【作者】 陈哲；

【导师】 陈宝元；

【作者基本信息】 天津医科大学 ， 内科学， 2007， 博士

【摘要】 目的肺癌对人类的威胁越来越严重，我国肺癌的发病率和死亡率在城市持续增加，以铂类为基础的一线联合化疗和以泰索帝为代表的二线联合化疗在治疗非小细胞肺癌方面取得了一定的疗效。但非小细胞肺癌的5年生存率仍小于5％。以表皮生长因子受体抑制剂为代表的靶向治疗为晚期非小细胞肺癌的治疗提供了新的选择。由于gefitinib和erlotinib是强有力的选择性酪氨酸激酶抑制剂，它们通过与ATP竞争EGFR上的ATP结合位点抑制EGFR的活性，因而EGFR与选择性酪氨酸激酶抑制剂疗效相关性的研究自然就成为了人们关注的焦点之一。最近的研究还表明，选择性酪氨酸激酶抑制剂治疗效果明显与否，存在一定的地区分布差异，亚洲国家如日本非小细胞肺癌患者的疗效好于美国的非小细胞肺癌患者。甚至有人戏称该类药物是上帝给亚洲肺癌患者的礼物。同时，临床疗效似乎与病理类型、性别、吸烟与否也有一定的相关性，不吸烟、女性、腺癌的临床效果较好。这些特点恰与EGFR基因突变的发生情况相一致，如日本人的EGFR基因突变率高于美国人，组织类型是以腺癌EGFR突变率为最高。即治疗效果好的患者中EGFR的突变率明显高于治疗无效的患者。本文分析我市非小细胞肺癌(NSCLC)中上皮生长因子受体(EGFR)基因突变的发生率和突变类型，以期待对临床产生一定的指导意义，并且获得社会效益和经济效益。方法收集24例正常肺组织、24例肺癌组织和21例转移淋巴结组织，采用PCR扩增和基因测序方法，对组织DNA中EGFR外显子19、21基因突变进行分析：结果正常肺组织中EGFR基因均为野生型，肺癌组织中EGFR的基因突变检出率为20．8％(5／24)。其中外显子19突变1例，占突变总数的4％(1／24)，外显子21突变4例，占16．6％(4／24)。外显子19突变发生在第746—753位密码子，为碱基缺失突变，外显子21突变全部是第858位密码子碱基替换突变。EGFR基因突变多见于肺腺癌和腺鳞癌。EGFE的突变与患者的性别和年龄无明显的相关性。21例淋巴结组织中检出突变1例。与其相对应的原发肺癌组织具有相似的突变类型，但另外4例原发肺癌组织有基因突变的患者相对应淋巴结没有检测到突变。结论EGFR基因突变是一种肿瘤特异性的突变，突变发生率约占肺癌总数的1／5，其中以外显子21为主。肺腺癌和腺鳞癌中突变多见。转移性淋巴结组织的EGFR的基因突变的检测尚不能全面准确的反应出相对应的肺癌组织的EGFR的基因突变类型。更多还原

【Abstract】 Lung cancer is a common fatal disease with highestmobidity and motality rate among tumors in urban China.With thedevelopment of standard platinum-based chemotherapy regimens andDocetaxel-based second line regimen,the 5-year survival remainspoor in non-small cell lung cancer (NSCLC).Epidermal growth factorreceptor (EGFR) tyrosine kinase inhibitor provides a noveltreatment for advanced non-small cell lung cancer(NSCLC).Gefitinib isa strong epidermal growth factor receptor (EGFR) tyrosinekinase inhibitor,which blocks the activity of EGFR by competes ATPbinding site on EGFR with ATP.So it is interesting evaluate therelationship of EGFR and tyrosinekinase inhibitor.Recently,two groups reported that the mutation rate of tyrosinekinase domain of EGFR was much higher among gefitinibresponders than non-responders,and Japanese has highermutation rate than American.There is a regionaldifference for EGFR mutation.Mutation rates were higheramong gefitinib responders,non-smokers,patients withadenocarcinoma or female patients.Objective To analyze theincidence and profile of mutations in epidermal growth factorreceptor (EGFR) in patients with cell lung cancer (NSCLC).Methods:A total of 24 cases of non-small cell lung cancertissue was enrolled in this study,among which 24 normallung samples and 21 lymph node were also included.The tissueDNA was extracted and the EGFR gene in exon 19 to 21was subjected for PCR amplification and direct sequencing.Results The EGFR gene in exon 19-21 was of wild typein all normal lung tissues detected.Mutations were found in5 cases of 24 lung cancer samples,with an incidence of20.8%.Mutations were mainly detected in the exon 21 (4/24cases,16.6%) and exon 19 (1/24 cases,4%),resulting inthe deletion of codon 746 to 753.The mutation in exon 21belonged to the single missense substitution in codon 858.The EGFR mutations were more frequent in adenocarcinomaand adenosquamous cell carcinoma versus cancer ofother histologies.There was no statistically significantdifference between the mutation with gender and age.Mutations were found in lcase of 21 lymph node samples,withan incidence of 4.8%.The type of mutation weresimilar between primary and corresponding metastatic lymphnode,and the mutation detected in metastatic tumors wasalso detected in the corresponding primary tumors.On theother hand,in 4 of the 5 cases,there were mutation detected onlyin primary tumors.Conclusion:EGFR mutation is atumor-specific somatic abnormality.Some one fifth of ChineseNSCLC tumors harbor EGFR mutations,especially in exons 21 and19.These mutations are more frequently detected inadenocarcinoma and adenosquamous cell carcinoma.EGFRmutations detected in lymph node samples may predict theEGFR mutations of NSCLC partially.更多还原