Epidermal growth factor receptor tyrosine kinase defines critical prognostic genes of stage I lung adenocarcinoma

PLoS One. 2012;7(9):e43923. doi: 10.1371/journal.pone.0043923. Epub 2012 Sep 19.

Abstract

Purpose: To identify stage I lung adenocarcinoma patients with a poor prognosis who will benefit from adjuvant therapy.

Patients and 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.

Conclusion: 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.

Trial registration: The Gene Expression Omnibus (GEO) GSE31210.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Cell Line, Tumor
  • Computational Biology / methods
  • Drug Resistance, Neoplasm / genetics
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Gefitinib
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Neoplasm Staging
  • Prognosis
  • Quinazolines / pharmacology
  • Reproducibility of Results

Substances

  • Quinazolines
  • Epidermal Growth Factor
  • ErbB Receptors
  • Gefitinib

Associated data

  • GEO/GSE31210

Grant support

This work was supported by a grant for the 3rd-term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan (http://www.mhlw.go.jp/english/) to JY, TK, and NG, by Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science & Technology (MEXT) of Japan (http://www.mext.go.jp/english/) to NG (22130009), by Research and Development of the Next-Generation Integrated Simulation of Living Matter, a part of the Development and Use of the Next-Generation Supercomputer Project of MEXT of Japan (http://www.mext.go.jp/english/) to SM, and by the National Cancer Center Research and Development Fund to TK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.