title: Gene Signatures Stratify Computed Tomography Screening Detected Lung Cancer in High-Risk Populations.
abstract: BACKGROUND
  Although screening programmes of smokers have detected resectable early lung cancers more frequently than expected, their efficacy in reducing mortality remains debatable. To elucidate the biological features of computed tomography (CT) screening detected lung cancer, we examined the mRNA signatures on tumours according to the year of detection, stage and survival.
  
  
  METHODS
  Gene expression profiles were analysed on 28 patients (INT-IEO training cohort) and 24 patients of Multicentre Italian Lung Detection (MILD validation cohort). The gene signatures generated from the training set were validated on the MILD set and a public deposited DNA microarray data set (GSE11969). Expression of selected genes and proteins was validated by real-time RT-PCR and immunohistochemistry. Enriched core pathway and pathway networks were explored by GeneSpring GX10.
  
  
  RESULTS
  A 239-gene signature was identified according to the year of tumour detection in the training INT-IEO set and correlated with the patients' outcomes. These signatures divided the MILD patients into two distinct survival groups independently of tumour stage, size, histopathological type and screening year. The signatures can also predict survival in the clinically detected cancers (GSE11969). Pathway analyses revealed tumours detected in later years enrichment of the PI3K/PTEN/AKT pathway, with up-regulation of PDPK1, ITGB1 and down-regulation of FOXO1A. Analysis of normal lung tissue from INT-IEO cohort produced signatures distinguishing patients with early from late detected tumours.
  
  
  CONCLUSIONS
  The distinct pattern of "indolent" and "aggressive" tumour exists in CT-screening detected lung cancer according to the gene expression profiles. The early development of an aggressive phenotype may account for the lack of mortality reduction by screening observed in some cohorts.
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom.
authors.forename: Jiangting
authors.initials: J
authors.lastname: Hu
authors.affiliation: Tumor Genomics Unit, Milan, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Boeri
authors.affiliation: Tumor Genomics Unit, Milan, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom.
authors.forename: Dongxia
authors.initials: D
authors.lastname: Liu
authors.affiliation: Division of Radiology, Milan, Italy ; Medical Statistics and Bioinformatics Unit, Milan, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Marchianò
authors.affiliation: Tumor Genomics Unit, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Roz
authors.affiliation: Pathology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Gatter
authors.affiliation: Division of Thoracic Surgery, Milan, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Pastorino
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pezzella
mesh_terms: D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000401:mortality; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed
chemical_list: D009363:Neoplasm Proteins
keywords: Aggressive; CT screening; Gene signature; Indolent; Lung cancer; PI3K/PTEN/AKT signalling pathway