title: Epidermal growth factor receptor tyrosine kinase defines critical prognostic genes of stage I lung adenocarcinoma.
abstract: OBJECTIVE
  To identify stage I lung adenocarcinoma patients with a poor prognosis who will benefit from adjuvant therapy.
  
  
  METHODS
  Whole gene expression profiles were obtained at 19 time points over a 48-hour time course from human primary lung epithelial cells that were stimulated with epidermal growth factor (EGF) in the presence or absence of a clinically used EGF receptor tyrosine kinase (RTK)-specific inhibitor, gefitinib. The data were subjected to a mathematical simulation using the State Space Model (SSM). "Gefitinib-sensitive" genes, the expressional dynamics of which were altered by addition of gefitinib, were identified. A risk scoring model was constructed to classify high- or low-risk patients based on expression signatures of 139 gefitinib-sensitive genes in lung cancer using a training data set of 253 lung adenocarcinomas of North American cohort. The predictive ability of the risk scoring model was examined in independent cohorts of surgical specimens of lung cancer.
  
  
  RESULTS
  The risk scoring model enabled the identification of high-risk stage IA and IB cases in another North American cohort for overall survival (OS) with a hazard ratio (HR) of 7.16 (P = 0.029) and 3.26 (P = 0.0072), respectively. It also enabled the identification of high-risk stage I cases without bronchioalveolar carcinoma (BAC) histology in a Japanese cohort for OS and recurrence-free survival (RFS) with HRs of 8.79 (P = 0.001) and 3.72 (P = 0.0049), respectively.
  
  
  CONCLUSIONS
  The set of 139 gefitinib-sensitive genes includes many genes known to be involved in biological aspects of cancer phenotypes, but not known to be involved in EGF signaling. The present result strongly re-emphasizes that EGF signaling status in cancer cells underlies an aggressive phenotype of cancer cells, which is useful for the selection of early-stage lung adenocarcinoma patients with a poor prognosis.
  
  
  BACKGROUND
  The Gene Expression Omnibus (GEO) GSE31210.
authors.affiliation: Division of Systems Biomedical Technology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Rui
authors.initials: R
authors.lastname: Yamaguchi
authors.forename: Asuka
authors.initials: A
authors.lastname: Nakata
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.forename: Masao
authors.initials: M
authors.lastname: Nagasaki
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
authors.forename: Ayumu
authors.initials: A
authors.lastname: Saito
authors.forename: Kazuko
authors.initials: K
authors.lastname: Ueno
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Hatanaka
authors.forename: Ryo
authors.initials: R
authors.lastname: Yoshida
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Higuchi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nomura
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077156:Gefitinib; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011799:Quinazolines / Q000494:pharmacology; D015203:Reproducibility of Results
chemical_list: D011799:Quinazolines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib