非小细胞肺癌驱动基因突变与临床病理特征的关系

Comprehensive investigation of driver gene expression and clinicopathological characteristics in non-small cell lung cancer

目的探讨非小细胞肺癌(non-small cell lung cancer,NSCLC)中驱动基因突变并分析其与临床病理特征的关系。方法选取病理资料完整的550例原发性NSCLC作为研究对象,采用蝎形探针扩增阻滞突变系统(scorpion ARMS)荧光定量PCR法对184例NSCLC进行9种驱动基因检测,对另外366例NSCLC患者采用Illumina测序法进行10种驱动基因检测,并回顾性分析患者的临床病理特征。结果550例NSCLC中有405例检测到基因突变(73.6%),分别为EGFR(57.3%)、KRAS(5.8%)、PIK3CA(2.2%)、ALK(3.8%)、RET(2.0%)、ROS1(1.1%)、NRAS(0.2%)、BRAF(1.5%)、HER-2(2.0%)和MET(0.3%),检出驱动基因联合突变12例(2.2%),EGFR双位点突变8例(1.5%)。在NSCLC中,腺癌、女性、无吸烟史、周围型和以腺泡型为主的腺癌患者更易发生驱动基因突变(P<0.05)。EGFR基因突变人群特征为女性、无吸烟史、腺癌、周围型,多发于以腺泡型为主型的腺癌中,少见于以实体型和黏液型的腺癌患者中(P<0.05)。KRAS基因突变率在男性、有吸烟史和以浸润性黏液型为主的腺癌中更高,不易发生在贴壁型腺癌中(P<0.05)。PIK3CA基因突变在男性中发病率较高(P<0.05)。ALK基因突变率在以实体型为主的腺癌和伴有淋巴结转移的患者中更高且不易发生在贴壁型腺癌中(P<0.05)。RET基因在以实体型为主的腺癌中突变率较高(P<0.05)。EGFR双位点突变多发于有淋巴结转移和以乳头型为主的肺腺癌中(P<0.05)。结论NSCLC中EGFR、KRAS、ALK基因存在较高的突变率,其他驱动基因改变以及联合突变的突变率虽低,但意义重大不容忽视,其中EGFR合并PIK3CA突变提示患者有较高的临床分期。多基因联合检测在临床上对加快筛选有效治疗目标人群具有重要意义。

Purpose To determine the frequency of oncogenic driver mutations in non-small cell lung cancer(NSCLC)patients,along with its correlation of clinicopathological features.Methods 550 patients selected with complete clinicopathological data were detected for NSCLC driver gene mutations.Scorpions amplification refractory mutation system(Scorpions ARMS)fluorescence quantitative PCR was performed in 184 patients for 9 genes detection,and Illumina NextSep 500 sequencing in 366 patients for 10 genes detection,respectively.The clinicopathological features of patients were retrospectively analyzed.Results Of 550 examined samples,405(73.6%)showed mutations of NSCLC driver genes,including EGFR(57.3%),KRAS(5.8%),PIK3CA(2.2%),ALK(3.8%),RET(2.0%),ROS1(1.1%),NRAS(0.2%),BRAF(1.5%),HER-2(2.0%)and MET(0.3%).Comutations and double EGFR mutations were discovered in 12(2.2%)and 8(1.5%)samples,respectively.The frequency of driver genes mutations was higher in adenocarcinoma,female,non-smokers,patients with peripheral lung cancer and acinar predominant adenocarcinoma(P<0.05).EGFR mutations were statistically prevalent in non-smokers,female and patients with peripheral lung cancer and acinar adenocarcinoma(P<0.05).Solid predominant and invasive mucinous adenocarcinoma(P<0.05),however,were less likely to occur any EGFR mutation.The frequency of KRAS mutations was higher in male smokers with invasive mucinous adenocarcinoma and significantly lower in patients with lepidic adenocarcinoma(P<0.05).PIK3CA mutations tended to occur in male patients(P<0.05).ALK mutations was significantly associated with patients having lymph node metastasis along with solid predominant adenocarcinoma,but scarcely ever been detected in lepidic adenocarcinoma(P<0.05).RET mutations showed an inclination to happen in the tumor histology of solid predominant.Double EGFR mutations were more likely to happen in papillary predominant adenocarcinoma with lymph node metastasis(P<0.05).Conclusion There are high mutation rate of EGFR,KRAS and ALK gene in NSCLC.Although the mutaition rates of other diveing genes or compound mutations are low,the significance can not be ignored.Comutations of EGFR and PIK3CA indicates that the patients have high clinical stage.The determination of multiple driving genes may have a positive impact on facilitation of screening patients for their most beneficial therapies.