【作者】 张树才；

【导师】 李琦；

【作者基本信息】 北京市结核病胸部肿瘤研究所 ， 肿瘤内科， 2009， 博士

【摘要】 背景及目的:有研究表明,切除修复交叉互补基因1(Excision Repair Cross-Complementation Group 1,ERCC1)和β-微管蛋白III(β-Tubulin III)的表达可能与非小细胞肺癌术后患者的预后有关,也与常用化疗药物顺铂、长春瑞滨、紫杉醇耐药有关;ERCC1基因多态性可能预测接受含铂方案化疗的晚期非小细胞肺癌患者的疗效及生存。本试验通过检测Ⅰ-ⅢB期非小细胞肺癌术后患者ERCC1、β-Tubulin III蛋白的表达,分析ERCC1、β-Tubulin III与术后患者各种临床因素、辅助化疗疗效及生存的关系,探讨二者能否作为预测术后患者生存及辅助化疗疗效的因素。通过检测ERCC1 C8092A、T19007C位点基因频率,探讨ERCC1基因多态性与接受含铂方案化疗的晚期非小细胞肺癌患者疗效及生存的关系。方法:通过免疫组织化学染色方法检测160例非小细胞肺癌手术切除病例、50例配对癌及癌周正常组织及40例良性肺部疾病病例组织标本的ERCC1和β-Tubulin III的表达情况。同时应用PCR和直接测序的方法检测68例接受含铂化疗方案化疗的晚期非小细胞肺癌患者ERCC1 C8092A、T19007C基因多态性。结果:非小细胞肺癌患者ERCC1阳性表达率46.9%,β-tubulin III阳性表达率49.4%,ERCC1、β-tubulin III表达与性别相关,男性患者可见ERCC1、β-tubulin III高表达。对于I期单纯手术的非小细胞肺癌患者,ERCC1阳性表达者生存期更长;对于II-IIIB期接受术后辅助化疗的非小细胞肺癌患者,ERCC1阴性表达者生存期更长。对于I-II期非小细胞肺癌患者,β-tubulin III表达与术后生存期无关;对于III期接受术后辅助化疗患者,β-tubulin III阴性表达者生存期更长。对于接受术后辅助化疗的非小细胞肺癌患者中,ERCC1、β-tubulin III表达均阴性者生存期更长。ERCC1 C8092A位点存在3种等位基因型,其基因频率分别为:C/C 38.2%,C/A 52.9%,A/A 8.8%;ERCC1 T19007C位点存在3种等位基因型,其基因频率分别为:C/C 57.4%,C/T 36.8%,T/T 5.9%;对于ERCC1 C8092A位点,携带C/C基因型患者与携带C/A、A/A基因型患者的化疗疗效和无进展生存期无显著差异;对于ERCC1 T19007C位点,携带C/C基因型患者与携带C/T、T/T基因型患者的化疗疗效和无进展生存期也无显著差异。结论:对于I期单纯手术非小细胞肺癌患者,ERCC1阳性表达是预后良好的独立因素;对于II-IIIB期接受术后辅助化疗非小细胞肺癌患者,ERCC1表达阴性者可从术后辅助化疗获益更多;对于III期接受术后辅助化疗非小细胞肺癌患者,β-tubulin III阴性表达是影响术后生存期的独立因素;而对于I-II期接受术后辅助化疗非小细胞肺癌患者,β-tubulin III表达与术后生存期无关;接受NP或者TP化疗方案术后辅助化疗的非小细胞肺癌患者中,ERCC1、β-tubulin III表达均阴性的患者可从术后辅助化疗获益更多;接受含铂化疗方案化疗的晚期非小细胞肺癌患者ERCC1 C8092A、T19007C基因多态性与化疗疗效、无进展生存期无关。更多还原

【Abstract】 Background and objective: Recent basic and clinical studies have showed that ERCC1 and Class IIIβTubulin were predictors of survival in resected patients with non-small cell lung cancer and associated with drug-resistance of cisplatin, vinorelbine and paclitaxel, polymorphisms of ERCC1 associated with response and survival in advanced non-small cell lung cancer treated with platinum-based chemotherapy. In our study, expression of ERCC1 and Class IIIβTubulin will be detected to analyze whether they would be predictors of prognosis of resected patients with non-small cell lung cancer in stage I-IIIB disease. Allele frequency of ERCC1 C8092A and T19007C will be tested to investigate the association between polymorphisms of ERCC1 C8092A and T19007C and response and survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.Methods:The expression of ERCC1 and Class IIIβTubulin were detected by immunohistochemical assay in one hundred and sixty resected lung cancer primary tumors, fifty matched cancer and adjacent normal tissues, and forty benign tissues. Gene polymorphisms of ERCC1 C8092A and T19007C in sixty-eight patients with advanced non-small cell lung cancer treated with platinum-based chemotherapy were examined by polymorphisms chain reaction and sequencing.Results:The expression rates of ERCC1 and Class IIIβtubulin in non-small cell lung cancer is 46.9%, 49.4% respectively, both are correlated to gender, high expression of them can be found in male patients. Positive expression of ERCC1 is associated with longer survival for patients with postoperative adjuvant chemotherapy in stage I, but with shorter survival for patients with postoperative adjuvant chemotherapy in stage II-IIIB. The expression of Class IIIβtubulin is unrelated to overall survival in stage I-II disease, while negative expression of Class IIIβtubulin is associated with longer survival in stage III disease. For NSCLC patients with post-operative adjuvant chemotherapy, negative expression of ERCC1 and Class IIIβtubulin is associated with longer survival. There are three genotypes of ERCC1 C8092A, which gene frequencies of C/C,C/A,A/A are 38.2%, 52.9%, and 8.8%, respectively ; There are three genotypes of ERCC1 T19007C, which gene frequencies of C/C, C/T, and T/T are 57.4%, 36.8%, and 5.9%, respectively.Compared with patients carrying genotype C/A and A/A, there is no significant difference in response and progress free survival in patients carrying genotype C/C in ERCC1 C8092A. Compared with patients carrying C/A and A/A, there is also no significant difference in response and progress free survival in patients receiving platinum-based chemotherapy carrying C/C in ERCC1 C8092A. Conclusions: Positive expression of ERCC1 is a good independent factor of prognosis in stage I disease, but for patients in stage II-IIIB negative expression of ERCC1 is associated with better advantage from postoperative adjuvant chemotherapy. The expression of Class IIIβtubulin is unrelated to overall survival in stage I-II disease. Negative expression of Class IIIβtubulin is an independent factor of longer survival for NSCLC patients with post-operative adjuvant chemotherapy in stage III disease. Negative expression of ERCC1 and Class IIIβtubulin is associated with longer survival for NSCLC patients with post-operative adjuvant chemotherapy.Gene polymorphisms of ERCC1 C8092A and T19007C have nothing with response and prognosis free survival in patents with advanced non-small cell lung cancer receiving platinum-based chemotherapy.更多还原