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

// Emilio Bria 1,2,* , Francesca Di Modugno 3,* , Isabella Sperduti 4 , Pierluigi Iapicca 3 , Paolo Visca 5 , Gabriele Alessandrini 6 , Barbara Antoniani 5 , Sara Pilotto 2 , Vienna Ludovini 7 , Jacopo Vannucci 8 , Guido Bellezza 9 , Angelo Sidoni 9 , Giampaolo Tortora 2 , Derek C. Radisky 10 , Lucio Crino 7 , Francesco Cognetti 1 , Francesco Facciolo 6 , Marcella Mottolese 5 , Michele Milella 1,* and Paola Nistico 3,* 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, hMENA 11a and hMENAΔv6, in early NSCLC. The epithelial hMENA 11a isoform was expressed in NSCLC lines expressing E-CADHERIN and was alternatively expressed with hMENAΔv6. Enforced expression of hMENAΔv6 or hMENA 11a 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 hMENA 11a were the only independent predictors of shorter disease-free and cancer-specific survival, and low hMENA 11a was an independent predictor of shorter overall survival, at multivariate analysis. Patients with low pan-hMENA/high hMENA 11a 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.