Circulating microRNA-99 family as liquid biopsy marker in pancreatic adenocarcinoma

Stroese AJ, Ullerich H, Koehler G, Raetzel V, Senninger N, Dhayat SA

Abstract

PURPOSE: Recently, we identified the microRNA-99 family as unfavorable prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to evaluate its value as circulating biomarker for PDAC. METHODS: Tissue and corresponding preoperative blood samples of 181 patients with PDAC UICC Stages I-IV (n = 90), intraductal papillary mucinous neoplasm (IPMN, n = 11), chronic pancreatitis (n = 40), pancreatic cystadenoma (n = 20), and age-matched healthy blood serum controls (n = 20) were collected between 2014 and 2017 prospectively. Expression of microRNA-21 as confirmatory marker and the microRNA-99 family, consisting of microRNA-99a, -99b, and -100, was analyzed by qRT-PCR. Target analysis of insulin-like growth factor 1 receptor (IGF1R) was performed using tissue array immunohistochemistry and Western blotting. RESULTS: Expression of microRNA-99 family members was significantly increased in macrodissected tumor tissue and corresponding blood serum samples (p < 0.05) of patients with PDAC of all stages. Correspondingly, its target protein IGF1R was upregulated (p < 0.001) in carcinoma tissue. Circulating and tissue-related microRNA-100 could well discriminate PDAC from healthy samples with area under the receiver operating characteristic (ROC) curve (AUC) values of 0.81 and 0.85, respectively. Low expression of circulating microRNA-100 was associated with significantly improved overall survival (p = 0.004) and recurrence-free survival (p = 0.03) in multivariate analyses. Circulating microRNA-21 was overexpressed in PDAC with fair discrimination between PDAC and healthy controls (AUC = 0.71) and decreased overall survival (p = 0.046) and recurrence-free survival (p = 0.03) in PDAC patients. CONCLUSIONS: Multivariate survival and ROC analyses identified circulating microRNA-100 as potential diagnostic and prognostic marker in PDAC patients.