Relationships between EGFR Mutation Status of Lung Cancer and Preoperative Factors - Are they Predictive?

Background: The epidermal growth factor receptor (EGFR) mutation status of lung cancer is importantbecause it means that EGFR-tyrosine kinase inhibitor treatment is indicated. The purpose of this prospectivestudy is to determine whether EGFR mutation status could be identified with reference to preoperative factors.Materials and Methods: One hundred-forty eight patients with lung cancer (111 adenocarcinomas, 25 squamouscell carcinomas and 12 other cell types) were enrolled in this study. The EGFR mutation status of each lungcancer was analyzed postoperatively. Results: There were 58 patients with mutant EGFR lung cancers (mutantLC) and 90 patients with wild-type EGFR lung cancers (wild-type LC). There were significant differences ingender, smoking status, maximum tumor diameter in chest CT, type of tumor shadow, clinical stage betweenmutant LC and wild-type LC. EGFR mutations were detected only in adenocarcinomas. Maximum standardizeduptake value (SUVmax:3.66±4.53) in positron emission tomography-computed tomography of mutant LC wassignificantly lower than that (8.26±6.11) of wild-type LC (p<0.0001). Concerning type of tumor shadow, thepercentage of mutant LC was 85.7% (6/7) in lung cancers with pure ground glass opacity (GGO), 65.3%(32/49)in lung cancers with mixed GGO and 21.7%(20/92) in lung cancers with solid shadow (p<0.0001). For the resultsof discriminant analysis, type of tumor shadow (p=0.00036) was most significantly associated with mutant EGFR.Tumor histology (p=0.0028), smoking status (p=0.0051) and maximum diameter of tumor shadow in chest CT(p=0.047) were also significantly associated with mutant EGFR. The accuracy for evaluating EGFR mutationstatus by discriminant analysis was 77.0% (114/148). Conclusions: Mutant EGFR is significantly associatedwith lung cancer with pure or mixed GGO, adenocarcinoma, never-smoker, smaller tumor diameter in chestCT. Preoperatively, EGFR mutation status can be identified correctly in about 77 % of lung cancers.     

Molecular changes of epidermal growth factor receptor (EGFR) and KRAS and their impact on the clinical outcomes in surgically resected adenocarcinoma of the lung

Recent studies have reported that clinical response to epidermal growth factor receptor (EGFR) inhibitors is associated with somatic changes of EGFR in the advanced stage of lung cancer. However, there is no clear data demonstrating whether such molecular changes of EGFR per se can affect the clinical outcome of early stage cancer after surgical resection. DNA mutations of EGFR and KRAS were investigated in 71 adenocarcinoma patients who received surgical resection. Fluorescence in situ hybridization (FISH) of EGFR gene amplification was performed in 48 samples. We detected EGFR mutations in 25 patients (35.2%). EGFR mutation was more frequently found in cases with BAC features (13/22 (59.1%):13/49 (26.5%); p=0.008) and in non-smokers (19/41 (46.3%):7/30 (23.3%); p=0.047). However, the EGFR mutation was not associated with age, gender, or clinical stage. The amplification of EGFR copy was frequently observed in the female gender (12/29 (41.4%):3/19 (15.8%); p=0.061) and in the advanced stage (> or =Stage IIIA, 9/19 (47.4%):6/29 (20.7%); p=0.051). KRAS mutations were present in five patients (7.0%) and none of them showed EGFR mutation. KRAS mutations (p=0.000), male gender (p=0.001), absence of BAC feature (p=0.003), advanced stage (p=0.039), and smoking history (p=0.030) were poor prognostic factors for overall survival, whereas EGFR mutation (p=0.184) and amplification (p=0.756) were not. The presence of EGFR mutation was not a prognostic factor of the clinical outcome of early lung cancer after surgical resection. This result provides an important message for the protocol design of future trials of EGFR inhibitors in early lung cancer. As the KRAS mutation was a poor prognostic factor and it presents reciprocally with EGFR mutation, KRAS mutation should be investigated in such trials. DNA mutations of EGFR and KRAS were investigated in 71 adenocarcinoma patients who received surgical resection. Whereas KRAS mutation was a poor prognostic factor, EGFR mutation was not, and its presence per se did not affect the clinical outcome of early lung cancer after surgical resection.     

Molecular markers and changes of computed tomography appearance in lung adenocarcinoma with ground-glass opacity

BACKGROUND: High-resolution computed tomography (HRCT) of lung adenocarcinoma at early stage shows pure ground-glass opacity (GGO) and most cases of pure GGO remain stable during follow-up. There is no consensus on the strategy for follow-up. Identification of the molecular mechanisms that are associated with the natural history of lung adenocarcinoma should provide useful information. METHODS: Twenty-three lung adenocarcinomas that were followed-up for more than 6 months pre-operatively by HRCT were included in this study. Patterns of radiological changes during the follow-up period were classified into three groups; type 1, pure GGO without consolidation; type 2, appearance or increase in consolidation within pure GGO; type 3, consolidation without pure GGO. Mutational analysis of the epidermal growth factor receptor (EGFR) and K-ras genes and immunohistochemical staining of p53 protein were performed. RESULTS: EGFR mutations were found in 17 cases (74%), and there was no K-ras mutation. Positive staining of p53 was found in 8 cases (35%). As for radiological findings during the follow-up period, the frequencies of EGFR mutations and positive p53 staining were 67 and 0% in type 1 (n = 9), 89 and 44% in type 2 (n = 9) and 60 and 80% in type 3 (n = 5). CONCLUSIONS: EGFR mutations were frequently found in lung adenocarcinoma with GGO on HRCT in this study. Inactivation of p53 may be associated with the appearance of central consolidation within pure GGO on HRCT which reflects invasive features and may be useful as a molecular marker during the follow-up of pure GGO.     

肺腺癌EGFR、KRAS基因突变、ALK融合蛋白状态分析

目的 分析肺腺癌中EGFR、KRAS、ALK三种肿瘤驱动基因的突变状态及与其临床病理特征、肿瘤分期的关系.方法 85例肺腺癌EGFR,KRAS基因突变采用ARMS法检测,ALK融合蛋白用特异性抗ALK单克隆抗体(克隆号:D5F3)采取免疫组织化学法检测.结果 EGFR,KRAS,和ALK融合蛋白检测阳性率分别是62％,15％,和14％.EGFR基因突变更常见于女性.KRAS基因突变更常见于男性及有吸烟史患者.ALK融合蛋白更常见于年轻及肿瘤分期Ⅲ/Ⅳ患者.检测中发现了8例双突变病例.结论 结果 进一步证实了EGFR、KRAS基因突变与ALK融合蛋白并非完全互斥.对于肺腺癌患者进行全面的基因检测非常重要,在选择靶向治疗时更应考虑到多种变异同时存在的情况.     

伴微乳头成分的肺腺癌EGFR KRAS基因突变和临床病理学特征相关研究

  目的   探讨伴微乳头成分的肺腺癌(pulmonary adenocarcinoma with a micropapillary pattern, MPPAC) EGFR、KRAS基因突变情况及其临床病理学特征。   方法   根据2011年的肺腺癌新分类诊断标准, 以是否伴有微小乳头状结构(micropapillary pat tern, MPP), 将144例肺腺癌病例分为MPP阳性组77例和MPP阴性组77例。MPP阳性组中又按MPP所占比例分为(+、++、+++) 三亚组。RT-PCR法检测两组EGFR、KRAS基因突变情况。   结果   在144例肺腺癌病例中EGFR突变62例(43.1%), KRAS突变9例(6.25%), EGFR突变与性别(P=0.018) 和肿瘤体积(P=0.016) 有关。MPP阳性组EGFR突变率高于MPP阴性组(P < 0.001);KRAS突变率低于MPP阴性组(P=0.016)。EGFR基因突变频率在MPP三亚组中无明显不同(P=0.932)。   结论   伴微乳头结构的肺腺癌EGFR突变频率高于肺腺癌其它亚型, KRAS突变频率低于肺腺癌其它亚型, 说明其有独特的分子生物学特点。      

肺腺癌患者EGFR和KRAS基因突变与预后的相关性研究

目的 探讨肺腺癌患者表皮生长因子受体(EGFR)和KRAS基因突变与预后的相关性.方法 选取134例肺腺癌患者的肺腺癌组织标本,应用探针扩增阻滞突变系统在PCR仪上进行EGFR和KRAS基因突变检测,分析EGFR和KRAS基因突变与肺腺癌患者临床病理特征及预后的关系.结果 134例患者中,EGFR基因突变53例,突变率为39.55%,KRAS基因突变6例,突变率为4.48%.肺腺癌患者EGFR基因突变率与年龄、吸烟史有关(P﹤0.01).EGFR基因突变型患者的KRAS基因突变率低于EGFR基因野生型患者(P﹤0.05).EGFR基因突变型患者的无进展生存期(PFS)长于EGFR基因野生型患者(P﹤0.05),KRAS基因野生型患者的PFS长于KRAS基因突变型患者(P﹤0.05).结论 EGFR基因突变的肺腺癌患者KRAS基因更倾向于野生型,EGFR基因突变型或KRAS基因野生型的肺腺癌患者PFS更长.     

EGFR gene copy number in adenocarcinoma of the lung by FISH analysis: investigation of significantly related factors on CT, FDG-PET, and histopathology

It has been suggested that a high EGFR gene copy number may be an indicator of good response to EGFR tyrosine kinase inhibitor therapy and a marker of poor prognosis in NSCLC. However, imaging features related to EGFR gene copy number status in adenocarcinoma are still unknown. We therefore retrospectively analyzed CT, FDG-PET, and histopathologic slides of surgical resected lung adenocarcinoma in 132 patients. Tumor characteristics on preoperative chest-CT, such as, GGO proportions, tumor diameters, and cavitation; FDG-PET SUV(max); and histopathologically determined differentiation degrees and tumor subtypes were evaluated. EGFR gene copy number status was categorized as FISH-positive or -negative. FISH-positivity was found in 53 patients (40.2%) and was significantly more frequent in tumors with a SUV(max)>7.0 (P=0.007). Furthermore, FISH-negativity was found to be more frequent in tumors with a GGO>50% (P=0.023) and diameter <15.5mm (P=0.006) on CT, or a well-differentiated histopathology (P=0.002). Moreover, the frequency of FISH-positivity increased as SUV(max) increased (P=0.0008) and as the proportion of GGO decreased (P=0.01). SUV(max)>7.0 was an independent predictor of FISH-positive results (odds ratio, 3.941; 95% CI, 1.691-9.182; P=0.01). In conclusion, a high SUV(max) on FDG-PET was significantly related to FISH-positive results. A high proportion of GGO, small tumor diameter on CT, and a well-differentiated histopathology were more frequent in FISH-negative adenocarcinomas.     

表现为磨玻璃样病变的肺腺癌临床特点与EGFR及K-RAS基因突变的关系

目的 探讨表现为磨玻璃样病变（GGO）的肺腺癌的临床特点与EGFR及K-RAS基因突变关系。方法 连续选择37例经胸腔镜手术及病理证实为肺腺癌的肺GGO病例,分析其临床特点,检测EGFR与K-RAS基因突变情况,及与各临床因素之间的关系。结果 34例行肺叶切除术,3例行肺楔形切除术,术后病理结果显示：16例为原位腺癌,13例为微浸润腺癌,8例为浸润性腺癌。EGFR基因突变22例,K-RAS基因突变1例;在单纯型GGO及混合型GGO病例中,EGFR与K-RAS基因突变均无明显差异;在女性、不吸烟病例中EGFR基因突变相较男性及吸烟病例差异具有统计学意义（P<0.05）。结论 EGFR基因在表现为GGO的肺腺癌病例中表现出较高的突变率,为肺GGO病例临床治疗提供了重要参考。     

High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor

Recent findings in tumor biopsies from lung adenocarcinoma patients suggest that somatic mutations in the genes encoding epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) confer sensitivity and resistance, respectively, to EGFR inhibition. Here, we provide evidence that these genetic mutations are not sufficient to modulate the biological response of lung adenocarcinoma cells to EGFR inhibition. We found high expression of ErbB family members, ErbB ligands, or both in three models that were sensitive to EGFR inhibition, including alveolar epithelial neoplastic lesions in mice that develop lung adenocarcinoma by oncogenic KRAS, human lung adenocarcinoma cell lines, and tumor biopsies from lung adenocarcinoma patients. Thus, lung adenocarcinoma cells that depend on EGFR for survival constitutively activate the receptor through a combination of genetic mutations and overexpression of EGFR dimeric partners and their ligands.     

Somatic mutations of the HER2 kinase domain in lung adenocarcinomas

Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the tyrosine kinase domain of HER2 in 671 primary non-small cell lung cancers (NSCLC), 80 NSCLC cell lines, and 55 SCLCs and other neuroendocrine lung tumors as well as 85 other epithelial cancers (breast, bladder, prostate, and colorectal cancers) and compared the mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 1.6% (11 of 671) of NSCLC and were absent in other types of cancers. Only one adenocarcinoma cell line (NCI-H1781) had a mutation. All HER2 mutations were in-frame insertions in exon 20 and target the identical corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in never smokers (3.2%, 8 of 248; P=0.02) and adenocarcinoma histology (2.8%, 11 of 394; P=0.003). In 394 adenocarcinoma cases, HER2 mutations preferentially targeted Oriental ethnicity (3.9%) compared with other ethnicities (0.7%), female gender (3.6%) compared with male gender (1.9%) and never smokers (4.1%) compared with smokers (1.4%). Mutations in EGFR, HER2, and KRAS genes were never present together in individual tumors and cell lines. The remarkable similarities of mutations in EGFR and HER2 genes involving tumor type and subtype, mutation type, gene location, and specific patient subpopulations targeted are unprecedented and suggest similar etiologic factors. EGFR, HER2, and KRAS mutations are mutually exclusive, suggesting different pathways to lung cancer in smokers and never smokers.     

Association of p16 homozygous deletions with clinicopathologic characteristics and EGFR/KRAS/p53 mutations in lung adenocarcinoma

PURPOSE: The p16 gene is frequently inactivated in lung adenocarcinoma. In particular, homozygous deletions (HD) have been frequently detected in cell lines; however, their frequency and specificity is not well-established in primary tumors. The purpose of this study was to elucidate the prevalence and the timing for the occurrence of p16 HDs in lung adenocarcinoma progression in vivo. EXPERIMENTAL DESIGN: Multiple ligation-dependent probe amplification was used for the detection of p16 HDs in 28 primary small-sized lung adenocarcinomas and 22 metastatic lung adenocarcinomas to the brain. Cancer cells were isolated from primary adenocarcinoma specimens by laser capture microdissection. HDs were confirmed by quantitative real-time genomic PCR analysis. RESULTS: HDs were detected in 8 of 28 (29%) primary tumors, including 2 of 8 (25%) noninvasive bronchioloalveolar carcinomas, and 5 of 22 (26%) brain metastases, respectively. No significant associations were observed between p16 HDs and gender, age, smoking history, stage, and prognosis. HDs were detected with similar frequencies (17-29%) among adenocarcinomas with epidermal growth factor receptor (EGFR) mutations, with KRAS mutations, and without EGFR/KRAS mutations, and with similar frequencies (22-28%) between adenocarcinomas with and without p53 mutations. CONCLUSIONS: p16 HDs occur early in the development of lung adenocarcinomas and with similar frequencies among EGFR type, KRAS type, and non-EGFR/KRAS type lung adenocarcinomas. Tobacco carcinogens would not be a major factor inducing p16 HDs in lung adenocarcinoma progression.     

Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking

Somatically acquired mutations in the epidermal growth factor receptor (EGFR) gene in lung cancer are associated with significant clinical responses to gefitinib, a tyrosine kinase inhibitor that targets EGFR. We screened the EGFR in 469 resected tumours of patients with lung cancer, which included 322 adenocarcinomas, 102 squamous cell carcinomas, 27 large cell carcinomas, 13 small cell carcinomas, and five other cell types. PCR with a specific condition was performed to identify any deletion in exon 19, while mutant-allele-specific amplification was performed to identify a mutation in codon 858 of exon 21. EGFR mutations were found in 136 cases (42.2%) with adenocarcinoma, in one case with large cell carcinoma, and in one case with pleomorphic carcinoma. An in-frame deletion in exon 19 was found in 62 cases while an L858R mutation was found in 77 cases. In the 322 cases with adenocarcinoma, these mutations were more frequently found in women than in men (P=0.0004), in well differentiated tumours than in poorly differentiated tumours (P=0.0014), and in patients who were never smokers than in patients who were current/former smokers (P<0.0001). The mutation was more frequently observed in patients who smoked 相似文献   

Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history

Mutations in the tyrosine kinase domain of the epidermal growth factor receptor EGFR are common in non-small cell lung cancer (NSCLC) of never smokers, whereas HER2 mutations are rare. We have analyzed EGFR and HER2 mutations and the expression of the two products of the CDKN2A gene (p14(arf) and p16(INK4a)) in 116 NSCLC that have been previously analyzed for TP53 and KRAS mutations in relation to smoking history of patients. EGFR mutations were detected in 20 of 116 (17%) tumors, whereas five (4.3%) tumors contained HER2 mutations. No tumor contained both mutations. Of tumors with EGFR or HER2 mutation, 72% were adenocarcinomas, 68% were from never smokers, and 32% were from former smokers. EGFR but not HER2 mutations were mutually exclusive with KRAS mutation. Among never smokers, 11 of 16 tumors with EGFR mutation also had TP53 mutation, in contrast with two of 17 tumors without EGFR mutation (P = 0.0008). Expression of p14(arf), but not p16(ink4a), was more frequently down-regulated in never smokers (62.5%) than ever smokers (35%; P = 0.008). All tumors with EGFR or HER2 mutations and wild-type TP53 showed down-regulation of p14(arf) expression. These observations suggest that functional inactivation of the p14(arf)/p53 connection is required in tumors with EGFR or HER2 mutations, consistent with the notion that these proteins are part of a fail-safe mechanism protecting cells against untimely or excessive mitotic signals.     

A correlation between EGFR gene mutation status and bronchioloalveolar carcinoma features in Japanese patients with adenocarcinoma

BACKGROUND: The presence of epidermal growth factor receptor (EGFR) mutations in gefitinib-naive lung cancer patients has been reported to be higher in females, in non-smokers, in Japanese, and in adenocarcinoma patients, especially in bronchioloalveolar carcinoma (BAC). To further investigate the prevalence of EGFR mutations in relation to pathological factors, we evaluated EGFR mutations in series of Japanese adenocarcinoma patients who had never been treated with gefitinib. METHODS: In the previous studies, we examined mutation status in the tyrosine kinase domain of EGFR, exon18 through exon21, in 112 primary lung adenocarcinoma samples. Using these data, adenocarcinomas were histologically classified according to the presence or absence of bronchioloalveolar components. RESULTS: Among 112 patients, 48 had adenocarcinoma with BAC components. Those with adenocarcinomas with BAC components had higher frequency of EGFR mutation (28/48, 58%) than those with non-BAC adenocarcinoma (24/64, 37%, P = 0.036). Male patients had the same trend; 12/23 (52%) male patients with adenocarcinoma with BAC components and 10/47 (21%) of those with non-BAC adenocarcinoma had EGFR mutation (P = 0.0135) but there was no correlation between the EGFR mutation status and with/without BAC components in 42 female patients (P = 0.30). Among 11 male non-smokers, patients with adenocarcinoma with BAC components had a tendency to have EGFR mutation more frequently than those with non-BAC adenocarcinoma (P = 0.061). In clear contrast, the frequency of EGFR mutation did not differ significantly between male smoker patients with adenocarcinoma with BAC components and those with non-BAC. Among patients with adenocarcinoma with BAC components, those with adenocarcinoma with EGFR gene mutation had a significantly better 5 year survival than those with adenocarcinoma with wild-type (85.7 versus 46.0%, P = 0.0017). CONCLUSIONS: Adenocarcinomas with BAC components in male non-smokers seem to predict the presence of EGFR mutation. Half of female adenocarcinoma patients with EGFR mutation exhibit adenocarcinomas with non-BAC suggesting a different behavior from those in males. The prognosis of patients with adenocarcinoma with BAC components with EGFR gene mutation is predicted to be better than that of patients with adenocarcinoma with BAC components with wild-type EGFR gene.     

18F-FDG PET/CT对肺腺癌EGFR突变状态的预测价值研究*

目的 :本研究旨在阐明18F-FDG PET/CT对于肺腺癌EGFR突变状态的预测价值。 方法: 选取2016年6月1日至2017年7月31日于天津医科大学肿瘤医院行术前PET/CT扫描及术后基因检测的肺腺癌患者117例。分析患者临床特征、肺内原发病灶SU? Vmax、SUVmean、SUVpeak及肺内原发病灶与纵隔血池SUVmax比值与EGFR突变状态间的关系。采用受试者工作特征曲线分析不同PET代谢参数对EGFR突变状态的预测能力。 结果: 117例患者中,EGFR突变型患者65例。未吸烟患者EGFR突变率高于吸烟患者（62.5% vs. 40.5%,P=0.026）。EGFR突变型肺内原发病灶SUVmax、SUVmean、SUVpeak及肺内原发病灶与纵隔血池SU? Vmax比值均明显低于野生型（SUVmax:8.02±3.96 vs. 10.31±5.80,P=0.017;SUVmean:4.97±2.51 vs. 6.45±3.68,P=0.015;SUVpeak:6.03±3.22 vs. 8.06±5.01,P=0.013;T/N:5.08±3.01 vs. 6.91±4.40,P=0.012）。不同诊断标准间诊断效能无明显差异。 结论: EGFR突变型患者肺内原发病灶FDG摄取值低于野生型患者,因此,18F-FDG PET/CT对肺腺癌患者EGFR突变状态的预测具有一定指导意义。      

18F-FDG PET/CT在预测非小细胞肺癌EGFR突变中的价值

目的:探讨18F脱氧葡萄糖（18F-fluorodeoxyglucose,18F-FDG）正电子发射计算机断层显像(PET/CT)最大标准摄取值（maximum standardized uptake value,SUVmax）及代谢体积（metabolic tumor volume,MTV）在预测非小细胞肺癌（non-small cell lung cancer,NSCLC）表皮生长因子受体（epidermal growth factor receptor,EGFR）突变中的价值。方法:回顾性分析141例经病理证实的NSCLC患者的临床资料,所有患者治疗前均行18F-FDG PET/CT 检查及EGFR突变检测。分析临床病理资料和PET/CT代谢参数SUVmax、MTV与EGFR突变状态的相关性。采用受试者工作特征（receiver operating characteristic,ROC）曲线获得SUVmax、MTV预测EGFR突变的最佳界值点。采用Logistic回归模型对预测EGFR突变状态的变量进行多因素分析。结果:141例入组患者中,EGFR突变型有74例（52.5%）。EGFR突变患者的MTV值明显低于野生型患者（P=0.033）,而EGFR突变患者的SUVmax与野生型患者的SUVmax间无统计学差异（P>0.05）。ROC曲线分析显示,SUVmax及MTV预测EGFR突变的最佳截断值分别是8.56,24.0 cm3,AUC分别是0.522,0.604。单因素分析结果显示,不吸烟者(P=0.001)、女性(P=0.003)、腺癌(P=0.022)及MTV＜24.0 cm3（P=0.003）的患者更易出现EGFR突变。Logistic 多因素分析显示,吸烟及MTV是预测EGFR突变的独立影响因子（P<0.05）。结论:MTV是预测NSCLC EGFR突变的独立影响因素,在预测EGFR突变中具有一定的参考价值。     

754例Ⅰ期-Ⅲa期可手术切除非小细胞肺癌患者EGFR和KRAS基因突变状态及其临床意义

背景与目的 表皮生长因子受体(epidermal growth factor receptor,EGFR)和KRAS基因是非小细胞肺癌(non-small cell lung cancer,NSCLC)重要的分子靶点,但目前研究主要集中在晚期NSCLC组织和血浆标本的EGFR检测,早期NSCLC组织样本中EGFR和KRAS突变特征尚不清楚.本研究将探讨Ⅰ期-Ⅲa期NSCLC EGFR和KRAS基因突变与相关临床病理特征的关系.方法 采用突变扩增系统(amplification refractory mutation system,ARMS)PCR方法检测北京协和医院病理科提供的754例Ⅰ期-Ⅲa期NSCLC组织样本的EGFR和KRAS基因突变状况,分析基因突变率及其与临床病理特征的关系.结果 EGFR和KRAS基因热点突变的突变率分别为34.5％和13.1％,其中有3例样本具有EGFR和KRAS基因的双突变.EGFR基因在女性中的突变率高于男性(39.5％vs 29.4％,P=0.076),在腺癌中的突变率(38.7％)高于鳞癌、腺鳞癌、大细胞癌(P＜0.01),但仍明显低于其他研究报道的亚裔晚期腺癌突变率(-50％).KRAS基因突变在男性中的突变率高于女性(16.6％vs 9％,P=0.048),且在腺癌中的突变率也高于其他类型,但差异不显著(P=0.268).与KRAS基因突变阳性组相比,EGFR基因突变阳性组在年龄分布上有年轻化的趋势(P=0.031,5),在性别分布上有显著性差异(P＜0.01).结论 Ⅰ期-Ⅲa期NSCLC EGFR基因突变率较晚期患者低,且EGFR和KRAS基因双突变的发生率为0.9％.     

A fully integrated, automated and rapid detection system for KRAS mutations

KRAS mutations are detected in tumors of various organs, and they are also markers of resistance for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and monoclonal antibodies against the EGFR. Thus, the accurate and rapid detection of KRAS mutations is crucial, not only for screening, but also for the prediction of the efficacy of molecular-targeted therapy. The aim of the present study was to establish a novel automated detection system for KRAS mutations. One hundred and thirty-six lung adenocarcinoma patients were genotyped for KRAS mutations with both the conventional direct sequence (DS) method and with the newly developed quenching probe (QP) method that obtains data automatically within 60 min. The detection limit of the QP method using a control plasmid containing the KRAS mutation was 50 copies, and 10% mutant plasmid was detected in the mixture of wild-type and mutants. The results obtained by the QP and DS methods were identical in all but two of the 136 cases. The two differentially identified samples, which consisted of substantially fewer lung cancer cells, were positive according to the QP method but negative as determined by DS for KRAS mutations. These findings characterize the QP method as an accurate and rapid detection system for KRAS mutations.     

早期肺腺癌EGFR基因突变的相关因素研究

目的：探讨早期（cT1N0M0期）肺腺癌EGFR突变的临床、病理及高分辨率CT（HRCT）相关因素,为早期肺腺癌患者术后行EGFR基因检测提供参考。方法回顾性分析行手术切除且术后采用DNA直接测序法完成EGFR基因突变状态检测的82例cT1N0M0期肺腺癌患者的病历资料。采用卡方检验、t检验、秩和检验分析临床、病理学及HRCT特征在EGFR有效突变组与非有效突变组中的差异;相关因素的界值采用ROC曲线确定;采用Logistic回归分析探寻EGFR突变的独立危险因素。结果82例肺腺癌中发生EGFR基因有效突变53例,非有效突变（包括野生型、无效突变）29例。EGFR有效突变组与非有效突变组在性别（P=0.017）,年龄（P=0.005）,吸烟与否（P=0.004）,是否为乳头为主型（P=0.048）,病灶大小（P=0.019）的差异具有统计学意义。患者年龄≥60岁（OR=6.852,95% CI 1.985~23.652,P=0.002）为cT1N0M0期肺腺癌EGFR基因有效突变的独立危险因素。结论cT1N0M0期肺腺癌中女性、年龄≥60岁、无吸烟、病理亚型为乳头为主型和病灶≥1.6 cm者出现EGFR有效突变概率较大。对于具有这些因素的cT1N0M0期肺腺癌患者,可考虑推荐于术后行EGFR基因检测。