Blood small extracellular vesicles derived miRNAs to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis

BACKGROUND: The differential diagnosis of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) is clinically challenging due to a lack of minimally invasive diagnosis methods. MicroRNAs (miRNAs) derived from small extracellular vesicles (EVs) in the blood have been reported as a promising diagnosis biomarker for various types of cancer. However, blood small EV miRNA signatures and their diagnostic value to differentiate between PDAC and CP remain to be determined. METHODS: In this study, 107 patients with PDAC or CP were recruited, and 90 patients were finally enrolled for a training cohort (n = 48) and test cohort (n = 42). Small RNA sequencing was used to assess the expression of blood small EV miRNAs in these patients. RESULTS: The linear model from the differentially expressed blood small EV miR‐95‐3p divided by miR‐26b‐5p showed an average sensitivity of 84.1% and an average specificity of 96.6% to identify PDAC from CP in the training cohort and the test cohort, respectively. When the model was combined with serum carbohydrate antigen 19‐9 (CA19‐9), the average sensitivity increased to 96.5%, and the average specificity remained at 96.4% of both cohorts, which demonstrated the best performance of all the published biomarkers for distinguishing between PDAC and CP. The causal analysis performed using the Bayesian network demonstrated that miR‐95‐3p was associated with a “consequence” of “cancer” and miR‐26b‐5p as a “cause” of “pancreatitis.” A subgroup analysis revealed that blood small EV miR‐335‐5p/miR‐340‐5p could predict metastases in both cohorts and was associated with an overall survival (p = 0.020). CONCLUSIONS: This study indicated that blood small EV miR‐95‐3p/miR‐26b‐5p and its combination with serum levels of CA19‐9 could separate PDAC from CP, and miR‐335‐5p/miR‐340‐5p was identified to associate with PDAC metastasis and poor prognosis. These results suggested the potentiality of blood small EV miRNAs as differential diagnosis and metastases biomarkers of PDAC.