Prognostic impact of alternative splicing-derived hMENA isoforms in resected, node-negative, non-small-cell lung cancer.
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.
Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy. Department of Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
Emilio
E
Bria
Laboratory of Immunology, Regina Elena National Cancer Institute, Rome, Italy.
Francesca
F
Di Modugno
Biostatistics and Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy.
Isabella
I
Sperduti
Laboratory of Immunology, Regina Elena National Cancer Institute, Rome, Italy.
Pierluigi
P
Iapicca
Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
Paolo
P
Visca
Department of Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy.
Gabriele
G
Alessandrini
Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
Barbara
B
Antoniani
Department of Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
Sara
S
Pilotto
Department of Medical Oncology, University of Perugia, Perugia, Italy.
Vienna
V
Ludovini
Department of Thoracic Surgery, University of Perugia, Perugia, Italy.
Jacopo
J
Vannucci
Institute of Pathological Anatomy and Histology, University of Perugia, Perugia, Italy.
Guido
G
Bellezza
Institute of Pathological Anatomy and Histology, University of Perugia, Perugia, Italy.
Angelo
A
Sidoni
Department of Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
Giampaolo
G
Tortora
Mayo Clinic Cancer Center, Jacksonville, FL, USA.
Derek C
DC
Radisky
Department of Medical Oncology, University of Perugia, Perugia, Italy.
Lucio
L
Crinò
Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.
Francesco
F
Cognetti
Department of Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy.
Francesco
F
Facciolo
Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
Marcella
M
Mottolese
Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.
Michele
M
Milella
Laboratory of Immunology, Regina Elena National Cancer Institute, Rome, Italy.
Paola
P
Nisticò
D017398:Alternative Splicing; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D018572:Disease-Free Survival; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D020033:Protein Isoforms; D018570:Risk Assessment
C511939:Enah protein, human; D008840:Microfilament Proteins; D020033:Protein Isoforms