PROGNOSTIC SIGNIFICANCE EXPRESSION OF MRNA TOP1, TOP2Α, TUBΒ3, TYMS, ABCC5 AND GSTP1 GENES IN PATIENTS WITH NON-SMALL CELL LUNG CANCER

DOI: https://doi.org/10.29296/24999490-2018-04-04

I.V. Deryusheva, M.M. Tsyganov, E.O. Rodionov, L.A. Efteev, M.K. Ibragimova, S.V. Miller, S.A. Tuzikov, N.V. Litviakov Саnсеr Rеsеаrсh Institute, Tomsk National Research Medical Center of Russian Academy of Sciences, Kooperativnystr, 5, Tomsk, Russian Federation,634050 E-mail: [email protected]

Introduction. Despite the continuous improvement of the surgical method of treatment of patients with non-small cell lung cancer (NSCLC), there is no noticeable tendency to improve survival data. This 5-year index does not exceed 15–25%. In this regard, it is important to search for new prognostic factors and markers that would provide a high probability to predict the outcome of the disease. The aim of the study was to evaluate the prognostic significance of the level of expression of chemosensitivity genes in NSCLC patients. Materials and methods. The study included 43 NSCLC patients at the stage IIA-IIIB. RNA was isolated from the operating samples of normal and tumor lung tissues after neoadjuvant chemotherapy (NAC). The level of expression of the chemosensitivity genes TOP1, TOP2α, TYMS, ABCC5, TUBβ3, GSTP1 was evaluated by reverse-transcriptase quantitative real-time PCR (RT-qPCR). Results. Analysis of survival curves by the Kaplan-Mayer method allowed to establish significant differences in the parameters of total and disease-free survival in groups of patients with different levels of expression of TUBβ3, TOP2α and GSTP1. The rates of total and disease-free survival in patients with TUBβ3 expression are less than 0,3 (p=0,006 and p=0,02, respectively). The presence in the residual tumor of GSTP1 expression above 0,9 is associated with low disease-free survival (p=0,04). Expression of the TOP2α gene less than 0,1 is statistically associated with a good prognosis of total disease-free survival (p
Keywords: 
non-small cell lung cancer, chemosensitivity genes, mRNA expression, total disease-free survival

Список литературы: 
  1. O’byrne K.J., Gatzemeier U., Bondarenko I., Barrios C., Eschbach C., Martens U.M., Hotko Y., Kortsik C., Paz-Ares L., Pereira J.R. Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. The lancet oncology. 2011; 12 (8): 795–05.
  2. Wei C.H., Gorgan T.R., Elashoff D.A., Hines O.J., Farrell J.J., Donahue T.R. A meta-analysis of gemcitabine biomarkers in patients with pancreatico-biliary cancers. Pancreas. 2013; 42 (8): 1303–10.
  3. Tsyganov M.M., Rodionov E.O., Miller S.V., Litvyakov N.V. Substantiation of Expressive Markers Use to Personalize Lung Cancer Chemotherapy. Antibiotics and chemoterapy. 2014; 60 (9–10): 38–45.
  4. Kucukoztas N., Oguz A., Rahatli S., Dizdar O., Yildiran Keskin G.S., Ozyilkan O., Altundag O. Correlation of histopahologic response and prognostic markers with survival in locally advanced non-small cell lung cancer patients who have treated with neoadjuvant chemotherapy. J. of Clinical Oncology. 2015; 35 (15): e18521.
  5. Hussein O., Karen D., Zidan J. Cisplatin based chemotherapy in patients with advanced differentiated thyroid carcinoma refractory to I131 treatment. Indian journal of medical and paediatric oncology: official journal of Indian Society of Medical & Paediatric Oncology. 2013; 34 (4): 234–7.
  6. Yumov E.L., Cyganov M.M., Litvyakov N.V., Polishhuk T.V., Miller S.V., Rodionov E.O., Tuzikov S.A. E`kspressiya genov mnozhestvennoy lekarstvennoy ustoychivosti i monorezistentnosti pri nemelkokletochnom rake legkogo. Sibirskiy onkologicheskiy zhurnal. 2013; 61 (1): 16–22. [Yumov E.L., Tsyganov M.M., Litviakov N.V., Polishchuk T.V., Miller S.V., Tuzikov S.A. Exspression of MDR-genes and monoresistance genes in non-small-cell lung cancer. Siberian Journal of Oncology. 2013; 61 (1): 16–22 (in Russian)]
  7. Crino L., Weder W., Van Meerbeeck J., Felip E. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2010; 21 (5): 103–15.
  8. Vansteenkiste J., De Ruysscher D., Eberhardt W., Lim E., Senan S., Felip E., Peters S. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2013; 24 (6): 89–98.
  9. Pfaffl M.W. A new mathematical model for relative quantification in real-time RT–PCR. Nucleic acids research. 2001; 29 (9): 2002–07.
  10. Sun S., Shi W., Wu Z., Zhang G., Yang B., Jiao S. Prognostic significance of the mRNA expression of ERCC1, RRM1, TUBB3 and TYMS genes in patients with non-small cell lung cancer. Experimental and therapeutic medicine. 2015; 10 (3): 937–41.
  11. Levallet G., Bergot E., Antoine M., Creveuil C., Santos A.O., Beau-Faller M., De Fraipont F., Brambilla E., Levallet J., Morin F. High TUBB3 expression, an independent prognostic marker in patients with early non–small cell lung cancer treated by preoperative chemotherapy, is regulated by k-ras signaling pathway. Molecular Cancer Therapeutics. 2012; 11 (5): 1203–13.
  12. Huang Z.L., Cao X., Luo R.Z., Chen Y.F., Zhu L.C., Wen Z. Analysis of ERCC1, BRCA1, RRM1 and TUBB3 as predictors of prognosis in patients with non-small cell lung cancer who received cisplatin-based adjuvant chemotherapy: A prospective study. Oncology Letters. 2016; 11 (1): 299–05.
  13. Zhou F., Yu Z., Jiang T., Lv H., Yao R., Liang J. Genetic polymorphisms of GSTP1 and XRCC1: prediction of clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. Swiss Med Wkly. 2011; 60 (141): w13275.
  14. Gonlugur U., Pinarbasi H., Gonlugur T.E., Silig Y. The association between polymorphisms in glutathione S-transferase (GSTM1 and GSTT1) and lung cancer outcome. Cancer investigation. 2006; 24 (5): 497–501.
  15. Joshi M.-B.M., Shirota Y., Danenberg K.D., Conlon D.H., Salonga D.S., Herndon J.E., Danenberg P.V., Harpole D.H. High gene expression of TS1, GSTP1, and ERCC1 are risk factors for survival in patients treated with trimodality therapy for esophageal cancer. Clinical Cancer Research. 2005; 11 (6): 2215–21.
  16. Wang J., Xu B., Yuan P., Zhang P., Li Q., Ma F., Fan Y. TOP2A amplification in breast cancer is a predictive marker of anthracycline-based neoadjuvant chemotherapy efficacy. Breast cancer research and treatment. 2012; 135 (2): 531–37.
  17. De Resende M.F., Vieira S., Chinen L., Chiappelli F., Da Fonseca F.P., Guimarães G.C., Soares F.A., Neves I., Pagotty S., Pellionisz P.A. Prognostication of prostate cancer based on TOP2A protein and gene assessment: TOP2A in prostate cancer. J. Transl Med. 2013; 11 (1): 1–9.
  18. Lu B., Zhang H., Zhang T., Cai Y., Hu Y., Zheng H., Li B. Topoisomerase I expression is associated with prognosis in postoperative non-small cell lung cancer patients. Thoracic cancer. 2016; 7 (4): 486–94.
  19. Lee Y.-C., Lee C.-H., Tsai H.-P., An H.-W., Lee C.-M., Wu J.-C., Chen C.-S., Huang S.-H., Hwang J., Cheng K.-T. Targeting of topoisomerase i for prognoses and therapeutics of Camptothecin-Resistant ovarian cancer. PLoS One. 2015; 10 (7): 1–19.
  20. Orlando L., Del Curto B., Gandini S., Ghisini R., Pietri E., Torrisi R., Balduzzi A., Cardillo A., Dellapasqua S., Veronesi P. Topoisomerase IIα gene status and prediction of pathological complete remission after anthracycline-based neoadjuvant chemotherapy in endocrine non-responsive Her2/neu-positive breast cancer. The Breast. 2008; 17 (5): 506–11.