title: Clinico-pathological and biological significance of tyrosine kinase domain gene mutations and overexpression of epidermal growth factor receptor for lung adenocarcinoma.
abstract: BACKGROUND
  Mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) gene have proven to be clinically significant in non-small cell lung cancer. However, relationships between these mutations and EGFR expression or deletion mutations in the extracellular domain of EGFR (EGFRvIII) remain unclear. The purpose of this study was to gain further insight into the clinical significance of these molecular abnormalities in lung adenocarcinoma.
  
  
  METHODS
  We investigated EGFR TKD mutations using direct sequencing, EGFR protein expression using Western blotting, and EGFRvIII using reverse transcriptase-polymerase chain reaction in samples from 48 adenocarcinoma patients. Correlations with various clinico-pathological features were analyzed.
  
  
  RESULTS
  EGFR TKD mutations were detected in 25 of 48 adenocarcinomas (52.1%), and overexpression of EGFR protein was identified in 19 patients (39.6%). Presence of EGFR TKD mutations was significantly correlated with EGFR overexpression (p = 0.021). EGFR TKD mutations were significantly correlated with never-smoker status (p = 0.043), absence of emphysematous or fibrotic appearance on computed tomography (p = 0.001), papillary subtype (p = 0.041), and bronchioloalveolar carcinoma features (p = 0.045). EGFRvIII was not detected in any adenocarcinomas. Retrospective analysis revealed that patients with EGFR TKD mutations displayed better postoperative prognosis than patients with wild-type EGFR (p = 0.033).
  
  
  CONCLUSIONS
  These results suggest that EGFR TKD mutation is associated with EGFR overexpression, representing an important factor for consideration when investigating the clinical significance, including susceptibility to chemotherapy, of EGFR TKD mutations in adenocarcinoma. EGFRvIII does not seem to play a major role in the development of lung adenocarcinoma.
authors.affiliation: Department of Surgery, Kyorin University, Mitaka, Tokyo, Japan. kouki7@kj9.so-net.ne.jp
authors.forename: Kouki
authors.initials: K
authors.lastname: Ohtsuka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Go
authors.initials: G
authors.lastname: Furuyashiki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nogami
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Koshiishi
authors.forename: Akiko
authors.initials: A
authors.lastname: Ooide
authors.forename: Satsuki
authors.initials: S
authors.lastname: Matsushima
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Goya
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011799:Quinazolines / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib