【作者】 吕铮；

【导师】 石远凯； 韩晓红； 何小慧；

【作者基本信息】 中国协和医科大学 ， 肿瘤学， 2010， 博士

【摘要】 CASP8、Fas和FasL基因多态与外周T细胞淋巴瘤易感性及临床特点和预后的相关性研究Fas-Fasl介导的细胞凋亡是经典的免疫细胞死亡机制,对于免疫自稳具有重要的作用,如果异常可导致疾病的发生,如肿瘤的发生。本研究主要探讨Fas、FasL和凋亡相关的半胱氨酸蛋白酶8 (CASP-8)的遗传变异与外周T细胞淋巴瘤(peripheral T-cell lymphoma, PTCL)发生的关系,以及Fas和CASP-8基因多态性与PTCL的临床特点和预后的关系。首先采用病例对照的方法分析了100例外周T细胞淋巴瘤和544例正常对照者Fas[-1377G→■T (rs1377)和-670A→G(rs670)]、FasL[-844T→C (rs844)]和CASP8启动子区-652 AGTAAG插入／缺失(-6526N ins/del, rs3834129)基因多态与PTCL易感性的关系,比值比(Odds,OR)和95%可信区间(confidence intervals, CI)用来评价易感性强弱,统计方法采用logistic regression,且所有统计都是双侧检验,P<0.05有意义。我们发现Fas和CASP8的基因多态性和PTCL的易感性相关,而FasL的基因多态性则与PTCL的易感性不相关。与携带Fas-1377GG基因型相比,携带Fas-1377AA基因型的PTCL患病风险降低,OR值为0.48(95%CI0.23-0.99,p=0.049)；与携带CASP8-6526N ins/ins基因型相比,携带CASP8-6526N ins/del基因型个体PTCL的患病风险增高,OR值为1.84(95%CI 1.18-2.87,p=0.007)；而Fas-670 A>G和FasL-844T> C的基因多态性与PTCL的易感性不相关。本研究同时分析了304例B细胞淋巴瘤与476例正常对照者Fas (-1377>T和-670A>G)、FasL (-844T>C)和CASP8 (-6526N ins/del)基因多态与B细胞淋巴瘤易感性的关系,我们发现,Fas和FasL基因多态性与B细胞淋巴瘤易感性相关。与携带Fas-1377GG基因型相比,携带Fas-1377GA基因型个体患B细胞淋巴瘤的风险性降低,OR值为0.57(95 %CI0.41-0.77,p<0.001),与携带FasL-844CC基因型相比,携带FasL-844CT基因型的个体患B细胞淋巴瘤的风险增高,OR值为1.37(95% CI1.01-1.90,p=0.043)；而Fas-670A>G和CASP8-6526N ins/del的基因多态性与B细胞淋巴瘤的易感性不相关。研究结果表明,CASP8-6526N ins/del是PTCL的易感因素,而FasL-844CT基因型是B细胞淋巴瘤的易感因素,Fas-1377AA和Fas-1377GA基因型分别是PTCL和B细胞淋巴瘤的保护性因素。根据CASP8和Fas基因多态性在PTCL中的研究结果,我们进一步采用相关性分析的方法分析CASP8和Fas基因多态性和89例PTCL的临床特点的关系,采用Kaplan-Meier统计方法分析CASP8和Fas基因多态性与89例PTCL患者预后的关系。除CASP8-6526N ins/del基因多态性在男性PTCL中更多见外(p=0.032), CASP8-6526N ins/del和Fas-1377G>A的基因多态性与PTCL的临床特点和预后均没有相关性。下一步我们需要扩大样本量继续研究它们的关系。更多还原

【Abstract】 Genetic polymorphisms in CASP8, Fas and Fas ligand and the risk of peripheral T-cell lymphoma and the relationship between the genetic polymorphisms and the clinical characteristics and prognosisFas-Fas ligand (FasL)-mediated cell apoptosis is a classic pathway of the immune cells death and is important for the immune homeostasis, if the function of the fas/fasL is impaired, which will result in disease, including carcinogenesis. Therefore this study examined the association between functional variants of Fas (-1377G>A and-670A>G), FasL (-844T>C), and caspase-8 (CASP8) six-nucleotide deletion polymorphism (-6526N ins-del) and risk of peripheral T-cell lymphoma(PTCL),also explored the relationship between the genetic polymorphisms in Fas and CASP8 and the clinical characteristics and prognosis. Genotypes of Fas, FasL and CASP8 were determined in 100 patients with PTCL and 544 frequency-matched controls. Odds ratios (OR) and 95%confidence intervals (95%CI) were estimated by logistic regression, and all statistical tests were two sided, p value must be less than 0.05.We found a significant correlation in risk of PTCL with Fas and CASP8 but not FasL polymorphisms. Compared with those with Fas-1377GG, the subjects with Fas-1377AA had a decreased risk for PTCL, OR=0.48(95%CI 0.23-0.99, p=0.049); Compared with those with the CASP8-6526N ins/ins genotype, the subjects with CASP8-6526N ins/del had an increased risk for T-cell lymphoma, OR=1.84 (95%CI 1.18-2.87, p=0.007). The genetic polymorphisms in Fas-670 A>G and FasL-844T> C had no correlationship with the risk of PTCL. We also investigated the association between genetic polymorphisms in Fas, FasL and CASP8 and B-cell lymphoma. We found that a significant correlation in risk of B-cell lymphoma with Fas and FasL but not CASP8 polymorphisms.Compared with those with Fas-1377GG, the subjects with Fas-1377GA had a decreased risk for B-cell lymphoma, OR=0.57 (95%CI 0.41-0.77, p<0.001); Compared with those with the FasL-844CC genotype, the subjects with FasL-844CT had an increased risk for B-cell lymphoma, OR=1.37 (95%CI 1.01-1.90, p=0.043). The genetic polymorphisms in Fas-670 A>G and CASP8-6526N ins/del had no correlationship with the risk of B-cell lymphoma. These data suggest that CASP8-6526N ins/del is associated with increased risk of PTCL, The FasL-844CT is associated with increased risk of B-cell lymphoma, and the Fas-1377GA and Fas-1377AA is a protective factor for B-cell lymphoma and PTCL respectively. Based on the relationship between the risk of PTCL and the genetic polymorphisms in Fas, FasL and CASP8. We further expored the the relationship between the genetic polymorphisms in Fas and CASP8 and the clinical characteristics and prognosis. Except that the CASP8-6526N ins/del genotype is more often in male than female (p=0.032),we couldn’t find any subjects with relationship between the the genetic polymorphisms in Fas and CASP8 and the clinical characteristics and prognosis.We need a large number patients to find the true relationship of them.更多还原