中国单中心肺腺癌患者基因突变特征及与欧美肺腺癌人群比较分析

Characteristics of gene mutations in Chinese single-center pulmonary adenocarcinoma patients and comparison with European and American pulmonary adenocarcinoma populations

目的 探讨肺腺癌的基因突变特征及其意义,为靶向用药提供依据。方法 利用高通量测序平台靶向捕获测序技术,检测昆山市第一人民医院2017年5月至2018年8月确诊的104例肺腺癌患者的56个癌相关基因突变情况。分析肺腺癌基因突变特征并与欧美肺腺癌人群基因突变特征进行比较,分析基因突变与临床特征相关性并筛查靶向用药位点。结果 104例肺腺癌患者中,84例(81%)检测到34种基因突变,前4位高频突变基因包括表皮生长因子受体(EGFR)(49%,51/104)、TP53(21%,22/104)、KRAS(13%,14/104)、BRAF(6%,6/104)。检测到的187个突变中,76%(142个)为错义点突变,13%(24个)为小片段缺失,6%(12个)为拷贝数扩增,3%(5个)为小片段插入,2%(4个)为无义突变。104例肺腺癌患者中,68例(65%)检测到涉及13个基因的34种靶向用药相关基因的突变,其中19例(18%)检测到≥2种靶向用药相关基因突变。女性患者比男性患者更容易发生EGFR基因突变[62%(34/55)比35%(17/49),χ2=7.629,P=0.006],男性患者比女性患者更容易发生KRAS基因突变[22%(11/49)比5%(3/55),χ2=6.424,P=0.011]。EGFR、TP53、KRAS、CDKN2A基因在昆山市第一人民医院与欧美肺腺癌人群中的突变率差异均有统计学意义(均P<0.05)。结论 肺腺癌的基因突变特征较为复杂,且在不同人群中的差异较大。基于高通量测序技术的多基因联合检测可相对全面地揭示患者肿瘤相关基因突变特征,对个体化的靶向用药指导、耐药监测及预后评估有一定的意义。

Objective To explore the characteristics and significances of gene mutations in pulmonary adenocarcinoma,and to provide evidence for targeted medication.Methods High throughput sequencing based target-capture sequencing was performed in 104 patients with pulmonary adenocarcinoma to detect the mutational status of 56 cancer-related genes.All patients were diagnosed in the First People's Hospital of Kunshan from May 2017 to August 2018.The mutational characteristics of pulmonary adenocarcinoma was analyzed and compared with European and American pulmonary adenocarcinoma populations.The correlations between mutational characteristics and clinical features were analyzed,and the mutation sites for targeted medication were screened.Results Among 104 patients with pulmonary adenocarcinoma,totally 34 mutational genes were detected in 84 patients(81%,84/104).Highly frequent mutations included epidermal growth factor receptor(EGFR)(49%,51/104),TP53(21%,22/104),KRAS(13%,14/104),and BRAF(6%,6/104).Among all the 187 variants,76%(142/187)were non-synonymous missense mutations,13%(24/187)were small fragment deletions,6%(12/187)were copy number variants,3%(5/187)were small fragment insertions,and 2%(4/187)were nonsense site mutations.Among 104 patients with pulmonary adenocarcinoma,34 targeted drug-associated mutations of 13 genes were detected in 68 patients(65%),and 19(18%)patients harbored≥2 targeted drug-associated mutations.EGFR mutations were more common in female patients than in male patients[62%(34/55)vs.35%(17/49),χ2=7.629,P=0.006],while KRAS mutations were more frequent in male patients than in female patients[22%(11/49)vs.5%(3/55),χ2=6.424,P=0.011].The mutation frequencies of gene EGFR,TP53,KRAS,and CDKN2A in Chinese single-center(the First People's Hospital of Kunshan)and European and American adenocarcinoma populations were significantly different(all P<0.05).Conclusions The molecular mutational characteristics of pulmonary adenocarcinoma are complex,and vary greatly among different populations.High throughput sequencing-based multiple-gene detection can reveal its mutational features comprehensively,and that has important roles in personal targeted medication guidance,drug-resistance monitoring and prognosis evaluation.