Research Papers:

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

Anna Truini, Simona Coco _, Ernest Nadal, Carlo Genova, Marco Mora, Maria Giovanna Dal Bello, Irene Vanni, Angela Alama, Erika Rijavec, Federica Biello, Giulia Barletta, Domenico Franco Merlo, Alessandro Valentino, Paola Ferro, Gian Luigi Ravetti, Sara Stigliani, Antonella Vigani, Franco Fedeli, David G. Beer, Silvio Roncella and Francesco Grossi

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Oncotarget. 2017; 8:68627-68640. https://doi.org/10.18632/oncotarget.19800

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Anna Truini1,2,*, Simona Coco1,*, Ernest Nadal3,4,5,*, Carlo Genova1,2, Marco Mora6, Maria Giovanna Dal Bello1, Irene Vanni1, Angela Alama1, Erika Rijavec1, Federica Biello1, Giulia Barletta1, Domenico Franco Merlo7, Alessandro Valentino8, Paola Ferro8, Gian Luigi Ravetti6, Sara Stigliani9, Antonella Vigani10, Franco Fedeli8, David G. Beer5, Silvio Roncella8 and Francesco Grossi1

1Lung Cancer Unit, Ospedale Policlinico San Martino, Genoa, Italy

2Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, Ospedale Policlinico San Martino, Genoa, Italy

3Thoracic Oncology Unit, Department of Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain

4Molecular Mechanisms and Experimental Therapeutics Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain

5Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA

6Department of Pathology, Ospedale Policlinico San Martino, Genoa, Italy

7Research and Statistics Infrastructure, Azienda Unità Sanitaria Locale di Reggio Emilia - IRCCS, Institute for Advanced Technologies and HealthCare Protocols in Oncology, Reggio Emilia, Italy

8Division of Histopathology and Cytopathology, ASL5, La Spezia, Italy

9UOS Physiopathology of Human Reproduction, Ospedale Policlinico San Martino, Genoa, Italy

10Division of Oncology, ASL5, La Spezia, Italy

*These authors have contributed equally to this work

Correspondence to:

Simona Coco, email: [email protected]

Keywords: malignant pleural mesothelioma, unresectable tumors, miRNA signature, miR-99a/let-7c/miR-125b miRNAs cluster, prognostic biomarkers

Received: January 31, 2017     Accepted: July 12, 2017     Published: August 02, 2017


Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date no 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 using biopsies on 27 unresected MPM patients with distinct clinical outcome: 15 patients had short survival (OS<12 months) and 12 patients had long survival (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 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 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.

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