非小细胞肺癌中表皮生长因子受体基因拷贝的检测及其临床意义

目的 检测国人非小细胞肺癌标本中表皮生长因子受体(EGFR)基因高拷贝的发生率及与临床特征的关系.方法 236例非小细胞肺癌标本制作成组织微阵列,使用Vysis公司的荧光原位杂交探针检测EGFR基因拷贝数.结果 193例标本得到结果 ,检测到EGFR基因高拷贝81例(占42.0%),其中42例(21.8%)为高多倍体,39例(20.2%)为基因扩增.其发生与病理、分期、性别、吸烟等临床特征无明显相关,与患者的1-3年生存率无明显相关.结论 国人肺癌中EGFR基因拷贝数的分布情况与西方人类似,与临床特征及预后无明显相关.     

K-ras突变导致肺癌细胞对表皮生长因子受体抑制剂耐药的机制

目的 比较不同细胞株引入K-ras突变质粒前后对表皮生长因子受体(EGFR)信号传导通路活性的变化,探讨K-ras突变对于EGFR抑制剂耐药的机制.方法 通过噻唑蓝(MTF)比色法检测HCC827及H292细胞在转染K-ras基因前后的EGFR下游AKT及STAT通路抑制剂敏感性变化,免疫印迹法(Western blot)检测EGFR下游通路激活状态变化.结果 转染后HCC827细胞对于AKT和STAT通路抑制剂敏感性仅下降1.9和5.3倍,H292细胞对于AKT和STAT通路抑制剂敏感性仅下降3.0和2.5倍,远低于吉非替尼敏感性下降程度,转染K-ras的HCC827细胞AKT通路和STAT3通路持续激活,而转染K-ras的H292细胞AKT通路和STAT3通路的活性降低.结论 K-ras导致EGFR抑制剂耐药的原因可能还存在其他耐药机制,携带EGFR基因突变或野生型的肺癌细胞中,K-ras突变对于AKT和STAT通路的影响可能存在不同.

Abstract：

Objective By comparing the activity of signaling pathway in different cell lines affected by K-ras mutation, to investigate the resisitance to epidermal growth factor receptor (EGFR) inhibitors due to K-ras mutation. Methods Methyl thiazol tetrazolium (MTF) method was used to mensure the sensitivity and half maximal inhibitory concentration ( IC50 ) of AKT and STAT inhibitors after transfection of K-ras or blank plasmid into HCC827 and H292 cells. Western blotting was used to compare the activity of downstream signaling pathway in different cell lines. Results After transfection of mutant K-ras, the IC50 of AKT and STAT inhibitors in HCC827 cells was reduced by 1.9 and 5.3 times respectively, and that in H292 cells was reduced by 3.0 and 2. 0 times respectively. The activity of AKT and STAT pathways in HCC827 cells transfected with mutant K-ras was continuously activated, while that in H292 cells was suppressed. Conclusion K-ras-induced resistance to EGFR inhibitors may be related to other mechanisms. In the tumor cells bearing mutant or wild-type EGFR gene, there may exist different influences of K-ras mutations on AKT and STAT pathways.     

表皮生长因子受体,多胺与肺癌的关系

探讨表皮生长因子受体（ＥＧＦＲ）和多胺（ＰＡ）对人肺癌及正常肺组织生长、分化的影响。方法放射性配体结合法检测ＥＧＦＲ含量；高效液相色谱分析法测ＰＡ含量。结果肺癌组织中ＥＧＦＲ的含量（５．６２±４．２６ｆｍｏｌ／ｍｇ膜蛋白）高于非癌肺组织（３．９０５±２．２７９ｆｍｏｌ／ｍｇ膜蛋白），有显著性差异（Ｐ＜０．０１）；肺癌组织ＰＡ的含量亦高于正常肺组织（Ｐ＜０．０１）。结论ＥＧＦＲ和ＰＡ可促使肺癌发展，可作为肺癌的肿瘤标记物     

肺癌中表皮生长因子受体过表达与女性、非吸烟、腺癌和基因突变的关系

目的探讨女性和非吸烟的肺腺癌标本中表皮生长因子受体（EGFR）过表达与EGFR基因突变的关系。方法应用组织微阵列和免疫组织化学方法检测137例国人非小细胞肺癌标本（鳞癌71例、腺癌66例）中EGFR的表达，采用测序的方法检测EGFR基因突变。结果EGFR过表达率在肺鳞癌中为63．4％显著高于腺癌的43．9％（P〈0．05），其与性别、吸烟情况无关，也与基因突变无关。结论EGFR的过表达率在女性、非吸烟、腺癌及存在EGFR突变的标本中未见升高，提示这些人群中EGFR抑制剂效果较好的原因与蛋白过表达无关。     

表皮生长因子受体酪氨酸激酶抑制剂与非小细胞肺癌的临床研究现状

表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)能显著改善EGFR激活突变的晚期非小细胞肺癌(NSCLC)患者的生存期。几乎所有EGFR突变的NSCLC肿瘤最终都获得了对EGFR-TKIs的耐药性,而获得EGFR-TKIs耐药性是目前治疗EGFR突变的NSCLC面临的巨大挑战。近几年来,在EGFR-TKI药物的研究及NSCLC的治疗方面有了新的突破,该文就EGFR-TKI与NSCLC的相关临床研究及应用取得的进展进行阐述。     

非小细胞肺癌中表皮生长因子受体基因及蛋白的异常

目的 检测国人非小细胞肺癌标本中表皮生长因子受体(EGFR)抑制剂疗效预测指标:EGFR蛋白过表达、基因高拷贝和基因突变的发生特点及相互关系.方法 226例肺腺、鳞癌标本制作成组织微阵列,使用免疫组织化学检测EGFR蛋白表达、荧光原位杂交检测基因拷贝数,其中94例腺癌标本进行EGFR基因突变检测.结果 国人非小细胞肺癌中EGFR蛋白过表达率为55.3%,鳞癌中的过表达率高于腺癌(P=0.001);EGFR基因高拷贝发生率42.0%,与各临床特征无显著相关(P>0.05);EGFR基因突变在腺癌标本发生率为42.6%,与女性和非吸烟显著相关(P=0.002);EGFR蛋白过表达与基因高拷贝显著相关(P=0.005),但EGFR基因突变与基因高拷贝和蛋白过表达均无相关(P>0.05).结论 EGFR抑制剂疗效预测指标中,EGFR蛋白过表达和基因高拷贝的发生情况在国人非小细胞肺癌与西方病人相近,仅EGFR基因突变的发生率高于西方病人.     

表皮生长因子受体及其在肺癌组织中的表达

表皮生长因子受体及其在肺癌组织中的表达黄云超综述杨俊杰周清华审校１９５９年Ｃｏｈｅｎ等在研究神经生长因子时以小鼠颌下腺组织中发现一种能刺激表皮细胞增生、角化的物质，命名为表皮生长因子（ＥｉｐｅｒｍａｌＧｒｏｗｔｈＦａｃｔｏｒ，ＥＧＦ）［１］。进一步研...     

胃癌中表皮生长因子受体表达的临床研究

目的：研究表皮生长因子受体（ＥＧＦＲ０在胃癌中的表达及其临床意义。方法：应用免疫组化技术（ＡＢＣ法）、对９４例胃癌及癌旁组织中ＥＧＦＲ的表达进行半定量检测，观察其同胃癌临床病理参数及预后的关系。结果：（１）ＥＧＦＲ在正常胃膜中无表达，而在胃癌中的表达率为４０．４％，癌旁组织及新生血管中ＥＧＦＲ有阳性表达；（２）ＥＧＦＲ的表达与患者的性别、年龄和肿瘤大小无关（Ｐ〉０．０５），而与肿瘤的生长方式、浆膜     

肺腺癌患者表皮生长因子受体基因突变的临床意义

目的 检测肺腺癌患者表皮生长因子受体（EGFR）基因第19和21外显子突变情况并探讨EGFR突变的临床意义。 方法 采用巢式PCR技术对161例肺腺癌患者手术标本的石蜡包埋癌组织EGFR基因第19和21外显子片段进行扩增并测序,分析EGFR突变与临床病理特征及预后的关系。 结果 161例肺腺癌组织中81例（50.3%）存在EGFR基因突变,其中第19外显子突变44例,第21外显子突变41例,4例第19和21外显子同时存在突变。年龄51～60岁和＞60岁的EGFR突变率均明显高于≤50岁的（P﹤0.05）,细支气管肺泡癌（69.7%）中的EGFR突变率明显高于腺癌（45.3%）（P=0.013）,存在EGFR突变的患者中位生存期较长（P=0.0177）,EGFR突变与性别、吸烟史和临床TNM分期无关。 结论 EGFR突变在年龄＞50岁肺腺癌患者中较多见,细支气管肺泡癌中的EGFR突变率明显高于腺癌,存在EGFR突变的患者预后较好。     

K-Ras突变对表皮生长因子受体抑制剂敏感细胞株的影响

目的 观察K-Ras突变对于携带表皮生长因子受体(EGFR)突变细胞的EGFR抑制剂敏感性的影响.方法 构建K-Ras突变真核表达质粒,采用脂质体转染技术转染肺癌细胞HCC827(EGFR突变,K-Ras野生)和H292(EGFR、K-Ras均野生),噻唑蓝(MTT)比色法测定转染K-Pas突变质粒和空白质粒后各细胞对EGFR抑制剂的半数抑制浓度(IC_(50)).结果 真核表达质粒构建成功.细胞HCC827未转染K-ras突变质粒对吉非替尼(Iressa)的IC_(50)为0.007,转染后对Iressa的IC_(50)为12.3,差异有统计学意义(P<0.01).细胞H292未转染K-ras突变质粒对Iressa的IC_(50)为0.04,转染后对Iressa的IC_(50)为12.0,差异有统计学意义(P<0.01).细胞A549(K-Ras突变)对Iressa的IC_(50)为12.8,与转染K-ras突变质粒的细胞HCC827及H292比较,差异无统计学意义(P>0.05).结论 野生型或突变型EGFR出现K-Ras突变均可引起吉非替尼耐药,其程度与K-Ras突变的细胞株相当.     

基于肺部CT生境模型预测表皮生长因子受体突变型肺腺癌脑转移

目的 观察基于肺部CT生境模型预测表皮生长因子受体（EGFR）突变型肺腺癌脑转移（BM）的价值。方法 回顾性分析198例EGFR突变型肺腺癌患者肺部平扫CT资料,按7∶3比例将其分为训练集（n=138）与测试集（n=60）并进一步划分BM亚组与非BM亚组。筛选训练集亚组间差异有统计学意义的变量构建逻辑回归（LR）临床模型;分别于瘤体及瘤体亚区提取特征,基于随机森林、高斯过程（GP）及支持向量机（SVM）算法构建影像组学及生境模型并筛选其中泛化能力最佳者,基于泛化能力最佳影像组学、生境模型及临床模型预测值构建LR联合模型;绘制受试者工作特征曲线,计算曲线下面积（AUC）,评估各模型预测EGFR突变型肺腺癌BM的效能,以Spearman相关分析观察EGFR突变型肺腺癌Ki-67水平与生境特征的相关性。结果 LR临床模型、GP影像组学模型、SVM生境模型及LR联合模型预测训练集EGFR突变型肺腺癌BM的AUC分别为0.700、0.726、0.801及0.834,在测试集分别为0.754、0.600、0.715及0.848。LR联合模型在训练集的AUC高于LR临床模型（P＜0.001）、在测试集的AUC高于GP影像组学模型（P=0.010）;其在训练集的效能相比GP影像组学模型及SVM生境模型均有显著正向提高[综合判别改善指数（IDI）=8.60%、8.55%,P均＜0.001]。EGFR突变型肺腺癌Ki-67水平与生境图谱中的habitatmap_original_glszm_lalgle呈低度正相关（│r_s│=0.201,P=0.004）。结论 基于肺部CT生境模型可有效预测EGFR突变型肺腺癌BM。     

Survival impact of epidermal growth factor receptor overexpression in patients with non-small cell lung cancer: a meta-analysis

BACKGROUND: It is thought that overexpression of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) might compromise patient survival, presumably by promoting tumour growth by an autocrine mechanism. However, conflicting results have been reported from various laboratories, and the clinical importance of EGFR overexpression remains unsettled. METHODS: A meta-analysis of previous studies was performed to quantitatively review the effects of EGFR overexpression on survival in patients with NSCLC using a DerSimonian-Laird random effects model. Eighteen studies including 2972 patients were subjected to final analysis. RESULTS: Overall, positivity for EGFR overexpression differed between histological types: 39% in adenocarcinomas, 58% in squamous cell carcinomas, 38% in large cell carcinomas, and 32% in cancers in a miscellaneous category (p<0.0001). The combined hazard ratio (HR) was 1.14 (95% CI 0.97 to 1.34; p = 0.103), indicating that EGFR overexpression has no significant impact on survival. When only the 15 immunohistochemistry based studies were considered, the combined HR was 1.08 (95% CI 0.92 to 1.28; p = 0.356), again suggesting that EGFR overexpression has no impact on survival. Heterogeneity testing indicated that there was heterogeneity between studies but publication bias was absent, which suggests that the summary statistics obtained may approximate the actual average. CONCLUSIONS: EGFR overexpression was not associated with poorer survival in patients with NSCLC. Specific mutations of the EGFR gene will need further study in terms of survival implications.     

High-risk-pattern lung adenocarcinoma with epidermal growth factor receptor mutation is associated with distant metastasis risk and may benefit from adjuvant targeted therapy

 Open in a separate windowOBJECTIVESThis study aimed to evaluate the value of the high-risk-pattern histology (micropapillary and solid components) for predicting distant metastasis in lung adenocarcinoma and to determine the survival benefit with adjuvant targeted therapy for resected non-small cell lung cancer with high-risk-pattern histology.METHODSPatients receiving surgery for non-small cell lung cancer were included in this retrospective study. Histological classification was performed according to 2015 World Health Organization classification. Tumours with micropapillary and solid components were defined as high-risk-pattern tumours. Univariable and multivariable Cox regression analyses were used for survival analysis. Adjuvant targeted therapy was alternative for patients with epidermal growth factor receptor (EGFR)-mutation and refusing adjuvant chemotherapy, and outcome was evaluated between 2 groups.RESULTSThe 514 patients (78 in high-risk group and 436 in low-risk group) were followed up for a median of 64 months. High-risk-pattern adenocarcinoma was significantly more common in male patients (P < 0.001) and in smokers (P < 0.001). Among patients with EGFR mutation (n = 164), the high-risk pattern was significantly associated with distant metastasis (P = 0.028) including brain metastasis (P = 0.022). In the 42 patients with high-risk pattern plus EGFR mutation, survival was significantly better after treatment with adjuvant targeted therapy than with chemotherapy (5-year overall survival: 56.4 ± 2.6 vs 44.7 ± 3.7 months, P = 0.011; 5-year disease-free survival: 54.0 ± 3.3 vs 41.9 ± 4.5 months, P = 0.006).CONCLUSIONSHigh-risk pattern is associated with distant metastasis in non-small cell lung cancer after surgery. Adjuvant targeted therapy may be superior to chemotherapy for treatment of patients with high-risk pattern and EGFR mutation.