Increased epidermal growth factor receptor (EGFR) gene copy number is strongly associated with EGFR mutations and adenocarcinoma in non-small cell lung cancers: a chromogenic in situ hybridization study of 182 patients

Lung Cancer. 2008 Sep;61(3):328-39. doi: 10.1016/j.lungcan.2008.01.009. Epub 2008 Mar 4.


To evaluate the association of epidermal growth factor receptor (EGFR) gene copy number with EGFR and k-ras mutation status and tyrosine kinase inhibitor (TKI) sensitivity in non-small cell lung cancer (NSCLC), EGFR gene copy number of 182 NSCLC tumor specimens were analyzed by chromogenic in situ hybridization (CISH). EGFR and k-ras mutation analyses were also performed for, respectively, 176 and 157 of the 182 patients. Additionally, 36 patients in this study had received TKI monotherapy. The tumor was considered to be CISH positive if the gene copy number was >or=5 signals per nucleus in >or=40% of tumor cells. CISH-positive tumors were strongly associated with adenocarcinoma (56.8%) compared with squamous cell carcinoma (15.9%) (p<0.0001). The CISH-positive tumors were also strongly associated with EGFR mutations (78%) compared with wild type (20.2%) (p<0.0001). Only six tumors had k-ras mutations. None had EGFR mutation and only one was CISH positive. In the patients treated with TKI, EGFR mutation was strongly associated with TKI responsiveness (22/25 responders) (p<0.0001), but the CISH-positive tumors were only marginally significant (18/25 responders) (p=0.0665). Patients with EGFR mutations or CISH-positive tumors were all associated with longer median survival, although not statistically significant. Our results suggest Increased EGFR copy number was highly correlated with EGFR mutation in adenocarcinoma. Although it is less correlated with TKI responsiveness when compared with EGFR mutations, it still could be a good alternative molecular predictive marker for TKI responsiveness, since CISH can be done on paraffin section and is much quicker than DNA sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Chi-Square Distribution
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride
  • Female
  • Gefitinib
  • Gene Dosage / drug effects
  • Genes, erbB-1 / drug effects*
  • Genes, ras / genetics*
  • Humans
  • In Situ Hybridization
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation
  • Protein Kinase Inhibitors / therapeutic use
  • Quinazolines / therapeutic use
  • Survival Analysis


  • Protein Kinase Inhibitors
  • Quinazolines
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Gefitinib