【作者】 廖瑜倩；

【导师】 徐兵河； 林东昕； 詹启敏； 宋咏梅；

【作者基本信息】 中国协和医科大学 ， 肿瘤学， 2009， 博士

【摘要】 第一部分:FAS、FASL和CASP8基因多态与接受吉非替尼治疗的进展期非小细胞肺癌患者疗效及生存的相关研究表皮生长因子受体酪氨酸激酶抑制剂(EGFR TKI)是局部晚期和转移性非小细胞肺癌患者的重要治疗药物。目前已经发现了一些可预测EGFR TKI疗效的临床病理或生物学指标,如病理类型、性别、吸烟状况、EGFR突变、EGFR基因扩增等,但是这些指标均有一定的局限性。本研究的目的是明确凋亡通路相关基因多态与吉非替尼治疗敏感性及患者生存之间的关系。共入组88例接受吉非替尼单药治疗的ⅢA-Ⅳ期非小细胞肺癌患者,分析临床病理特征以及FAS-1377G/A、FAS-670 A/G、FASL-844T/C、CASP8-652 6N ins/del基因多态与吉非替尼治疗的临床获益率及患者生存的相关性。结果显示腺癌患者临床获益率及总生存期显著优于非腺癌患者(P=0.009和P=0.048);既往治疗的无进展生存期与吉非替尼治疗的临床获益率和无进展生存期显著相关(P=0.003和P=0.001)。本研究首次发现携带FAS-1377 AA基因型的患者接受吉非替尼治疗的临床获益率显著低于携带GG基因型的患者(P=0.008,OR:0.15,95%CI:0.036-0.602)。携带FAS-670 AG+AA基因型的患者总生存期显著优于携带GG基因型的患者(P=0.007)。CASP8-652 6N ins/del基因多态与吉非替尼治疗的无进展生存期相关,携带del遗传变异的患者吉非替尼治疗的无进展生存期显著短于携带ins/ins基因型的患者(P=0.039)。FASL-844T/C基因多态与吉非替尼治疗的临床获益率、无进展生存期及总生存期均无关。多因素预后分析显示病理类型(P=0.020,RR:2.466,95%CI:1.150-5.288)、FAS-670基因多态(P=0.036,RR:0.503,95%CI:0.264-0.955)是独立的预后因素。可见,促进肿瘤细胞凋亡是吉非替尼抗肿瘤作用的重要部分,FAS、CASP8基因多态是吉非替尼治疗敏感性及治疗结局的预测指标。第二部分:CYP1A1基因多态与接受吉非替尼治疗的进展期非小细胞肺癌患者疗效及生存的相关研究环境和遗传因素均可影响个体对药物的反应。在亚裔人群中进行的许多研究显示CYP1A1基因多态与肺癌的发生风险相关,尤其与不吸烟个体以及鳞癌发生风险的关系更为密切。由于吉非替尼的疗效也与吸烟状况及病理类型相关,且吉非替尼的代谢部分依赖CYP1A1,因此我们对88例接受吉非替尼单药治疗ⅢA-Ⅳ期非小细胞肺癌患者的CYP1A1 m1和m2基因多态进行了研究,并分析这些基因多态与患者疗效和生存的关系。结果显示,全组患者CYP1A1 m1或m2基因多态与吉非替尼治疗的晚期NSCLC患者的临床获益率或生存不相关。但是对于不吸烟患者,CYP1A1 m2 Ile/Ile基因型携带者的2年总生存率为55.7%,Ile/Val+Val/Val基因型携带者的2年总生存率为42.5%,有显著差异(P=0.044),对不吸烟患者进行COX多因素预后分析,发现病理类型(P=0.017,RR:2.958,95%CI:1.215-7.199)、CYP1A1 m1(P=0.016,RR:0.631.95%CI:0.434-0.917)和m2(P=0.001,RR:4.864,95%CI:1.902-12.441)基因多态是独立的预后因素。这些结果提示CYP1A1 m1和m2基因多态可能是接受吉非替尼治疗的晚期、不吸烟NSCLC患者的预后因素。但是由于环境与遗传因素之间、各基因多态之间存在复杂的相互作用,且本研究病例数有限,还需要进一步的研究。更多还原

【Abstract】 PartⅠ:Association between Polymorphisms in FAS,FASL,CASP8 and the Clinical Outcome in Advanced Non-Small-Cell Lung Cancer Patients Treated with GefitinibEpidermal growth factor receptor tyrosine kinase inhibitors play a very important role in the treatment of advanced non-small-cell lung cancer patients.Till now,some clinical and biological predictors have been identified,such as pathological types,sex, smoke,EGFR mutation and EGFR gene copy number,but they all have some limitations.In our study,88 patients with stageⅢA,ⅢB andⅣNSCLC were treated with gefitinib.We investigated the association between polymorphisms in FAS, FASL and CASP8 and the clinical benefit and outcome of these patients.We observed that patients with adenocarcinoma had a significantly higher clinical benefit rate and longer overall survival(P=0.009 and P=0.048,respectively).Longer time from completion of previous chemotherapy were associated with significantly higher clinical benefit rate and longer progression free survival of gefitinib(P=0.003 and P=0.001,respectively).We first documented that FAS-1377 AA genotype carriers had a significantly lower clinical benefit rate compared with GG genotype carriers (P=0.008,OR:0.15,95%CI:0.038-0.614).FAS-670 AG+AA genotype carriers had a significantly longer overall survival time than GG genotype carriers(P=0.007). CASP8-652 6N del/del+del/ins genotype carriers had a significantly shorter progression free survival than ins/ins genotype carriers(P=0.039).After the multi-variants’ cox regression analysis,pathological types(P=0.020,RR:2.466, 95%CI:1.150-5.288)and FAS-670 genotype(P=0.036,RR:0.503,95%CI: 0.264-0.955)were found to be independent prognostic factors for these patients.We concluded that polymorphisms in FAS and CASP8 could be predictive or prognostic factors for locally advanced and metastatic NSCLC patients treated with gefitinib. PartⅡ:Association between Polymorphisms in CYP1A1 and the Clinical Outcome in Advanced Non-Small-Cell Lung Cancer Patients Treated with GefitinibThe variability in treatment response is due to a lot of environmental and genetic factors.In Asia population,polymorphisms in CYP1A1 have been proved to be associated with lung cancer risk.The CYP1A1 genotype was particularly important at a low level of smoking and in the development of squamous cell carcinoma.Since the benefit from gefitinib was also associated with pathological types and smoking status, and gefitinib was metabolized partly by CYP1A1,we investigated the relationship between polymorphisms in CYP1A1 and the clinical benefit and outcome in 88 advanced non-small-cell lung cancer patients treated with gefitinib.We observed that the polymorphisms in CYP1A1 m1 and m2 were not related to the clinical benefit or outcome of these patients.But the subgroup analysis in non-smoking patients showed that CYP1A1 m2 Ile/Ile genotype carriers had a longer overall survival time than Ile/Val + Val/Val genotype carriers(P=0.044).After the multi-variants’ cox regression analysis in non-smoking patients,pathological types(P=0.017,RR:2.958,95%CI: 1.215-7.199) and CYP1A1 ml(P=0.016,RR:0.631,95%CI:0.434-0.917) and m2 (P=0.001,RR:4.864,95%CI:1.902-12.441) genotype were found to be independent prognostic factors.So we concluded that polymorphisms in CYP1A1 may be prognostic factors for non-smoking advaced NSCLC patients treated with gefitnib. But since the sample size was small and the interaction between environmental and genetic factors was complicated,it is necessary to do more research work in this field.更多还原