Serum extracellular vesicle-derived microRNAs as potential biomarkers for pleural mesothelioma in a European prospective study

Abstract Background. Malignant Pleural Mesothelioma (MPM) is an aggressive cancer with a dismal prognosis. Early therapeutic interventions could improve patient outcomes.We aimed at identifying a pattern of microRNAs (miRNAs) as potential early non-invasive markers of MPM. Methods. In a case–control study nested in the European Prospective Investigation into Cancer and nutrition cohort, we screened the whole miRNome in serum extracellular vesicles (EVs) of preclinical MPM cases, by means a next generation sequencing approach.In a case–control study nested in the European Prospective Investigation into Cancer and nutrition (EPIC) cohort, we screened the whole miRNome in serum extracellular vesicles (EVs) derived from 80 pre-clinical cases of MPM (median time to diagnosis = 8 years) and 80 matched cancer-free controls. Results. We did not detect any miRNA in serum EVs significantly differentially expressed between 80 pre-clinical MPM and matched controls. On the other hand, in a subgroup of 20 preclinical samples collected five years prior MPM diagnosis, we observed an up-regulation of miR-11400 (Fold change =2.6, adjusted p-value=0.01), miR-148a-3p (Fold change =1.5, p-value=0.001) and miR-409-3p (Fold change =1.5, p-value=0.04) respect to matched controls. The three-miRNA panel showed a good classification capacity with an area under the receiver operating characteristic curve (AUC) of 0.81 (specificity=0.75, sensitivity=0.70). The diagnostic ability of the model was also evaluated in an independent retrospective cohort, yielding a higher predictive power (AUC = 0.86). Conclusions. A signature of EV miRNA can be detected up to five years before MPM; moreover, the identified miRNAs could provide functional insights into the molecular changes related to the late carcinogenic process, preceding MPM development. However, the potential role of the three identified miRNAs requires further validation in a larger independent MPM prospective study.