Circulating microRNAs discriminate cholangiocarcinoma from pancreatic cancer

Introduction: Accurate diagnosis of distal cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) is a challenge with clinical consequences. Both are lethal malignancies with distinct therapeutic options. This study aimed to identify a circulating microRNA (miRNA) signature to diagnose and discriminate distal CCA from PDAC. Methods: In the discovery phase, microarray profiling of 752 miRNAs was performed on plasma samples of seven patients with distal CCA and seven age- and sex-matched healthy controls. Significant candidate miRNAs were selected for validation based on predefined selection criteria. In the validation phase, these miRNAs were analyzed by RT-qPCR in an independent cohort of healthy controls (n=32), benign periampullary disease (n=15), distal CCA (n=22), PDAC (n=30), and other hepatobiliary malignancies (n=38). Data were normalized to a combination of two reference genes. The optimal diagnostic combination of miRNAs was determined by logistic regression. Sensitivity and specificity were evaluated by ROC curves and AUC values. Results: In the discovery phase, 19 miRNAs were significantly deregulated in patients with distal CCA compared to healthy controls. In the validation phase, 13 candidate miRNAs were considered. A three-miRNA panel was constructed with the most robust signature to discriminate malignant from benign disease (AUC=0.881). The combination of two of these miRNAs was able accurately distinguish distal CCA from PDAC, with an AUC of 0.814. Conclusion: This is the first study to identify a combined panel of plasma miRNAs which shows promising diagnostic capability to serve as distal CCA signature with the potential to discriminate distal CCA from PDAC.