Prognostic significance of thymidylate synthase in postoperative non-small cell lung cancer patients

Abstract

The aim of the present study was to investigate the clinicopathologic/prognostic significance of thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT), and thymidine phosphorylase (TP) proteins in postoperative non-small cell lung cancer (NSCLC) patients. Microarray slides from a set of 178 NSCLC patients were used for the detection of TS, OPRT, and TP expression by immunohistochemistry. The correlation between clinicopathologic factors and protein expression of three proteins was analyzed. Ninety seven carcinomas (57.4%) were TS-positive, 90 carcinomas (53.9%) were OPRT-positive, and 102 carcinomas (69.4%) were TP-positive. Compared with the TS-positive patients, the overall survival (OS) was significantly lower in the TS-negative patients (hazard ratio [HR] =1.766, 95% confidence interval [CI] =1.212-2.573, P=0.003). Significant differences between TS-positive and TS-negative patients was also observed in the following stratified analyses: 1) adenocarcinoma subgroup (HR =2.079, 95% CI =1.235-3.500, P=0.006); 2) less than 60-year-old subgroup (HR =1.890, 95% CI =1.061-3.366, P=0.031); 3) stage II/III subgroup (HR =1.594, 95% CI =1.036-2.453, P=0.034); and 4) surgery plus adjuvant therapy subgroup (HR =1.976, 95% CI =1.226-3.185, P=0.005). However, the OS was not significantly correlated with OPRT or TP protein expression. This study demonstrates that the TS level in tumor tissues may be a useful marker to predict the postoperative OS in NSCLC patients.

Keywords: orotate phosphoribosyltransferase; thymidine phosphorylase.

Figure 1

Representative images of immunohistochemical staining in human NSCLC tissues (original magnification, ×200). Notes: (A) TS-positive expression; (B) TS-negative control; (C) OPRT-positive expression; (D) OPRT-negative control; (E) TP-positive expression; and (F) TP-negative control. Abbreviations: NSCLC, non-small cell lung cancer; OPRT, orotate phosphoribosyltransferase; TP, thymidine phosphorylase; TS, thymidylate synthase.

Figure 2

(A) Kaplan–Meier plot of OS in TS negative and positive groups; (B) adenocarcinoma patients; (C) patients under 60 years old; (D) patients with pT1/T2; (E) patients with pN0/N1; (F) patients with stage II/III; (G) patients with surgery plus chemotherapy and/or radiation treatment. Abbreviations: C, chemotherapy; OS, overall survival; pN, pathologic nodal; pT, pathologic tumor size; R, radiotherapy; S, surgery; TS, thymidylate synthase; y, years.