Systematic review and critique of circulating miRNAs as biomarkers of stage I-II non-small cell lung cancer

Francesca Moretti, Paola D’Antona, Emanuele Finardi, Marco Barbetta, Lorenzo Dominioni, Albino Poli, Elisabetta Gini, Douglas M. Noonan, Andrea Imperatori, Nicola Rotolo, Maria Cattoni and Paola Campomenosi _

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Oncotarget. 2017; 8:94980-94996. https://doi.org/10.18632/oncotarget.21739

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Francesca Moretti1, Paola D’Antona2, Emanuele Finardi1, Marco Barbetta1, Lorenzo Dominioni3, Albino Poli1, Elisabetta Gini2, Douglas M. Noonan2,4, Andrea Imperatori3, Nicola Rotolo3, Maria Cattoni3 and Paola Campomenosi2,5

1Department of Diagnostic and Public Health, University of Verona, Verona, Italy

2Department of Biotechnology and Life Sciences, DBSV, University of Insubria, Varese, Italy

3Department of Medicine and Surgery, DMS, Center for Thoracic Surgery, University of Insubria, Varese, Italy

4Scientific and Technological Pole, IRCCS MultiMedica, Milan, Italy

5The Protein Factory, Centro Interuniversitario di Ricerca in Biotecnologie Proteiche, Politecnico di Milano, ICRM-CNR Milano and University of Insubria, Varese, Italy

Correspondence to:

Paola Campomenosi, email: [email protected]

Keywords: microRNA, biomarkers, circulating, non-small cell lung cancer, stage I-II NSCLC

Received: August 09, 2017     Accepted: September 22, 2017     Published: October 11, 2017


Selected circulating microRNAs (miRNAs) have been suggested for non-invasive screening of non-small cell lung cancer (NSCLC), however the numerous proposed miRNA signatures are inconsistent.

Aiming to identify miRNAs suitable specifically for stage I-II NSCLC screening in serum/plasma samples, we searched the databases “Pubmed”, “Medline”, “Scopus”, “Embase” and “WOS” and systematically reviewed the publications reporting quantitative data on the efficacy [sensitivity, specificity and/or area under the curve (AUC)] of circulating miRNAs as biomarkers of NSCLC stage I and/or II. The 20 studies fulfilling the search criteria included 1110 NSCLC patients and 1009 controls, and were of medium quality according to Quality Assessment of Diagnostic Accuracy Studies checklist. In these studies, the patient cohorts as well as the control groups were heterogeneous for demographics and clinicopathological characteristics; moreover, numerous pre-analytical and analytical variables likely influenced miRNA determinations, and potential bias of hemolysis was often underestimated. We identified four circulating miRNAs scarcely influenced by hemolysis, each featuring high sensitivity (> 80%) and AUC (> 0.80) as biomarkers of stage I-II NSCLC: miR-223, miR-20a, miR-448 and miR-145; four other miRNAs showed high specificity (> 90%): miR-628-3p, miR-29c, miR-210 and miR-1244. In a model of two-step screening for stage I-II NSCLC using first the above panel of serum miRNAs with high sensitivity and high AUC, and subsequently the panel with high specificity, the estimated overall sensitivity is 91.6% and overall specificity is 93.4%. These and other circulating miRNAs suggested for stage I-II NSCLC screening require validation in multiple independent studies before they can be proposed for clinical application.

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