Sakuma Yuji, Matsukuma Shoichi, Yoshihara Mitsuyo, Nakamura Yoshiyasu, Nakayama Haruhiko, Kameda Yoichi, Tsuchiya Eiju, Miyagi Yohei
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Kanagawa Cancer Center Hospital, Asahi-ku, Yokohama, Japan.
Mod Pathol. 2007 Sep;20(9):967-73. doi: 10.1038/modpathol.3800929. Epub 2007 Jul 6.
Activating epidermal growth factor receptor (EGFR) gene mutations are frequently detected in lung adenocarcinomas, especially adenocarcinomas with a nonmucinous bronchioloalveolar carcinoma component. EGFR-mutated lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors. We previously found that most (88%) pure nonmucinous bronchioloalveolar carcinomas (adenocarcinoma in situ) already harbor EGFR mutations, indicating that the mutations are an early genetic event in the pathogenesis. We examined 54 atypical adenomatous hyperplasias, precursor lesions of lung adenocarcinomas, obtained from 28 Japanese patients for the hotspot mutations of EGFR exons 19 and 21 and K-ras codon 12. EGFR mutations were observed in 17 of the 54 (32%) atypical adenomatous hyperplasias examined: Ten and seven atypical adenomatous hyperplasias had deletion mutations at exon 19 or point mutations (L858R) at exon 21, respectively. We did not observe apparent histological differences between atypical adenomatous hyperplasias with and without EGFR mutations. K-ras mutation (G12S) was detected in only one atypical adenomatous hyperplasia. As EGFR mutational frequency of atypical adenomatous hyperplasias was much lower than that of nonmucinous bronchioloalveolar carcinomas, we surmise that EGFR-mutated atypical adenomatous hyperplasias, but not atypical adenomatous hyperplasias with wild-type EGFR, are likely to progress to nonmucinous bronchioloalveolar carcinomas.
激活表皮生长因子受体（EGFR）基因突变在肺腺癌中经常被检测到，尤其是具有非黏液性细支气管肺泡癌成分的腺癌。EGFR突变的肺腺癌对EGFR酪氨酸激酶抑制剂反应良好。我们之前发现，大多数（88%）纯非黏液性细支气管肺泡癌（原位腺癌）已经存在EGFR突变，这表明这些突变是发病机制中的早期遗传事件。我们检测了从28名日本患者获取的54例肺腺癌前体病变——非典型腺瘤样增生，以检测EGFR外显子19和21的热点突变以及K-ras密码子12。在所检测的54例非典型腺瘤样增生中，有17例（32%）观察到EGFR突变：分别有10例和7例非典型腺瘤样增生在外显子19有缺失突变或在外显子21有热点突变（L858R）。我们未观察到有EGFR突变和无EGFR突变的非典型腺瘤样增生之间存在明显的组织学差异。仅在1例非典型腺瘤样增生中检测到K-ras突变（G12S）。由于非典型腺瘤样增生的EGFR突变频率远低于非黏液性细支气管肺泡癌，我们推测EGFR突变的非典型腺瘤样增生而非野生型EGFR的非典型腺瘤样增生可能会进展为非黏液性细支气管肺泡癌。
