Association between EML4-ALK fusion gene and thymidylate synthase mRNA expression in non-small cell lung cancer tissues

Xu,Chun‑Wei; Wang,Gang; Wang,Wu‑Long; Gao,Wen‑Bin; Han,Chuan‑Jun; Gao,Jing‑Shan; Zhang,Li‑Ying; Li,Yang; Wang,Lin; Zhang,Yu‑Ping; Tian,Yu‑Wang; Qi,Dong‑Dong

doi:10.3892/etm.2015.2372

Association between EML4-ALK fusion gene and thymidylate synthase mRNA expression in non-small cell lung cancer tissues

Authors:
- Chun‑Wei Xu
- Gang Wang
- Wu‑Long Wang
- Wen‑Bin Gao
- Chuan‑Jun Han
- Jing‑Shan Gao
- Li‑Ying Zhang
- Yang Li
- Lin Wang
- Yu‑Ping Zhang
- Yu‑Wang Tian
- Dong‑Dong Qi
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Affiliations: Department of Pathology, The General Military Hospital of Beijing PLA, Beijing 100700, P.R. China, Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China, Graduate School of Dalian University, Dalian, Liaoning 116622, P.R. China, Department of Clinical Medicine, Dalian Medical University, Dalian, Liaoning 116044, P.R. China, Department of Oncology, The General Military Hospital of Beijing PLA, Beijing 100700, P.R. China, Department of Pathology, Shanxi Dayi Hospital, Shanxi Academy of Medical Sciences, Taiyuan, Shanxi 030001, P.R. China, Department of Pathology, The People's Hospital of Weifang, Weifang, Shandong 261041, P.R. China
Published online on: March 19, 2015 https://doi.org/10.3892/etm.2015.2372
Pages: 2151-2154

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Abstract

This study aimed to investigate the association of the mRNA expression of the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene with that of thymidylate synthase (TYMS) in non‑small cell lung cancer (NSCLC) tissues. Quantitative polymerase chain reaction was used to detect the expression of EML4‑ALK fusion gene and TYMS mRNA in 257 cases of NSCLC. The positive rate of EML4‑ALK fusion gene was 4.28% in the NSCLC tissues (11/257), and was higher in nonsmokers than in smokers (P<0.05); TYMS mRNA expression was detected in 63.42% (163/257) of cases. An association of the EML4‑ALK fusion gene with TYMS expression was detected; a low expression level of TYMS mRNA was observed more frequently when the EML4‑ALK fusion gene was present than when it was not detected (P<0.05). In conclusion, patients positive for the EML4‑ALK fusion gene in NSCLC tissues are likely to have a low expression level of TYMS, and may benefit from the first‑line chemotherapy drug pemetrexed.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Sher T, Dy GK and Adjei AA: Small cell lung cancer. Mayo Clin Proc. 83:355–367. 2008. View Article : Google Scholar : PubMed/NCBI
3	Horn L and Pao W: EML4-ALK: Honing in on a new target in non-small-cell lung cancer. J Clin Oncol. 27:4232–4235. 2009. View Article : Google Scholar : PubMed/NCBI
4	Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 448:561–566. 2007. View Article : Google Scholar : PubMed/NCBI
5	Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H, Okui M, Satoh Y, Okumura S, Nakagawa K, Soda M, et al: EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol. 3:13–17. 2008. View Article : Google Scholar : PubMed/NCBI
6	Perner S, Wagner PL, Demichelis F, Mehra R, Lafargue CJ, Moss BJ, Arbogast S, Soltermann A, Weder W, Giordano TJ, et al: EML4-ALK fusion lung cancer: A rare acquired event. Neoplasia. 10:298–302. 2008. View Article : Google Scholar : PubMed/NCBI
7	Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC, Ho KK, Au JS, Chung LP and Pik Wong M: University of Hong Kong Lung Cancer Study Group: The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 115:1723–1733. 2009. View Article : Google Scholar : PubMed/NCBI
8	Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U, et al: Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 27:4247–4253. 2009. View Article : Google Scholar : PubMed/NCBI
9	Martelli MP, Sozzi G, Hernandez L, Pettirossi V, Navarro A, Conte D, Gasparini P, Perrone F, Modena P, Pastorino U, et al: EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am J Pathol. 174:661–670. 2009. View Article : Google Scholar : PubMed/NCBI
10	Sasaki T, Rodig SJ, Chirieac LR and Jänne PA: The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 46:1773–1780. 2010. View Article : Google Scholar : PubMed/NCBI
11	Diasio RB and Johnson MR: The role of pharmacogenetics and pharmacogenomics in cancer chemotherapy with 5-fluorouracil. Pharmacology. 61:199–203. 2000. View Article : Google Scholar : PubMed/NCBI
12	Fukushima M, Morita M, Ikeda K and Nagayama S: Population study of expression of thymidylate synthase and dihydropyrimidine dehydrogenase in patients with solid tumors. Int J Mol Med. 12:839–844. 2003.PubMed/NCBI
13	Chu E, Copur SM, Ju J, Chen TM, Khleif S, Voeller DM, Mizunuma N, Patel M, Maley GF, Maley F and Allegra CJ: Thymidylate synthase protein and p53 mRNA form an in vivo ribonucleoprotein complex. Mol Cell Biol. 19:1582–1594. 1999.PubMed/NCBI
14	Kawakami K, Graziano F, Watanabe G, Ruzzo A, Santini D, Catalano V, Bisonni R, Arduini F, Bearzi I, Cascinu S, et al: Prognostic role of thymidylate synthase polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy. Clin Cancer Res. 11:3778–3783. 2005. View Article : Google Scholar : PubMed/NCBI
15	Righi L, Papotti MG, Ceppi P, Billè A, Bacillo E, Molinaro L, Ruffini E, Scagliotti GV and Selvaggi G: Thymidylate synthase but not excision repair cross-complementation group 1 tumor expression predicts outcome in patients with malignant pleural mesothelioma treated with pemetrexed-based chemotherapy. J Clin Oncol. 28:1534–1539. 2010. View Article : Google Scholar : PubMed/NCBI
16	Gomez HL, Santillana SL, Vallejos CS, Velarde R, Sanchez J, Wang X, Bauer NL, Hockett RD, Chen VJ, Niyikiza C and Hanauske AR: A phase II trial of pemetrexed in advanced breast cancer: Clinical response and association with molecular target expression. Clin Cancer Res. 12:832–838. 2006. View Article : Google Scholar : PubMed/NCBI
17	Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 363:1693–1703. 2010. View Article : Google Scholar : PubMed/NCBI
18	Kim DW, Ahn MJ, Shi YK, et al: Updated results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol. 30:(Suppl): abstr. 75332012. View Article : Google Scholar
19	Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 368:2385–2394. 2013. View Article : Google Scholar : PubMed/NCBI
20	Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, Haruta H, et al: ALK Lung Cancer Study Group: EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 363:1734–1739. 2010. View Article : Google Scholar : PubMed/NCBI
21	Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, et al: Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 131:1190–1203. 2007. View Article : Google Scholar : PubMed/NCBI
22	Zhang X, Zhang S, Yang X, Yang J, Zhou Q, Yin L, An S, Lin J, Chen S, Xie Z, et al: Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. Mol Cancer. 9:1882010. View Article : Google Scholar : PubMed/NCBI
23	Sun Y, Ren Y, Fang Z, Li C, Fang R, Gao B, Han X, Tian W, Pao W, Chen H and Ji H: Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. J Clin Oncol. 28:4616–4620. 2010. View Article : Google Scholar : PubMed/NCBI
24	Gandara DR, Huang E and Desai S: Thymidylate synthase (TS) gene expression in patients with ALK positive(+) non-small cell lung cancer (NSCLC): Implications for therapy. J Clin Oncol. 30:(Suppl). a75822012.