致癌驱动基因突变与环境因素的前瞻性分析：日本肺癌分子流行病学研究。
Prospective Analysis of Oncogenic Driver Mutations and Environmental Factors: Japan Molecular Epidemiology for Lung Cancer Study.
机构信息
Tomoya Kawaguchi, Akihiro Tamiya, Shigeki Shimizu, Shun-ichi Isa, and Akihide Matsumura, National Hospital Organization Kinki-chuo Chest Medical Center; Tomoya Kawaguchi and Naoki Yoshimoto, Osaka City University, Osaka; Yasuhiro Koh, Seiichi Kakegawa, Masakuni Serizawa, Akihito Kubo, and Hideo Saka, National Hospital Organization Nagoya Medical Center; Masahiko Ando, Nagoya University, Nagoya; Yasuhiro Koh, Wakayama Medical University, Wakayama; Yasuhiro Koh and Masakuni Serizawa, Shizuoka Cancer Center Research Institute, Shizuoka; Norimasa Ito, National Hospital Organization Matsue Medical Center, Matsue; Sadanori Takeo, National Hospital Organization Kyushu Medical Center; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hirofumi Adachi, National Hospital Organization Hokkaido Cancer Center, Hokkaido; Tsutomu Tagawa, National Hospital Organization Nagasaki Medical Center, Omura; Seiichi Kakegawa, National Hospital Organization Nishigunma National Hospital, Shibukawa; Motohiro Yamashita, National Hospital Organization Shikoku Cancer Center, Matsuyama; Kazuhiko Kataoka, National Hospital Organization Iwakuni Clinical Center, Iwakuni; Yukiyasu Takeuchi, National Hospital Organization Toneyama National Hospital, Toyonaka; Shigeki Shimizu, Hyogo Medical Collage, Hyogo; and Akihito Kubo, Aichi Medical University School of Medicine, Aichi, Japan.
出版信息
J Clin Oncol. 2016 Jul 1;34(19):2247-57. doi: 10.1200/JCO.2015.64.2322. Epub 2016 May 9.
PURPOSE
Oncogenic driver mutations are critical for lung cancer development and serve as therapeutic targets. However, their associations with environmental factors are not fully understood. We aimed to elucidate the relationship between tumor developmental biology and exposure to environmental factors.
PATIENTS AND METHODS
This was a prospective, multicenter, molecular epidemiology study. Eligible patients were those with newly diagnosed stages I to IIIB non-small-cell lung cancer (NSCLC) who underwent surgery. The tumors were examined for somatic mutations in 72 cancer-associated genes by targeted deep sequencing, estrogen receptor β (ERβ) expression using immunohistochemical staining, and infection with any of 37 types of human papillomavirus (HPV) using a polymerase chain reaction-based microarray system. Detailed information on patient demographics and environmental factors was obtained from a comprehensive questionnaire.
RESULTS
From July 2012 to December 2013, 957 patients were enrolled, and molecular analyses were performed on 876 samples (from 441 ever- and 435 never-smokers). Oncogenic driver mutations in P53 and KRAS increased proportionally with smoking status, whereas mutations in EGFR and SMAD4 decreased. KRAS mutations in smokers and SMAD4 mutations were observed more frequently in proportion to body mass index. TP53 and NFE2L2 mutations were observed more frequently in advanced NSCLC stages. As for never-smokers, no environmental factors were significantly associated with mutational changes. EGFR mutations and TP53 mutations were observed more frequently in women and in men, respectively. Mutations in these two genes were also potentially associated with ERβ expression. Only three patients (0.3%) were HPV positive.
CONCLUSION
The mutational spectrum is associated with smoking, body mass index, and other environmental factors, as well as with ERβ expression. Little association was observed between HPV and NSCLC.
目的
致癌驱动突变对肺癌的发生发展至关重要，是治疗的靶点。然而，它们与环境因素的关系尚不完全清楚。本研究旨在阐明肿瘤发生发展生物学与环境因素暴露之间的关系。
方法
这是一项前瞻性、多中心的分子流行病学研究。纳入标准为接受手术治疗的ⅠB 期至ⅢB 期非小细胞肺癌（NSCLC）患者。通过靶向深度测序检测 72 个癌症相关基因的体细胞突变，采用免疫组织化学染色检测雌激素受体β（ERβ）的表达，采用聚合酶链反应（PCR）为基础的微阵列系统检测 37 种人乳头瘤病毒（HPV）的感染情况。通过综合问卷调查获取患者人口统计学和环境因素的详细信息。
结果
2012 年 7 月至 2013 年 12 月，共纳入 957 例患者，对 876 例样本（441 例现吸烟者和 435 例从不吸烟者）进行了分子分析。P53 和 KRAS 中的致癌驱动突变与吸烟状态呈正相关增加，而 EGFR 和 SMAD4 中的突变则呈负相关减少。现吸烟者中 KRAS 突变和吸烟者中 SMAD4 突变与体重指数呈正相关，更常见于较高的体重指数。TP53 和 NFE2L2 突变在晚期 NSCLC 中更常见。从不吸烟者中，没有环境因素与突变变化显著相关。EGFR 突变和 TP53 突变在女性和男性中更常见，这两个基因的突变也与 ERβ 的表达有关。仅 3 例患者（0.3%）HPV 阳性。
结论
突变谱与吸烟、体重指数和其他环境因素有关，也与 ERβ 的表达有关。HPV 与 NSCLC 之间相关性很小。
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