Association Between Mismatch Repair Gene And Efficacy To Irinotecan-based Chemotherapy In Metastatic Colon Cancer

Background&Objective:Mismatch repair (MMR) gene is closely related to pathogenesis of colon cancer and is a potential prognostic factor. Our aim is to investigate the association between MMR status and efficacy of irinotecan-based chemotherapy in metastatic colon cancer patients.Methods:Datas of184metastatic colon cancer patients accepting irinotecan-based chemotherapy for the the first-line treatment were collected. MMR statuses were determined by immunohistochemistry. Associations of MMR and clinicopathologic features were determined by χ2tests.3-year progression-free survival (DFS) and3-year overall survival (OS) were analyzed using multivariable Cox models and Kaplan-Meier method.Two sets of contrasting cell lines including dMMR and pMMR statuses were established through hMLH1gene transfection and interference technology. Sensitivity of colon cancer cell lines to CPT-11was studied by MTT assay and the changes of IC50were assessed by ANOVA and SNK test. Regulation of thymidylate Synthase (TS) by CPT-11in colon cancer cell lines with different MMR status was also studied through western blotting and quantitative real-time PCR (qRT-PCR) assay. All statistical tests in the study were two-sided and statistical significance was set atp<0.05.Results:DMMR was found in18.5%evaluable patients and related with proximal colon cancer (p=0.005) and poorly differentiated tumors (p=0.018), with no correlation with TS, which was showed in preclinical and clinical level in this study.DCR in dMMR and pMMR patients were84.8%and66.2%respectively (p=0.037). The mean PFS was8.6months (95%CI:7.1-10.0months) in dMMR tumours and6.6months (95%CI:6.0-7.3months) in pMMR tumours, with statistical significance (p=0.018). Mean OS was18.7months (95%CI:17-20.4months) and17.5months (95%CI:16.7-18.3months) respectively, but the difference was not statistically significant (p=0.246).DMMR colon cancer cells (SW480-shRNA-hMLH1and HCT-116hMLH1vector) were more sensitive to CPT-11than pMMR cells. After being exposed to CPT-11, TS expression in each group of colon cancer cells was reduced, especially in dMMR cells (p<0.05).Conclusions:DMMR was associated with proximity and poor differentiation in colon cancer, with no relation with TS. MMR is a predictive marker for response to irinotecan-based chemotherapy in metastatic colon cancer. Colon cancer cell lines with dMMR status were more sensitive to CPT-11. TS expression level was reduced after CPT-11treatment, especially in dMMR cells.