title: An Aggressive Subtype of Stage I Lung Adenocarcinoma with Molecular and Prognostic Characteristics Typical of Advanced Lung Cancers.
abstract: OBJECTIVE
  The National Lung Cancer Screening Trial has confirmed that lung cancer mortality can be reduced if tumors are diagnosed early, that is, at stage I. However, a substantial fraction of stage I lung cancer patients still develop metastatic disease within 5 years from surgery. Prognostic biomarkers are therefore needed to identify patients at risk of an adverse outcome, who might benefit from multimodality treatment.
  
  
  METHODS
  We extensively validated a 10-gene prognostic signature in a cohort of 507 lung adenocarcinoma patients using formalin-fixed paraffin-embedded samples. Furthermore, we performed an integrated analysis of gene expression, methylation, somatic mutations, copy number variations, and proteomic profiles on an independent cohort of 468 patients from The Cancer Genome Atlas (TCGA).
  
  
  RESULTS
  Stage I lung cancer patients (N = 351) identified as high-risk by the 10-gene signature displayed a 4-fold increased risk of death [HR = 3.98; 95% confidence interval (CI), 1.73-9.14], with a 3-year overall survival of 84.2% (95% CI, 78.7-89.7) compared with 95.6% (92.4-98.8) in low-risk patients. The analysis of TCGA cohort revealed that the 10-gene signature identifies a subgroup of stage I lung adenocarcinomas displaying distinct molecular characteristics and associated with aggressive behavior and poor outcome.
  
  
  CONCLUSIONS
  We validated a 10-gene prognostic signature capable of identifying a molecular subtype of stage I lung adenocarcinoma with characteristics remarkably similar to those of advanced lung cancer. We propose that our signature might aid the identification of stage I patients who would benefit from multimodality treatment. Clin Cancer Res; 23(1); 62-72. ©2016 AACR.
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan, Italy.|IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Dama
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Melocchi
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Dezi
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pirroni
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan, Italy.|IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.
authors.forename: Rose Mary
authors.initials: RM
authors.lastname: Carletti
authors.affiliation: Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Brambilla
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bertalot
authors.affiliation: Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Casiraghi
authors.affiliation: Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
authors.forename: Patrick
authors.initials: P
authors.lastname: Maisonneuve
authors.affiliation: Division of Pathology, European Institute of Oncology, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Barberis
authors.affiliation: Division of Pathology, European Institute of Oncology, Milan, Italy.|DIPO, Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan, Italy.|IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Vecchi
authors.affiliation: Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy.|DIPO, Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Spaggiari
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan, Italy. f.bianchi@operapadrepio.it pierpaolo.difiore@ieo.eu.|Institute for Stem-cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Casa Sollievo della Sofferenza - IRCCS, San Giovanni Rotondo, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bianchi
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan, Italy. f.bianchi@operapadrepio.it pierpaolo.difiore@ieo.eu.|IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.|DIPO, Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D040901:Proteomics; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor