青年不吸烟肺腺癌患者易感基因突变分析及功能验证

Lung cancer is more common in older individuals. The majority of lung cancers were from smokers. However, the incidence of lung adenocarcinoma from young (≤ 40 years old) never-smokers is rising recently. The fact of early-onset and non-smoking suggests the presence of genetic susceptibility in this lung cancer subgroup. We previously investigated 14 common tumor suppressor genes in 25 young never-smoking lung adenocarcinoma patients using Ion Torrent sequencing, and found 18 (72%) patients harbored mutations in one or more genes. Our results also implicated a role of genetic susceptibility in lung cancer carcinogenesis of these patients. We plan to conduct whole exome sequencing in peripheral blood samples from 120 young never-smoking lung adenocarcinoma patients. Functional analysis of the detected germline mutations will be carried out to identify lung cancer predisposing mutations. We will then perform drug sensitive tests against these mutations. Finally, the clinicopathologic characteristics of these newly identified predisposing mutations will be well defined in 1000 never-smoking lung adenocarcinomas. Hopefully, our study can identify germline mutations predisposing to lung adenocarcinoma from young never-smokers.

肺癌好发于中老年患者，且绝大多数具有吸烟史。然而近年来，青年（≤40岁）不吸烟肺腺癌患者的发病率呈上升趋势。早发且不伴有吸烟史提示这一群体存在肺癌遗传易感因素。我们前期通过Ion Torrent测序平台对25例青年肺腺癌患者的14个常见抑癌基因进行检测，结果发现18例（72%）患者具有上述1个或数个抑癌基因突变，也提示了该疾病背后的遗传易感因素。我们计划对120例青年不吸烟肺腺癌患者的外周血标本进行全外显子组测序，筛选可能的易感基因突变进行功能验证、靶向药物药敏实验。最后在1000例不吸烟肺腺癌中阐明新发现的易感基因突变的临床病理特征。我们的研究有望阐明青年不吸烟肺腺癌患者的遗传易感基因突变。

肺癌的传统高危人群为中老年吸烟者，然而近年来，青年（≤40岁）不吸烟肺腺癌患者的发病率呈上升趋势。青年不吸烟提示这一群体的环境暴露较少，可能具有较大的遗传易感性。本研究对123例青年（≤40岁）不吸烟肺腺癌患者的外周血样本进行了全外显子组测序，发现了ATR、FANCD2、GATA2、HFE、MSH2、PDGFRA、SDHB和WAS是青年不吸烟肺腺癌患者的易感基因。而且，ASB18、B3GALT5、CLEC4F、CYP4B1、EXO1、GATA4、HCK、NPHP4、PPIL2、PPP1R3G以及RRBP1上的胚系基因突变出现了2次及以上，可能为潜在的青年不吸烟肺腺癌患者的易感基因。本研究阐明了青年不吸烟肺腺癌患者的胚系基因突变谱，为肺腺癌的筛查和早期诊断提供了重要依据。