Document Type : Original Article


1 Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran

2 Department of Hematology and Oncology, Hazrat Rasool-e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran

3 Cancer Pharmacogenetics Research Group (CPGRG), Iran University of Medical Sciences, Tehran, Iran

4 Department of Health Information Management, School of Health Management and Information Sciences, Iran University of Medical Sciences, Tehran, Iran


Background: Lung cancer is the leading cause of cancer deaths worldwide. Pharmacogenomics plays an important role in tailoring cancer patients’ treatment. Pemetrexed is widely used in first- and second-line chemotherapy of non-small cell lung cancer (NSCLC); however, there is no available predictive biomarker for pemetrexed treatment. The present study aimed to investigate the role of polymorphisms in thymidylate synthase and SLC19A1 polymorphisms with clinical outcome in patients with advanced NSCLC treated in first-line with pemetrexed or pemetrexed plus cisplatin.
Method: This cohort study included 40 metastatic lung cancer patients treated with pemetrexed plus cisplatin. We utilized the tetra-primer amplification refractory mutation system-polymerase chain (ARMS-PCR) reaction for genotyping of rs3788189 and rs1051298. TYMS 28-VNTR and rs16430 were genotyped in the patients via PCR amplification and PCR-RFLP, respectively. Fisher's exact test and Kaplan-Meier curve were used for statistical analysis.
Results: We recruited 40 patients in this research with a median age of 58.9 years. The median survival of all the 40 patients was 11.6 months. The overall survival of the patients, as well as their gender, age, and metastatic sites were not found to be statistically associated with rs1051298, rs3788189, TYMS VNTR, and rs16430.
Conclusion: Our study did not identify any associations between the SLC19A1 and TYMS VNTR and rs16430 and clinical outcomes in advanced NSCLC patients. However, further investigation will be conducive to finding effective clinical biomarkers for the treatment of patients with NSCLC.


How to cite this article:

Abbasian MH, Ansarinejad N, Ramim T, Fardad F, Abbasi B. SLC19A1 and thymidylate synthase polymorphisms do not predict survival outcome in nonsmall- cell lung cancer treated with pemetrexed-cisplatin chemotherapy regimen. Middle East J Cancer. 2023;14(1):73- 80. doi: 10.30476/mejc.2022. 89424.1600.

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi: 10.3322/caac.21492. Erratum in: CA Cancer J Clin. 2020;70(4):313.
  2. Postmus P, Kerr K, Oudkerk M, Senan S, Waller D, Vansteenkiste J, et al. Early and locally advanced nonsmall- cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and followup. Ann Oncol. 2017;28:iv1-iv21. doi: 10.1093/annonc/ mdx222.
  3. Bilfinger T, Keresztes R, Albano D, Nemesure B. Five-year survival among stage IIIA lung cancer patients receiving two different treatment modalities. Med Sci Monit. 2016;22:2589-94. doi: 10.12659/ msm.898675.
  4. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, Von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22(9):1589-97. doi: 10.1200/JCO.2004.08.163.
  5. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636-44. doi: 10.1200/JCO.2003.11.136.
  6. Krawczyk P, Kucharczyk T, Kowalski DM, Powrózek T, Ramlau R, Kalinka-Warzocha E, et al. Polymorphisms in TS, MTHFR and ERCC1 genes as predictive markers in first-line platinum and pemetrexed therapy in NSCLC patients. J Cancer Res Clin Oncol. 2014;140(12):2047-57. doi: 10.1007/ s00432-014-1756-6.
  7. Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1(1):65-70. doi: 10.1038/sj.tpj.6500012.
  8. Kumagai K, Hiyama K, Oyama T, Maeda H, Kohno N. 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. 2003;11(5):593-600.
  9. Ozasa H, Oguri T, Uemura T, Miyazaki M, Maeno K, Sato S, et al. Significance of thymidylate synthase for resistance to pemetrexed in lung cancer. Cancer Sci. 2010;101(1):161-6. doi: 10.1111/j.1349- 7006.2009.01358.x.
  10. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K. 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. 1995;20(3):191-7. doi: 10.1247/csf.20.191.
  11. Ulrich CM, Bigler J, Velicer CM, Greene EA, Farin FM, Potter JD. Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev. 2000;9(12):1381-5.
  12. Pei L, Zhu H, Ye R, Wu J, Liu J, Ren A, et al. Interaction between the SLC19A1 gene and maternal first trimester fever on offspring neural tube defects. Birth Defects Res A Clin Mol Teratol. 2015;103(1):3- 11. doi: 10.1002/bdra.23257.
  13. Mohtaram S, Sheikhha MH, Honarvar N, Sazegari A, Maraghechi N, Feizollahi Z, et al. An association study of the SLC19A1 gene polymorphisms/haplotypes with idiopathic recurrent pregnancy loss in an Iranian population. Genet Test Mol Biomarkers. 2016;20(5): 235-40. doi: 10.1089/gtmb.2015.0230.
  14. Bohanec Grabar P, Leandro-García LJ, Inglada-Pérez L, Logar D, Rodríguez-Antona C, Dožlan V. Genetic variation in the SLC19A1 gene and methotrexate toxicity in rheumatoid arthritis patients. Pharmacogenomics. 2012;13(14):1583-94. doi: 10.2217/pgs.12.150.
  15. Gong Z, Yao S, Zirpoli G, David Cheng TY, Roberts M, Khoury T, et al. Genetic variants in one-carbon metabolism genes and breast cancer risk in E uropean A merican and A frican A merican women. Int J Cancer. 2015;137(3):666-77. doi: 10.1002/ijc.29434.
  16. Dy GK, Bogner PN, Tan W, Demmy TL, Farooq A, Chen H, et al. Phase II study of perioperative chemotherapy with cisplatin and pemetrexed in non– small-cell lung cancer. J Thorac Oncol. 2014;9(2): 222-30. doi: 10.1097/JTO.0000000000000062.
  17. Adjei AA, Mandrekar SJ, Dy GK, Molina JR, Adjei AA, Gandara DR, et al. Phase II trial of pemetrexed plus bevacizumab for second-line therapy of patients with advanced non-small-cell lung cancer: NCCTG and SWOG study N0426. J Clin Oncol. 2010;28(4): 614-9. doi: 10.1200/JCO.2009.23.6406.
  18. Abbasian MH, Ansarinejad N, Abbasi B, Iravani M, Ramim T, Hamedi F, et al. The role of dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms in fluoropyrimidine-based cancer chemotherapy in an Iranian population. Avicenna J Med Biotechnol. 2020;12(3):157-64.
  19. Scagliotti GV, Parikh P, Von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-51. doi: 10.1200/JCO.2007.15.0375.
  20. Abbasian MH, Ansarinejad N, Ramim T, Fardad F, Abbasi B. Methylenetetrahydrofolate reductase C677T (rs1801133) polymorphism and pemetrexed treatment outcome in patients with non–small-cell lung cancer. Pers MJ. 2021; 6(23):5-9. doi: 10.22034/pmj. 2021.249035.
  21. Abbasian MH, Abbasi B, Ansarinejad N, Motevalizadeh Ardekani A, Samizadeh E, Gohari Moghaddam K, et al. Association of interleukin-1 gene polymorphism with risk of gastric and colorectal cancers in an Iranian population. Iran J Immunol. 2018;15(4):321-8. doi: 10.22034/IJI.2018.39401.
  22. Otake Y, Tanaka F, Yanagihara K, Hitomi S, Okabe H, Fukushima M, et al. Expression of thymidylate synthase in human non-small cell lung cancer. Jpn J Cancer Res. 1999;90(11):1248-53.
  23. Sigmond J, Backus HH, Wouters D, Temmink OH, Jansen G, Peters GJ. Induction of resistance to the multitargeted antifolate Pemetrexed (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. Biochem Pharmacol. 2003;66(3):431-8. doi: 10.1016/s0006- 2952(03)00287-9.
  24. Longley DB, Ferguson PR, Boyer J, Latif T, Lynch M, Maxwell P, et al. Characterization of a thymidylate synthase (TS)-inducible cell line: a model system for studying sensitivity to TS-and non-TS-targeted chemotherapies. Clin Cancer Res. 2001;7(11):3533-9.
  25. Kim JH, Lee KW, Jung Y, Kim TY, Ham HS, Jong HS, et al. Cytotoxic effects of pemetrexed in gastric cancer cells. Cancer Sci. 2005;96(6):365-71. doi: 10.1111/j.1349-7006.2005.00058.x.
  26. Gomez HL, Santillana SL, Vallejos CS, Velarde R, Sanchez J, Wang X, et al. A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression. Clin Cancer Res. 2006;12(3):832-8. doi: 10.1158/1078- 0432.CCR-05-0295.
  27. Nakagawa T, Otake Y, Yanagihara K, Miyahara R, Ishikawa S, Fukushima M, et al. Expression of thymidylate synthase is correlated with proliferative activity in non-small cell lung cancer (NSCLC). Lung Cancer. 2004;43(2):145-9. doi: 10.1016/j.lungcan. 2003.09.004.
  28. Wang X, Wang Y, Wang Y, Cheng J, Wang Y, Ha M. Association of thymidylate synthase gene 3'- untranslated region polymorphism with sensitivity of non-small cell lung cancer to pemetrexed treatment: TS gene polymorphism and pemetrexed sensitivity in NSCLC. J Biomed Sci. 2013;20(1):1-8. doi: 10.1186/1423-0127-20-5.
  29. Takezawa K, Okamoto I, Okamoto W, Takeda M, Sakai K, Tsukioka S, et al. Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br J Cancer. 2011;104(10):1594- 601. doi: 10.1038/bjc.2011.129.
  30. Kanazawa K, Yokouchi H, Wang X, Ishida T, Fujita Y, Fujiuchi S, et al. Phase II trial of carboplatin and pemetrexed as first-line chemotherapy for nonsquamous non-small cell lung cancer, and correlation between the efficacy/toxicity and genetic polymorphisms associated with pemetrexed metabolism: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0902. Cancer Chemother Pharmacol. 2014;74(6):1149-57. doi: 10.1007/s00280- 014-2589-3.
  31. Arévalo E, Castañón E, López I, Salgado J, Collado V, Santisteban M, et al. Thymidylate synthase polymorphisms in genomic DNA as clinical outcome predictors in a European population of advanced nonsmall cell lung cancer patients receiving pemetrexed. J Transl Med. 2014;12(1):1-9 doi: 10.1186/1479-5876- 12-98.
  32. Li WJ, Jiang H, Fang XJ, Ye HL, Liu MH, Liu YW, et al. Polymorphisms in thymidylate synthase and reduced folate carrier (SLC19A1) genes predict survival outcome in advanced non-small cell lung cancer patients treated with pemetrexed-based chemotherapy. Oncol Lett. 2013;5(4):1165-70. doi: 10.3892/ol.2013.1175.
  33. Lee SH, Noh KB, Lee JS, Lee EJ, Min KH, Hur GY, et al. Thymidylate synthase and ERCC1 as predictive markers in patients with pulmonary adenocarcinoma treated with pemetrexed and cisplatin. Lung Cancer. 2013;81(1):102-8. doi: 10.1016/j.lungcan.2013.03.002.
  34. Hu Q, Li X, Su C, Chen X, Gao G, Zhang J, et al. Correlation between thymidylate synthase gene polymorphisms and efficacy of pemetrexed in advanced non-small cell lung cancer. Exp Ther Med. 2012;4(6): 1010-6. doi: 10.3892/etm.2012.730.
  35. Adjei AA, Salavaggione OE, Mandrekar SJ, Dy GK, Ziegler KLA, Endo C, et al. Correlation between polymorphisms of the reduced folate carrier gene (SLC19A1) and survival after pemetrexed-based therapy in non-small cell lung cancer: a North Central Cancer Treatment Group-based exploratory study. J Thorac Oncol. 2010;5(9):1346-53. doi: 10.1097/JTO. 0b013e3181ec18c4.
  36. Corrigan A, Walker JL, Wickramasinghe S, Hernandez MA, Newhouse SJ, Folarin AA, et al. Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations. Pharmacogenomics J. 2014;14(5):411- 7. doi: 10.1038/tpj.2014.13.
  37. Zhang X, Zhang D, Huang L, Li G, Chen L, Ma J, et al. Discovery of novel biomarkers of therapeutic responses in Han Chinese pemetrexed-based treated advanced NSCLC patients. Front Pharmacol. 2019;10:944. doi: 10.3389/fphar.2019.00944.