title: Occurrence of mutations in the epidermal growth factor receptor gene in X-ray-induced rat lung tumors.
abstract: Epidermal growth factor receptor (EGFR) gene alterations have been found in human lung cancers. However, there is no information on the factors inducing EGFR mutations. In rodents, K-ras mutations are frequently found in many lung carcinogenesis models, but hitherto, Egfr mutations have not been reported. Their presence was therefore investigated in representative lung carcinogenesis models with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosobis(2-hydroxypropyl)amine (BHP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and ethyl carbamate (urethane), as well as X-ray irradiation. With the chemical carcinogenesis models, no mutations were detected in Egfr, which is in clear contrast to the high rates observed in either codon 12 or 61 of K-ras (21/23 of the lung tumors induced with NNK, 4/5 with MeIQx, 1/4 with urethane and 7/18 with BHP). However, in the X-ray-induced lung tumors, Egfr mutations with amino acid substitution were observed in exons 18 and 21 (4/12, 33%), but no activating mutation of K-ras was detected. In addition, one and four silent mutations were identified in K-ras (exon 1) and Egfr (exons 18, 20 and 21), respectively. Most mutations in both Egfr and K-ras were G/C-->A/T transitions (7/8, 88% and 31/34, 91%, respectively). Although, the mutational patterns in equivalent human lesions were not completely coincident, this first report of Egfr mutations in an experimental lung tumor model suggests that X-rays or other factors producing oxygen radicals could cause EGFR mutations in some proportion of lung cancers in humans.
authors.affiliation: Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Kitahashi
authors.forename: Mami
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamada
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Oghiso
authors.forename: Masanao
authors.initials: M
authors.lastname: Yokohira
authors.forename: Katsumi
authors.initials: K
authors.lastname: Imaida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsutsumi
authors.forename: Nobuo
authors.initials: N
authors.lastname: Takasuka
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugimura
authors.forename: Keiji
authors.initials: K
authors.lastname: Wakabayashi
mesh_terms: D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity; D005091:Exons; D005260:Female; D018773:Genes, erbB-1; D011905:Genes, ras; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000378:metabolism; D009602:Nitrosamines / Q000633:toxicity; D051381:Rats; D014520:Urethane / Q000633:toxicity; D014965:X-Rays
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; D014520:Urethane; C012457:diisopropanolnitrosamine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone