非小细胞肺癌中EGFR和K-ras基因突变与蛋白表达相关性的研究

Study of the correlation of EGFR and K-ras gene mutations with its protein expression in non-small cell lung cancer

背景与目的:当前表皮生长因子受体(epidermal growth factor receptor,EGFR)基因靶向治疗已成为晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)治疗的研究的热点之一。本研究旨在探讨NSCLC患者中EGFR基因和K-ras(Kirsten rat sarcoma viral oncogene)基因突变的情况,分析其与蛋白表达的相关性及对吉非替尼(gefitinib)治疗的指导意义。方法:收集200例NSCLC患者新鲜组织,采用基因测序法检测EGFR及K-ras基因突变的状态;同时采用免疫组织化学法检测EGFR和K-ras蛋白的表达。结果:200例患者中,EGFR基因突变率为33%,主要发生在19号和21号外显子;K-ras基因突变率为5.5%,主要位于第12密码子;不存在同时携带有EGFR和K-ras两种基因突变的病例。腺癌尤其是含细支气管肺泡癌(bronchioloalveolar carcinoma,BAC)病理分型的患者、非吸烟患者和女性患者EGFR突变率较高。EGFR蛋白表达阳性率为16%,与总的EGFR突变无关(P>0.05),但与19号外显子突变具有统计学意义(P<0.05)。K-ras蛋白表达阳性率为52.5%,与K-ras基因突变无关(P>0.05)。15例携带有EGFR基因突变的NSCLC患者服用吉非替尼,12例(其中8例为EGFR蛋白表达阴性)有效。结论:EGFR蛋白表达与EGFR基因19号外显子突变具有一定相关性;联合检测EGFR和K-ras基因突变可用来筛选对EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)治疗敏感的人群,并预测吉非替尼治疗晚期NSCLC的疗效及预后。

Background and purpose：EGFR （epidermal growth factor receptor） gene targeted therapy has been used for advanced NSCLC （non-small cell lung cancer）.This study investigated gene mutations of EGFR and K-ras （Kirsten rat sarcoma viral oncogene） in Chinese patients with NSCLC,analyzed the correlation with its protein expression and its clinical signify cancer after the treatment of gefitinib.Methods：Gene sequencing was used to detect the EGFR and K-ras gene mutations status,immunohistochemistry was used to detect EGFR and K-ras protein expression.Results：The frequency of EGFR mutations,which were mainly located in exon 19 and exon 21,was 33%.The frequency of K-ras mutations was 5.5%,which were mainly located in codon 12.There was no instance of which both had EGFR and K-ras mutations occurring simultaneously.EGFR mutations were more common in adenocarcinomas （particularly those with bronchioloalveolar features）,non smokers and females.16% of patients were detected with EGFR positive expression and had no correlation with EGFR mutation （P〉0.05）,but were significantly correlated with mutation in exon 19 （P〈0.05）.The frequency of K-ras positive expression was 52.5% and had no correlation with K-ras mutation （P〈0.05）.12 （8 cases were protein-negative） out of 15 gefitinib-treated NSCLC patients under disease control carried EGFR mutations.Conclusion：EGFR protein expression has some correlation with exon 19 mutations.Combined detection of EGFR and K-ras gene mutations can help determined whether the patients may benefit more from EGFR tyrosine kinase inhibitor （EGFR-TKI） and also help predict the response and prognosis of gefitinib.