Role of thymidylate synthase as a predictor of neoadjuvant chemoradiation therapy in rectal cancer

Cover Page


Aim. To study the level of thymidylate synthase gene expression in biopsy material from patients with rectal cancer treated with neoadjuvant chemoradiation therapy. Methods. Analysis of treatment of 101 patients with locally advanced rectal cancer (T3-4, N0-2, M0) was conducted. Measurement of the level of thymidylate synthase gene expression was performed by polymerase chain reaction. To extract ribonucleic acid Qiagen (RNA easy FFPEkit; Qiagen,GmbH,Germany) reagents were used. Results. Cancer pathomorphosis stage TRG 1 was revealed in 23 (22.7%) patients, TRG 2 - in 31 (30.7%) patients, TRG 3 - in 32 (31.7%) patients, complete clinical response (i.e. complete tumor resorption TRG 4) - in 15 (14.9%) patients. Analysis of thymidylate synthase gene expression in patients with poor response to chemoradiation therapy showed that in 34.8% of cases high expression was revealed, while in 65.2% of cases - low expression. Among patients with complete clinical response significant prevalence of patients with high expression of thymidylate synthase gene was revealed - 73.3%, and in 26.7% of patients with pathomorphosis of grade 4 low expression of this gene was registered. In patients with tumor regression grade 2 and 3 no significant difference in patients’ ratio was revealed. The most prominent correlation according to the level of thymidylate synthase gene expression was found in patients without the response to conducted chemoradiation therapy (with prevalence of patients with low expression) and complete tumor regression (with prevalence of patients with high expression). Conclusion. There is inverse correlation between the grade of tumor regression and thymidylate synthase gene expression; evaluation of the level of thymidylate synthase gene expression and response of rectal cancer to neoadjuvant chemoradiation therapy requires further investigation both on molecular and clinical levels.

Yu R Aliyarov

Author for correspondence.
National Centre of Oncology Baku, Azerbaijan

L A Melikova
National Centre of Oncology Baku, Azerbaijan

A Kh Kerimov
National Centre of Oncology Baku, Azerbaijan

E E Bagirova
National Centre of Oncology Baku, Azerbaijan

S G Mekhdizade
National Centre of Oncology Baku, Azerbaijan

  • Habr-Gama A., Perez R.O. et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann. Surg. 2004; 240 (4): 711-717; discussion 717-718. doi: 10.1097/01.sla.0000141194.27992.32.
  • Sauer R., Becker H., Hohenberger W. et al. Preoperative versus postoperative chemoradiation for rectal cancer. N. Engl. J. Med. 2007; 351 (17): 1731-1740. doi: 10.1056/NEJMoa040694.
  • Salonga D., Danenberg K.D., Johnson M. et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin. Cancer Res. 2000; 6 (4): 1322-1327. PMID: 10778957.
  • Soma G., Zulfiquer H.M. Analysis of region: Atool for pharmacogenetic studies. PLOS ONE. 2012; 7 (4): e34426. doi: 10.1371/journal.pone.0034426.
  • Saw R.P., Morgan M., Koorey D. et al. P53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced rectal cancer treated with preoperative adjuvant therapy. Dis. Colon Rectum. 2003; 46 (2): 192-202. doi: 10.1007/s10350-004-6524-2.
  • Diez M., Ramos P., Medrano M. et al. Preoperatively irradiated rectal carcinoma: analysis of the histopathologic response and predictive value of proliferating cell nuclear antigen immunostaining. Oncology. 2003; 64 (3): 213-219. doi: 10.1159/000069307.
  • Jakob C., Liersch T., Meyer W. et al. Predictive value of Ki67 and p53 in locally advanced rectal cancer: correlation with thymidylatesybthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiotherapy. World J. Gastroenterol. 2008; 14 (7): 1060-1066. doi: 10.3748/wjg.14.1060.
  • Negri F.V., Campanini N., Camisa R. et al. Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy. Br. J. Cancer. 2008; 98 (1): 143-147. doi: 10.1038/sj.bjc.6604131.
  • Dworak O., Keilholz L., Hoffmann A. Pathologic features of rectal cancer after preoperative radiochemotherapy. Int. J. Colorect. Dis. 1997; 12 (1): 19-23. doi: 10.1007/s003840050072.
  • Kwon J., Oh E., Lee S. et al. Identification of novel reference genes using multiplatform expression data and their validation for quantitative gene expression analysis. PLOS ONE. 2009; 4 (7): e6162. doi: 10.1371/journal.pone.0006162.
  • Real Time PCR Handbook. University of Illniois at Chicago, 2013. (access date: 25.04.2017).
  • The center for computational and integrative Biology. Protocol for Real-Time PCR. 2006. (access date: 04.05.2017).
  • Shimamoto Y., Nukatsuka M., Takechi T., Fukushima M. Association between mRNA expression of chemotherapy-related genes and clinicopathological features in colorectal cancer: A large-scale population analysis. Intern. J. Mol. Med. 2016; 37 (2): 319-328. doi: 10.3892/ijmm.2015.2427.
  • Wakasa K., Kawabata R., Nakao S. et al. Dynamic modulation of thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells. PLOS ONE. 2015; 10 (4): e012307. doi: 10.1371/journal.pone.0123076.


Abstract - 9

PDF (Russian) - 12

© 2017 Aliyarov Y.R., Melikova L.A., Kerimov A.K., Bagirova E.E., Mekhdizade S.G.

Creative Commons License

This work is licensed
under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.