The influence of GSTM1-null, TS-del6bp, XRCC1-A751C gene polymorphisms on overall survival in colorectal cancer patients related to the TNM parameters: A Romanian single-center study
Authors: L. Procopciuc, G. Osian, M. Iancu
Journal: Annals of Oncology (2018)

Introduction: Sporadic colorectal cancer (CRC) can be caused by different polymorphisms located in genes associated with methylation defects (thymidylate synthase-TS), genes implicated in carcinogen metabolism (glutathione S-transferase Mu 1-GSTM1), and genes involved in the DNA repair process (XRCC1). The objective of this study was to investigate: i) the associations between clinical factors: Duke's stages and certain parameters of TNM classification such as tumor extension (pT), distant metastases (M), lymph nodes (N), grade of cancer cells (G) and survival in colorectal cancer patients; ii) the influence of the studied gene polymorphisms stratified by TNM parameters. Methods: This was a prospective study on 75 patients who were genotyped for GSTM1-null, thymidylate synthase enhancer region (TSER) double and triple tandem repeats (TSER-2R, TSER-3R), TS3'-UTR (1494del6), and XRCC1-A751C using PCR-RFLP. The Kaplan–Meier method, log-rank test and univariate Cox regression were used to analyze differences in survival time based on genetic and clinical factors. The magnitude of association was quantified by hazard ratio (HR) and 95% confidence level for HR. All statistical tests and calculations were performed in R-software, v.4.3.0. Results: We analyzed survival data in a sample of 75 colorectal cancer patients with a mean age of 65.3±9.7 years. The GSTM1, TS-del6bp, XRCC1-A751C variant genotypes were observed in 46 (61.3%), 44 (58.7%) and 41 (54.7%) patients. The distribution of Duke's stages was as follows: A (20%), B (24%), C (48%), D (8%), and the tumor characteristics were: pT1 (16%), pT2/pT3 (58.7%), pT4 (25.3%), N0 (42.7%), N1/pN2 (57.3%), M0 (42.7%), M1 (57.3%), G1/G2 (77.3%), G3/G4 (22.7%). The mean survival times (months) of Duke's stages (A, B, C and D) were 45.4, 43.4, 26.9 and 37.5, respectively (p < 0.001). Patients with Duke's C stage of CRC had a poor survival rate compared to Duke's A stage (HR = 16.4, p = 0.006). The pT and N parameters were significant predictors with a negative effect on overall survival (pT2/pT3 vs. pT1: HR = 4.7, p = 0.136, pT4 vs. pT1: HR = 15.9, p = 0.008 and N1 vs. N0: HR = 3.2, 95% HR: 1.4-7.6), while M and G were not significant predictors of survival time. The results of stratified survival analysis by the presence of distant metastases (M) showed that TS-del6bp gene polymorphism was a significant predictor with a negative effect on overall survival only for CRC patients with M1 (p = 0.009, HR = 7.32, 95% CI: 1.63-32.94). Stratification by grade of cancer cells evidenced that XRCC1-A751C gene polymorphism was a significant predictor with a positive effect on survival for patients with G1/G2 (p = 0.005, HR = 0.27, 95%CI: 0.10-0.66), while GSTM1 gene polymorphism tended to be a predictor with a positive effect on survival for patients with G3/G4 (p = 0.104, HR = 0.30, 95% CI: 0.07-1.3). Conclusion: The pT, N parameters and Duke's stages are predictors of poor overall survival. The effect of the studied gene polymorphisms on overall survival of CRC patients was different depending on M and G parameters: TS-del6bp gene polymorphism was a negative predictor of survival only for patients with distant metastases, while XRCC1-A751C gene polymorphism was a significant predictor with a positive effect on survival for patients with G1/G2.