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Prognostic impact of alternative splicing-derived hMENA isoforms in resected, node-negative, non-small-cell lung cancer

Emilio Bria, Francesca Di Modugno, Isabella Sperduti, Pierluigi Iapicca, Paolo Visca, Gabriele Alessandrini, Barbara Antoniani, Sara Pilotto, Vienna Ludovini, Jacopo Vannucci, Guido Bellezza, Angelo Sidoni, Giampaolo Tortora, Derek C. Radisky, Lucio Crinò, Francesco Cognetti, Francesco Facciolo, Marcella Mottolese _, Michele Milella and Paola Nisticò

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Oncotarget. 2014; 5:11054-11063. https://doi.org/10.18632/oncotarget.2609

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Abstract

Emilio Bria1,2,*, Francesca Di Modugno3,*, Isabella Sperduti4, Pierluigi Iapicca3, Paolo Visca5, Gabriele Alessandrini6, Barbara Antoniani5, Sara Pilotto2, Vienna Ludovini7, Jacopo Vannucci8, Guido Bellezza9, Angelo Sidoni9, Giampaolo Tortora2, Derek C. Radisky10, Lucio Crinò7, Francesco Cognetti1, Francesco Facciolo6, Marcella Mottolese5, Michele Milella1,* and Paola Nisticò3,*

1 Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy

2 Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy

3 Laboratory of Immunology, Regina Elena National Cancer Institute, Rome, Italy

4 Biostatistics and Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy

5 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy

6 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy

7 Medical Oncology, University of Perugia, Perugia, Italy

8 Department of Thoracic Surgery, University of Perugia, Perugia, Italy

9 Institute of Pathological Anatomy and Histology, University of Perugia, Perugia, Italy

10 Mayo Clinic Cancer Center, Jacksonville, FL, USA

* These authors contributed equally to this work

Correspondence:

Marcella Mottolese, email:

Keywords: Lung cancer; Splicing; Biomarkers

Received: July 08, 2014 Accepted: October 21, 2014 Published: October 21, 2014

Abstract

Risk assessment and treatment choice remain a challenge in early non-small-cell lung cancer (NSCLC). Alternative splicing is an emerging source for diagnostic, prognostic and therapeutic tools. Here, we investigated the prognostic value of the actin cytoskeleton regulator hMENA and its isoforms, hMENA11a and hMENAΔv6, in early NSCLC.

The epithelial hMENA11a isoform was expressed in NSCLC lines expressing E-CADHERIN and was alternatively expressed with hMENAΔv6. Enforced expression of hMENAΔv6 or hMENA11a increased or decreased the invasive ability of A549 cells, respectively. hMENA isoform expression was evaluated in 248 node-negative NSCLC. High pan-hMENA and low hMENA11a were the only independent predictors of shorter disease-free and cancer-specific survival, and low hMENA11a was an independent predictor of shorter overall survival, at multivariate analysis. Patients with low pan-hMENA/high hMENA11a expression fared significantly better (P≤0.0015) than any other subgroup. Such hybrid variable was incorporated with T-size and number of resected lymph nodes into a 3-class-risk stratification model, which strikingly discriminated between different risks of relapse, cancer-related death, and death. The model was externally validated in an independent dataset of 133 patients.

Relative expression of hMENA splice isoforms is a powerful prognostic factor in early NSCLC, complementing clinical parameters to accurately predict individual patient risk.


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