L27 - MiR-21 expression as prognostic biomarker in extrahepatic but not intrahepatic radically resected cholangiocarcinomas

Abstract

Background: Cholangiocarcinoma (CCA) is an aggressive malignant tumor affecting the biliary tree. Increasing evidence suggests the importance of key microRNAs (miRNAs), such as miR-21, in CCA pathogenesis and progression, but previous reports demonstrated the pathological and molecular heterogeneity of intrahepatic (ICC) and extrahepatic cholangiocarcinomas (ECC). Therefore, the aim of our study was to evaluate the prognostic role of miR-21 expression in ICC and ECC.Patients and methods: RNA isolated from 69 paraffin-embedded ICC and ECC tumors was used for expression analysis of mir-21 by quantitative Real-Time PCR. Comparison of clinical information and miR-21 expression was made using the Mann-Whitney U nonparametric test. Disease-free survival (DFS) and overall survival (OS) curves were constructed using Kaplan-Meier method, and differences were analyzed using log-rank test. A Cox proportional hazards model analysis was performed to determine the joint association of all ten clinicopathological factors investigated.Results: ECC patients showed significantly worse median OS compared to ICC (i.e., 32.5 vs. 47 months, respectively, p = 0.047). ICC and the ECC showed also differences in the occurrence of lymphatic and perineural invasion (p = 0.043 and p = 0.010) and miR-21 expression (p = 0.037), which was significantly higher in the ECC. Strikingly, Cox proportional hazards model analysis in the subgroup of ECC patients (N = 41) showed that higher than median miR-21 expression was associated with a significantly higher hazard ratio (HR) for both death (HR = 4.95; 95%CI = 1.07-22.98; p = 0.041) and recurrence (HR = 6.21; 95%CI = 1.29-29.89; p = 0.023). Moreover, miR-21 expression emerged as the single most predictive biomarker for DFS and OS among all the clinicopathological factors evaluated in ECC, while not significant association with prognosis was detected in ICC patients.Conclusions: Several clinicopathologic diversities between ICC and ECC tumors exist. MiR-21 expression might be considered a prognostic factor in ECC, but not in ICC tumors. ECC patients with worse prognosis have high miR-21 expression which therefore represents a promising target for prognostic and therapeutic approaches, suggesting a certain similarity with pancreatic cancer. These results prompt further prospective studies on the prognostic vs. predictive role of miR-21 in larger cohorts of radically resected CCA/ECC patients, including patients who were not treated with adjuvant chemotherapy. Background: Cholangiocarcinoma (CCA) is an aggressive malignant tumor affecting the biliary tree. Increasing evidence suggests the importance of key microRNAs (miRNAs), such as miR-21, in CCA pathogenesis and progression, but previous reports demonstrated the pathological and molecular heterogeneity of intrahepatic (ICC) and extrahepatic cholangiocarcinomas (ECC). Therefore, the aim of our study was to evaluate the prognostic role of miR-21 expression in ICC and ECC. Patients and methods: RNA isolated from 69 paraffin-embedded ICC and ECC tumors was used for expression analysis of mir-21 by quantitative Real-Time PCR. Comparison of clinical information and miR-21 expression was made using the Mann-Whitney U nonparametric test. Disease-free survival (DFS) and overall survival (OS) curves were constructed using Kaplan-Meier method, and differences were analyzed using log-rank test. A Cox proportional hazards model analysis was performed to determine the joint association of all ten clinicopathological factors investigated. Results: ECC patients showed significantly worse median OS compared to ICC (i.e., 32.5 vs. 47 months, respectively, p = 0.047). ICC and the ECC showed also differences in the occurrence of lymphatic and perineural invasion (p = 0.043 and p = 0.010) and miR-21 expression (p = 0.037), which was significantly higher in the ECC. Strikingly, Cox proportional hazards model analysis in the subgroup of ECC patients (N = 41) showed that higher than median miR-21 expression was associated with a significantly higher hazard ratio (HR) for both death (HR = 4.95; 95%CI = 1.07-22.98; p = 0.041) and recurrence (HR = 6.21; 95%CI = 1.29-29.89; p = 0.023). Moreover, miR-21 expression emerged as the single most predictive biomarker for DFS and OS among all the clinicopathological factors evaluated in ECC, while not significant association with prognosis was detected in ICC patients. Conclusions: Several clinicopathologic diversities between ICC and ECC tumors exist. MiR-21 expression might be considered a prognostic factor in ECC, but not in ICC tumors. ECC patients with worse prognosis have high miR-21 expression which therefore represents a promising target for prognostic and therapeutic approaches, suggesting a certain similarity with pancreatic cancer. These results prompt further prospective studies on the prognostic vs. predictive role of miR-21 in larger cohorts of radically resected CCA/ECC patients, including patients who were not treated with adjuvant chemotherapy.