Mutations of the epidermal growth factor receptor gene in atypical adenomatous hyperplasia and bronchioloalveolar carcinoma of the lung

Yukihiro Yoshida, Tatsuhiro Shibata, Akiko Kokubu, Koji Tsuta, Yoshihiro Matsuno, Yae Kanai, Hisao Asamura, Ryosuke Tsuchiya, Setsuo Hirohashi

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109 Citations (Scopus)


A hypothesis of multistep carcinogenesis of lung adenocarcinoma from atypical adenomatous hyperplasia (AAH) to invasive adenocarcinoma through bronchioloalveolar carcinoma (BAC) has been proposed. However, the genetic alterations that play a role during these processes are not yet clear. Recently, somatic mutations of the epidermal growth factor receptor (EGFR) gene were found in lung adenocarcinoma. We examined the status of EGFR mutations in AAH and BAC to elucidate the role they play during multistage of lung adenocarcinoma. We found somatic EGFR mutations in 3% (1/35) of AAH, 10.8% (4/37) of BAC and 41.9% (13/31) of invasive adenocarcinoma. Sixteen of 18 EGFR mutations were found in exon 19 and two were in exon 21. Among the 16 EGFR mutations in exon 19, 13 were deletions of 15 bp and one was an insertion/duplication of 18 bp. Mutations of the K-ras gene were detected in 26.7% (8/30) of AAH, 16.7% (5/30) of BAC and 10% (3/30) of invasive adenocarcinoma. None of the tumors with EGFR mutations had K-ras mutation simultaneously. Patients who had invasive adenocarcinoma with EGFR mutations were younger than those without mutations (60.6 versus 67.4 years, p = 0.03). These results suggest that tumors with EGFR mutations may progress more rapidly and develop into invasive cancer faster than those without mutations. Alternatively it is also possible that some invasive adenocarcinomas with EGFR mutations may not follow the AAH-adenocarcinoma sequence. We analyzed 24 patients with multiple lung lesions and 13 patients had at least one lesion that had either an EGFR or K-ras mutation. In all cases each lesion had a different mutation status. This finding suggests that the genetic alterations responsible for the development of lung adenocarcinoma occur randomly even under exposure to the same carcinogen.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalLung Cancer
Issue number1
Publication statusPublished - 2005 Oct
Externally publishedYes


  • Adenocarcinoma
  • Atypical adenomatous hyperplasia (AAH)
  • Bronchioloalveolar carcinoma (BAC)
  • Epidermal growth factor receptor (EGFR)
  • K-ras
  • Non-small cell lung cancer (NSCLC)

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research


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