Down modulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date few molecular markers are available to guide patient management. This study aimed to identify a prognostic miRNA signature in MPM patients who did not undergo tumor resection. Whole miRNA profiling using a microarray platform was performed on 26 unresected MPM with distinct clinical outcome: 15 patients had aggressive disease (OS<12 months) and 11 patients indolent disease (OS>36 months). Three prognostic miRNAs (mir-99a, let-7c and miR-125b) encoded at the same cluster (21q21) were selected for further validation and tested on publicly available miRNA sequencing data (TCGA) from 72 MPM patients with survival data. A risk model was built based on these 3 miRNAs that was validated by quantitative PCR in an independent set of 30 MPM patients. High risk patients had shorter median OS (7.6 months) as compared with low-risk patients (median not reached). In the multivariate Cox model, a high risk score was an independently associated with shorter OS (HR=3.14; 95% CI, 1.18–8.34; P=0.022). Our study identified that the downregulation of the miR-99a/let-7/miR-125b miRNA cluster predicts poor outcome in unresected MPM. In the present study the whole miRNA profile was evaluated in a cohort of 26 malignant pleural mesothelioma (MPM) sample derived from patients who did not undergo surgery and in 3 nonmalingnat pleura (NMP) as normal control (NC). The comparison between MPM and NC samples allowed to identify miRNA linked to tumorigenesis. The second aim was the identification of miRNA correlated with overall survival (OS); for this purpose the MPM patients were divided based on the survival rate in: i) long survivors (LS; patients whose OS was greater than 36 months); and ii) short survivors (SS; patients died within 12 months from the diagnosis).