title: Mutations of the epidermal growth factor receptor gene in atypical adenomatous hyperplasia and bronchioloalveolar carcinoma of the lung.
abstract: 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 15bp and one was an insertion/duplication of 18bp. 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.
authors.affiliation: Pathology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Akiko
authors.initials: A
authors.lastname: Kokubu
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsuno
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
authors.forename: Hisao
authors.initials: H
authors.lastname: Asamura
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tsuchiya
authors.forename: Setsuo
authors.initials: S
authors.lastname: Hirohashi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000503:physiopathology; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics* / Q000503:physiopathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000503:physiopathology; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction
chemical_list: D002273:Carcinogens; D066246:ErbB Receptors