Characterization of the MicroRNA Cargo of Extracellular Vesicles Isolated from a Pulmonary Tumor‐Draining Vein Identifies miR‐203a‐3p as a Relapse Biomarker for Resected Non‐Small Cell Lung Cancer

Abstract

In resected non‐small cell lung cancer (NSCLC), post‐surgical recurrence occurs in around 40% of patients, highlighting the necessity to identify relapse biomarkers. An analysis of the extracellular vesicle (EV) cargo from a pulmonary tumor‐draining vein (TDV) can grant biomarker identification. We studied the pulmonary TDV EV‐miRNAome to identify relapse biomarkers in a two-phase study (screening and validation). In the screening phase, a 17‐miRNA relapse signature was identified in 18 selected patients by small RNAseq. The most expressed miRNA from the signature (EV‐miR‐203a‐3p) was chosen for further validation. Pulmonary TDV EV‐miR‐203a‐3p was studied by qRT‐PCR in a validation cohort of 70 patients, where it was found to be upregulated in relapsed patients (p = 0.0194) and in patients with cancer spread to nearby lymph nodes (N+ patients) (p = 0.0396). The ROC curve analysis showed that TDV EV‐miR‐203a‐3p was able to predict relapses with a sensitivity of 88% (AUC: 0.67; p = 0.022). Moreover, patients with high TDV EV‐miR‐203a‐3p had a shorter time to relapse than patients with low levels (43.6 vs. 97.6 months; p = 0.00703). The multivariate analysis showed that EV‐miR‐203a‐3p was an independent, predictive and prognostic post‐surgical relapse biomarker. In conclusion, pulmonary TDV EV‐miR‐203a‐3p is a promising new relapse biomarker for resected NSCLC patients.