Occurrence of mutations in the epidermal growth factor receptor gene in X-ray-induced rat lung tumors
Occurrence of mutations in the epidermal growth factor receptor gene in X-ray-induced rat lung tumors
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DOI：
10.1111/j.1349-7006.2008.00680.x
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发表时间：
2008-02-01
期刊：
影响因子：
5.7
通讯作者：
Wakabayashi, Keiji
中科院分区：
文献类型：
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作者：
Kitahashi, Tsukasa;Takahashi, Mami;Wakabayashi, Keiji
在人类肺癌中发现了表皮生长因子受体（EGFR）基因改变。然而，目前还没有关于诱导EGFR突变的因素的信息。在啮齿类动物中，许多肺癌发生模型中经常发现K-ras突变，但迄今为止，Egfr突变尚未见报道。因此，在具有代表性的肺癌模型中研究了它们的存在，包括 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK)、N-亚硝基双(2-羟丙基)胺 (BHP)、2-氨基-3,8-二甲基咪唑[4,5-f]喹喔啉 (MeIQx) 和氨基甲酸乙酯（氨基甲酸乙酯）以及 X 射线照射。在化学致癌模型中，Egfr 中未检测到突变，这与 K-ras 密码子 12 或 61 中观察到的高突变率形成鲜明对比（NNK 诱导的肺肿瘤为 21/23，MeIQx 为 4/5，乌拉坦为 1/4，BHP 为 7/18）。然而，在X射线诱导的肺部肿瘤中，在外显子18和21中观察到氨基酸取代的Egfr突变（4/12，33%），但没有检测到K-ras的激活突变。此外，在 K-ras（外显子 1）和 Egfr（外显子 18、20 和 21）中分别发现了 1 个和 4 个沉默突变。 Egfr 和 K-ras 中的大多数突变都是 G/C -> A/T 转换（分别为 7/8, 88% 和 31/34, 91%）。尽管同等人类病变中的突变模式并不完全一致，但实验性肺肿瘤模型中 Egfr 突变的首次报告表明，X 射线或其他产生氧自由基的因素可能会导致人类某些肺癌中的 EGFR 突变。
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.