泛素蛋白酶体通路基因SNPs与晚期食管鳞癌紫杉醇敏感性

The incidence of esophageal cancer has risen to 4th in malignant tumor in China, and more than 90% patients are squamous cell carcinoma. Taxol is the foundation of chemotherapy drug for advanced esophageal squamous cell carcinoma. However, the clinical effect and adverse reaction are entirely different among different patients, which indicate that individual genetic factors is very significant for drug sensitivity. Singal nucleotide polymorphisms (SNPs) is the critical genetic basis for the difference of drug sensitivity. Gene specific SNPs genotype not only influenced the prognosis of the treatment, and could be used as a clinical effect and the toxicity of the predictors. This topic is to study the pharmacogenomics of taxol and to observe the relations of genotype and clinical characteristics which will be able to affect the overall survival through the ubiquitin-proteasome-protease body pathways FBW7 and MCL-1 gene SNPs strategies on chemotherapy effects and toxicity. According to the results we expect to find SNPs sites which can predict the efficacy and the toxicity of taxol in special pepole in China, to guide the clinical chemotherapy. The patients with advanced esophageal squamous cell carcinoma would accept resonable treatment during the limited time. At the same time, we can provide the scientific basis of individual chemotherapy for patients with advanced esophageal squamous cell carcinoma.

食管癌发病率在我国恶性肿瘤中已上升为第四位，其中食管鳞癌所占比例达90%以上。紫杉醇是晚期食管鳞癌化疗的基础药物，但不同患者的临床疗效和毒副反应相差甚远，提示个体遗传因素在药物敏感性中意义重大。单核苷酸多态性（SNPs）是药物敏感性差异的重要遗传学基础,相关基因特异SNPs不仅影响治疗结果，而且可以作为疗效和毒副反应的预测因子。本课题拟通过泛素-蛋白酶体（ubiquitin-proteasome）通路FBW7和MCL1等基因SNPs研究策略对紫杉醇化疗的疗效和毒性作用进行临床研究，并探讨影响总生存期的基因型和临床特征，以期发现中国人群特有的能够预测紫杉醇疗效和毒副作用的SNPs位点，为晚期食管鳞癌化疗个体化方案的选择、实施提供依据。

研究背景：食管癌是常见的恶性肿瘤之一，中国食管癌死亡率居世界首位。由于东西方人遗传背景以及食管癌发病病因等方面的差异，我国食管癌鳞癌的比例高达90%以上。食管癌的预后很差，中晚期食管癌自然生存期7-8个月，5年生存率5%～10%。其特有的生物学行为和对化疗的敏感性使联合化疗成为晚期食管癌的主要治疗手段。目前DDP/PTX方案因其显著疗效及良好的耐受性广泛用于晚期食管鳞癌的治疗。然而，在化疗方案与给药剂量相同的情况下，不同个体对化疗药物的敏感性存在显著差异，因此迫切需要寻找能够预测紫杉醇疗效的生物学标记。泛素蛋白酶体（FBW7）系统与紫杉醇化疗敏感性的研究在分子、细胞水平的研究取得一定的进展，但是泛素蛋白酶体通路中重要调控因素与紫杉醇敏感性之间的关联性尚缺乏临床验证。研究目的：考察FBW7信号转导通路相关基因多态性与紫杉醇在晚期食管鳞癌疗效相关性，寻找紫杉醇疗效预测因子。研究方法：选择晚期食管鳞癌患者，经组织病理学确诊为食管鳞癌，一线接受紫杉醇联合顺铂化疗；紫杉醇 175mg/m2 d1, 静脉滴注3小时；顺铂 30 mg/m2 d1-3，静脉滴注大于2小时，21天重复。肿瘤进展或出现不可耐受的毒副作用终止化疗；化疗至多进行6周期。按照RECIST1.1标准，每6周评价疗效一次，全部治疗结束后4周评价疗效。化疗药物的毒性反应每周1次进行评估，主观和客观症状按NCI不良反应分度标准4.0进行分级。收集入组患者临床信息及生存资料。选择泛素-蛋白酶体通路基本成员FBW7、SKP1、CUL1及RBX1，蛋白底物cyclin E,c-Myc, c-Jun, notch, presenilin, Mcl-1, mTOR和c-Myb等基因，对入组的晚期食管鳞癌患者进行血液标本采集并提取DNA采用多重SNaPshot进行上述基因分型。研究结果：基因型非条件Logistic回归结果显示，晚期食管鳞癌患者FBW7信号通路中mTOR rs1057079 位点杂合突变型AG 接受紫杉醇治疗疗效较于野生纯合型AA(ORadjusted: 4.59; 95% CI: 1.78-11.86)在调整性别、年龄及化疗周期数后更显著。晚期食管鳞癌患者一线接受紫杉醇联合顺铂化疗中位无进展生（PFS）存14.3月(95%CI: 9.0-19.60months)。mTOR rs1057079 位点杂合突变型A