Tumor Biology

, Volume 36, Issue 9, pp 7151–7157 | Cite as

Effect of thymidylate synthase gene polymorphism on the response to chemotherapy and clinical outcome of non-small cell lung cancer patients

  • Honglin Dong
  • Dengke Bao
  • Xu Guo
  • Jie Hu
  • Xiaofei Li
  • Shaogui Wan
  • Jinliang Xing
Research Article


Genetic polymorphisms of thymidylate synthase (TYMS) gene have been reported to be associated with development or prognosis of several cancers. However, the association between polymorphisms of TYMS gene and clinical outcomes of non-small cell lung cancer (NSCLC) patients are still unknown. In the present study, we investigated the associations between single nucleotide polymorphisms (SNPs) of TYMS gene and response to chemotherapy as well as clinical outcomes in NSCLC patients. Five SNPs in TYMS gene were genotyped using the Sequenom iPLEX genotyping system in a hospital-based cohort with 500 NSCLC patients, and their associations with NSCLC outcomes were evaluated by Cox proportional hazard regression analysis under three genetic models (additive, dominant, and recessive models). Our data showed that there was no significant association between individual SNP and overall survival of NSCLC patients. However, SNP rs2847153 was significantly associated with NSCLC recurrence under recessive model. We further identified a significant interaction between rs2847153 and chemotherapy in modifying clinical outcome of patients. Our data showed that individuals carrying GG/GA genotypes of rs2847153 had a significantly better response to chemotherapy when comparing to those carrying AA genotype. Conclusively, our data suggest that SNPs rs2847153 in TYMS gene may be a potential biomarker for predicting clinical outcome and personalized treatment in NSCLC patients.


Thymidylate synthase Non-small cell lung cancer Single nucleotide polymorphisms Prognosis 



This work was supported by Program for New Century Excellent Talents in University and National Basic Research Program (2015CB553703).

Supplementary material

13277_2015_3447_MOESM1_ESM.xls (21 kb)
Table S1 (XLS 21 kb)


  1. 1.
    Cox G, Jones JL, Andi A, Waller DA, O’Byrne KJ. A biological staging model for operable non-small cell lung cancer. Thorax. 2001;56(7):561–6.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Grondin SC, Liptay MJ. Current concepts in the staging of non-small cell lung cancer. Surg Oncol. 2002;11(4):181–90.CrossRefPubMedGoogle Scholar
  3. 3.
    Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur Respir J. 2001;18(6):1059–68.CrossRefPubMedGoogle Scholar
  4. 4.
    Wakelee H, Belani CP. Optimizing first-line treatment options for patients with advanced NSCLC. Oncologist. 2005;10 Suppl 3:1–10. doi: 10.1634/theoncologist.10-90003-1.CrossRefPubMedGoogle Scholar
  5. 5.
    Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer. 2005;5(11):845–56. doi: 10.1038/nrc1739.CrossRefPubMedGoogle Scholar
  6. 6.
    Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92–8. doi: 10.1056/NEJMoa011954.CrossRefPubMedGoogle Scholar
  7. 7.
    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 Off J Am Soc Clin Oncol. 2008;26(21):3543–51. doi: 10.1200/JCO.2007.15.0375.CrossRefGoogle Scholar
  8. 8.
    Tahara E, Yasui W, Ito H, Harris CC. Recent progress in carcinogenesis, progression and therapy of lung cancer: the 19th Hiroshima Cancer Seminar: the 3rd Three Universities’ Consortium International Symposium, November 2009. Jpn J Clin Oncol. 2010;40(7):702–8. doi: 10.1093/jjco/hyq031.CrossRefPubMedGoogle Scholar
  9. 9.
    Wu MF, Hsiao YM, Huang CF, Huang YH, Yang WJ, Chan HW, et al. Genetic determinants of pemetrexed responsiveness and nonresponsiveness in non-small cell lung cancer cells. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2010;5(8):1143–51. doi: 10.1097/JTO.0b013e3181e0b954.Google Scholar
  10. 10.
    Johnston PG, Drake JC, Trepel J, Allegra CJ. Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5-fluorouracil-sensitive and -resistant human cancer cell lines. Cancer Res. 1992;52(16):4306–12.PubMedGoogle Scholar
  11. 11.
    Johnston PG, Lenz HJ, Leichman CG, Danenberg KD, Allegra CJ, Danenberg PV, et al. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 1995;55(7):1407–12.PubMedGoogle Scholar
  12. 12.
    Igawa S, Ryuge S, Wada M, Otani S, Maki S, Takakura A, et al. Pemetrexed for previously treated patients with non-small cell lung cancer and differences in efficacy according to thymidylate synthase expression. Chemotherapy. 2012;58(4):313–20. doi: 10.1159/000343048.CrossRefPubMedGoogle Scholar
  13. 13.
    Chen CY, Chang YL, Shih JY, Lin JW, Chen KY, Yang CH, et al. Thymidylate synthase and dihydrofolate reductase expression in non-small cell lung carcinoma: the association with treatment efficacy of pemetrexed. Lung Cancer. 2011;74(1):132–8. doi: 10.1016/j.lungcan.2011.01.024.CrossRefPubMedGoogle Scholar
  14. 14.
    Wang X, Wang Y, Cheng J, 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;20:5. doi: 10.1186/1423-0127-20-5.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Xu J, Tian S, Yin Z, Wu S, Liu L, Qian Y, et al. MicroRNA-binding site SNPs in deregulated genes are associated with clinical outcome of non-small cell lung cancer. Lung Cancer. 2014;85(3):442–8. doi: 10.1016/j.lungcan.2014.06.010.CrossRefPubMedGoogle Scholar
  16. 16.
    Zhao HY, Ma GW, Zou BY, Li M, Lin SX, Zhao LP, et al. Prognostic significance of thymidylate synthase in postoperative non-small cell lung cancer patients. OncoTargets Ther. 2014;7:1301–10. doi: 10.2147/OTT.S65067.CrossRefGoogle Scholar
  17. 17.
    Tanaka F, Wada H, Fukui Y, Fukushima M. Thymidylate synthase (TS) gene expression in primary lung cancer patients: a large-scale study in Japanese population. Ann Oncol Off J Eur Soc Med Oncol / ESMO. 2011;22(8):1791–7. doi: 10.1093/annonc/mdq730.CrossRefGoogle Scholar
  18. 18.
    Arevalo E, Castanon E, Lopez 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 non-small cell lung cancer patients receiving pemetrexed. J Transl Med. 2014;12:98. doi: 10.1186/1479-5876-12-98.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Liu HB, Peng YP, Dou CW, Su XL, Gao NK, Tian FM, et al. Comprehensive study on associations between nine SNPs and glioma risk. Asian Pac J Cancer Prev : APJCP. 2012;13(10):4905–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Laing RE, Hess P, Shen Y, Wang J, Hu SX. The role and impact of SNPs in pharmacogenomics and personalized medicine. Curr Drug Metab. 2011;12(5):460–86.CrossRefPubMedGoogle Scholar
  21. 21.
    Vesell ES. Advances in pharmacogenetics and pharmacogenomics. J Clin Pharmacol. 2000;40(9):930–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Chamary JV, Parmley JL, Hurst LD. Hearing silence: non-neutral evolution at synonymous sites in mammals. Nat Rev Genet. 2006;7(2):98–108. doi: 10.1038/nrg1770.CrossRefPubMedGoogle Scholar
  23. 23.
    Shen R, Liu H, Wen J, Liu Z, Wang LE, Wang Q, et al. Genetic polymorphisms in the microRNA binding-sites of the thymidylate synthase gene predict risk and survival in gastric cancer. Mol Carcinog. 2014. doi: 10.1002/mc.22160.Google Scholar
  24. 24.
    Ho V, Massey TE, King WD. Thymidylate synthase gene polymorphisms and markers of DNA methylation capacity. Mol Genet Metab. 2011;102(4):481–7. doi: 10.1016/j.ymgme.2010.12.015.CrossRefPubMedGoogle Scholar
  25. 25.
    Xing J, Myers RE, He X, Qu F, Zhou F, Ma X, et al. GWAS-identified colorectal cancer susceptibility locus associates with disease prognosis. Eur J Cancer. 2011;47(11):1699–707. doi: 10.1016/j.ejca.2011.02.004.CrossRefPubMedGoogle Scholar
  26. 26.
    Zhou F, He X, Liu H, Zhu Y, Jin T, Chen C, et al. Functional polymorphisms of circadian positive feedback regulation genes and clinical outcome of Chinese patients with resected colorectal cancer. Cancer. 2012;118(4):937–46. doi: 10.1002/cncr.26348.CrossRefPubMedGoogle Scholar
  27. 27.
    Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006;355(10):983–91. doi: 10.1056/NEJMoa060570.CrossRefPubMedGoogle Scholar
  28. 28.
    Zheng Z, Chen T, Li X, Haura E, Sharma A, Bepler G. DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med. 2007;356(8):800–8. doi: 10.1056/NEJMoa065411.CrossRefPubMedGoogle Scholar
  29. 29.
    Sharp L, Little J. Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol. 2004;159(5):423–43.CrossRefPubMedGoogle Scholar
  30. 30.
    Shintani Y, Ohta M, Hirabayashi H, Tanaka H, Iuchi K, Nakagawa K, et al. New prognostic indicator for non-small-cell lung cancer, quantitation of thymidylate synthase by real-time reverse transcription polymerase chain reaction. Int J Cancer J Int Cancer. 2003;104(6):790–5. doi: 10.1002/ijc.11014.CrossRefGoogle Scholar
  31. 31.
    Grimminger PP, Schneider PM, Metzger R, Vallbohmer D, Holscher AH, Danenberg PV, et al. Low thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase mRNA expression correlate with prolonged survival in resected non-small-cell lung cancer. Clin Lung Cancer. 2010;11(5):328–34. doi: 10.3816/CLC.2010.n.041.CrossRefPubMedGoogle Scholar
  32. 32.
    Miyoshi T, Kondo K, Toba H, Yoshida M, Fujino H, Kenzaki K, et al. Predictive value of thymidylate synthase and dihydropyrimidine dehydrogenase expression in tumor tissue, regarding the efficacy of postoperatively administered UFT (tegafur+uracil) in patients with non-small cell lung cancer. Anticancer Res. 2007;27(4C):2641–8.PubMedGoogle Scholar
  33. 33.
    Shimizu T, Nakanishi Y, Nakagawa Y, Tsujino I, Takahashi N, Nemoto N, et al. Association between expression of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase and efficacy of pemetrexed in advanced non-small cell lung cancer. Anticancer Res. 2012;32(10):4589–96.PubMedGoogle Scholar
  34. 34.
    Peters EJ, Kraja AT, Lin SJ, Yen-Revollo JL, Marsh S, Province MA, et al. Association of thymidylate synthase variants with 5-fluorouracil cytotoxicity. Pharmacogenet Genomics. 2009;19(5):399–401. doi: 10.1097/FPC.0b013e328329fdec.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Vascular SurgerySecond Hospital of Shanxi Medical UniversityTaiyuanChina
  2. 2.State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic MedicineFourth Military Medical UniversityXi’anChina
  3. 3.Institute of PharmacyPharmaceutical College of Henan UniversityKaifengChina
  4. 4.Department of Thoracic Surgery, Tangdu HospitalFourth Military Medical UniversityXi’anChina

Personalised recommendations