-control analysis of thymidylate synthase polymorphisms and risk of lung cancer. Carcinogenesis, 26, 649-56.
- Spitz MR, Wei Q, Dong Q, et al (2003). Genetic susceptibility to lung cancer: the role of DNA damage and repair. Cancer Epidemiol Biomarkers Prev, 12, 689-98.
- Sulzyc-Bielicka V, Bielicki D, Binczak-Kuleta A, et al (2013). Thymidylate synthase gene polymorphism and survival of colorectal cancer patients receiving adjuvant 5-fluorouracil. Genet Test Mol Biomarkers, 17, 799-806. https://doi.org/10.1089/gtmb.2013.0171
- Suzuki T, Matsuo K, Hiraki A, et al (2007). Impact of onecarbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case control study. Carcinogenesis, 28, 1718-25. https://doi.org/10.1093/carcin/bgm104
- Tang J, Wang PP, Zhuang YY, et al (2012). Thymidylate synthase genetic polymorphisms and cancer risk: a meta-analysis of 37 case-control studies. Chin Med J (Engl), 125, 2582-8.
- Tarawneh M, Nimri O, Arkoob K, et al 2010. cancer incidence in Jordan-2010 [Online]. Amman, Jordan: Ministry of Health. Available: www.moh.jov.jo/documents/annual%20incidence%20of%20cancer%20in%20Jordan@202010.pdf [Accessed July,2015 2015].
- 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.
- Wang LE, Gorlova OY, Ying J, et al (2013a). Genome-wide association study reveals novel genetic determinants of DNA repair capacity in lung cancer. Cancer Res, 73, 256-64.
- Wang X, Yue K, Hao L (2015). Meta-analysis of methylenetetrahydrofolate reductase polymorphism and lung cancer risk in Chinese. Int J Clin Exp Med, 8, 1521-5.
- Wang YC, Xue HP, Wang ZH, et al (2013b). An integrated analysis of the association between ts gene polymorphisms and clinical outcome in gastric and colorectal cancer patients treated with 5-FU-based regimens. Mol Biol Rep, 40, 4637-44. https://doi.org/10.1007/s11033-013-2557-8
- Winkler-Heil R, Hofmann W, Hussain M, et al (2015). Analyses of local dose distributions in the lungs for the determination of risk apportionment factors. Radiat Prot Dosimetry.
- Wu GQ, Liu NN, Xue XL, et al (2014). Multiplex real-time PCR for RRM1, XRCC1, TUBB3 and ts mRNA for prediction of response of non-small cell lung cancer to chemoradiotherapy. Asian Pac J Cancer Prev, 15, 4153-8. https://doi.org/10.7314/APJCP.2014.15.10.4153
- Wu X, Zhao H, Suk R, et al (2004). Genetic susceptibility to tobacco-related cancer. Oncogene, 23, 6500-23. https://doi.org/10.1038/sj.onc.1207811
- Yang Z, Liu HX, Zhang XF (2012). 2R of thymidylate synthase 5'-untranslated enhanced region contributes to gastric cancer risk: a meta-analysis. Asian Pac J Cancer Prev, 13, 1923-7. https://doi.org/10.7314/APJCP.2012.13.5.1923
- Yim DJ, Kim OJ, An HJ, et al (2010). Polymorphisms of thymidylate synthase gene 5'-and 3'-untranslated region and risk of gastric cancer in Koreans. Anticancer Res, 30, 2325-30.
- Yousef A-M, Shomaf M, Berger S, et al (2013). Allele and genotype frequencies of the polymorphic methylenetetrahydrofolate reductase and colorectal cancer among Jordanian population. Asian Pacific Journal of Cancer Prevention, 14, 4559-65. https://doi.org/10.7314/APJCP.2013.14.8.4559
- Yousef AM, Davis RA, Sticca RP, et al (2001). Structural analysis of cDNA encoding thymidylate synthase in hepatic metastases of human colorectal tumors. Int J Colorectal Dis, 16, 318-25. https://doi.org/10.1007/s003840100319
- Zhai X, Gao J, Hu Z, et al (2006). Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case-control analysis. BMC Cancer, 6, 138. https://doi.org/10.1186/1471-2407-6-138