Top

Published in:

01-09-2015 | Research Article

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

Authors: Honglin Dong, Dengke Bao, Xu Guo, Jie Hu, Xiaofei Li, Shaogui Wan, Jinliang Xing

Published in: Tumor Biology | Issue 9/2015

Abstract

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.

Available only for authorised users

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.CrossRefPubMedPubMedCentral

Grondin SC, Liptay MJ. Current concepts in the staging of non-small cell lung cancer. Surg Oncol. 2002;11(4):181–90.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer. 2005;5(11):845–56. doi:10.1038/nrc1739.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.

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.PubMed

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.PubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRef

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

21.

Vesell ES. Advances in pharmacogenetics and pharmacogenomics. J Clin Pharmacol. 2000;40(9):930–8.CrossRefPubMed

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.CrossRefPubMed

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.

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.PubMed

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.PubMed

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.CrossRefPubMed

Title: Effect of thymidylate synthase gene polymorphism on the response to chemotherapy and clinical outcome of non-small cell lung cancer patients
Authors: Honglin Dong
Dengke Bao
Xu Guo
Jie Hu
Xiaofei Li
Shaogui Wan
Jinliang Xing
Publication date: 01-09-2015
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 9/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-3447-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 9/2015

ShRNA-mediated knock-down of CXCR7 increases TRAIL-sensitivity in MCF-7 breast cancer cells

Clinical pathological characteristics of breast cancer patients with secondary diabetes after systemic therapy: a retrospective multicenter study

ALDH1 might influence the metastatic capability of HeLa cells

Reply to: “in vivo post-contrast 1H-MRS evaluation of malignant and benign breast lesions: a meta-analysis”

Expression of myeloid zinc finger 1 and the correlation to clinical aspects of oral squamous cell carcinoma

Retraction Note to: Silencing of the Smad nuclear interacting protein 1 (SNIP1) by siRNA inhibits proliferation and induces apoptosis in pituitary adenoma cells

Keynote webinar | Spotlight on antibody–drug conjugates in cancer