title: Sequential molecular changes during multistage pathogenesis of small peripheral adenocarcinomas of the lung.
abstract: BACKGROUND
  We investigated EGFR and KRAS alterations among atypical adenomatous hyperplasia and small lung adenocarcinomas with bronchioloalveolar features to understand their role during multistage pathogenesis.
  
  
  METHODS
  Sixty lesions measuring 2 cm or less were studied, including 38 noninvasive lesions (4 atypical adenomatous hyperplasias, 19 Noguchi type A and 15 type B) and 22 invasive lesions (type C) based on the World Health Organization classification and Noguchi's criteria. EGFR and KRAS mutations were examined using PCR-based assays. EGFR copy number was evaluated using fluorescence in situ hybridization.
  
  
  RESULTS
  EGFR and KRAS mutations were found in 26 (43.3%) and 5 (8.3%) lesions, respectively. Increased EGFR copy number status was identified in 10 lesions (16.7%), both mutant and wild type. EGFR or KRAS mutations were present in 39.5% and 7.9% (respectively) of noninvasive lesions and 50% or 9.1% (respectively) of invasive lesions. EGFR copy number was increased in 7.9% and 31.8% of noninvasive and invasive lesions (P = 0.029). Multivariate analysis revealed that increased EGFR copy number was the only significant factor to associate with invasive lesions (P = 0.035).
  
  
  CONCLUSIONS
  EGFR and KRAS mutations occur early during the multistage pathogenesis of peripheral lung adenocarcinomas. By contrast, increased EGFR copy number is a late event during tumor development and plays a role in the progression of lung adenocarcinoma independent of the initiating molecular events.
authors: Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors: Junichi
authors: J
authors: Soh
authors: Shinichi
authors: S
authors: Toyooka
authors: Shuji
authors: S
authors: Ichihara
authors: Hiroaki
authors: H
authors: Asano
authors: Naruyuki
authors: N
authors: Kobayashi
authors: Hiroshi
authors: H
authors: Suehisa
authors: Hiroki
authors: H
authors: Otani
authors: Hiromasa
authors: H
authors: Yamamoto
authors: Kouichi
authors: K
authors: Ichimura
authors: Katsuyuki
authors: K
authors: Kiura
authors: Adi F
authors: AF
authors: Gazdar
authors: Hiroshi
authors: H
authors: Date
mesh_terms: D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics*; D018255:Adenomatosis, Pulmonary / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins