Yang Ming, Sun Tong, Wang Li, Yu Dianke, Zhang Xuemei, Miao Xiaoping, Liu Junniao, Zhao Dan, Li Hui, Tan Wen, Lin Dongxin
Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China.
Clin Cancer Res. 2008 May 15;14(10):3230-6. doi: 10.1158/1078-0432.CCR-08-0177.
Fas-Fas ligand (FasL)-mediated death pathway is important in the life and death of immune cells and, therefore, influences immune surveillance of carcinogenesis. 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 (-652 6N ins-->del) and risk of pancreatic cancer.
Genotypes were determined in 397 cases with pancreatic cancer and 907 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression, and all statistical tests were two sided.
We found a significant decrease in risk of pancreatic cancer associated with FasL and CASP8 but not Fas polymorphisms. Compared with noncarriers, the ORs of developing pancreatic cancer for FasL -844CT and TT carriers were 0.73 (95% CI, 0.57-0.94) and 0.35 (95% CI, 0.19-0.63), and for CASP8 -652 6N ins/del and del/del carriers were 0.65 (95% CI, 0.50-0.85) and 0.56 (95% CI, 0.33-0.98), respectively. Gene-gene interaction between the FasL and CASP8 variants further reduced the cancer risk in a multiplicative manner (OR for the presence of both FasL -844TT and CASP8 -652 6N del/del genotype, 0.10; 95% CI, 0.01-0.75). On the other hand, a multiplicative joint effect between the FasL -844CC or CASP8 -652 6N ins/ins genotype and smoking or diabetes mellitus in intensifying risk of pancreatic cancer was also evident.
These results suggest that genetic variations in the death pathway genes FasL and CASP8 are involved in susceptibility to developing pancreatic cancer.
Fas-Fas配体（FasL）介导的死亡途径在免疫细胞的生死过程中起重要作用，因此影响对癌变的免疫监视。本研究检测了Fas（-1377G→A和-670A→G）、FasL（-844T→C）的功能变异以及半胱天冬酶-8（CASP8）六核苷酸缺失多态性（-652 6N ins→del）与胰腺癌风险之间的关联。
对397例胰腺癌患者和907例对照进行基因分型。通过逻辑回归估计比值比（OR）和95%置信区间（95%CI），所有统计检验均为双侧检验。
我们发现胰腺癌风险显著降低与FasL和CASP8相关，但与Fas多态性无关。与非携带者相比，FasL -844CT和TT携带者患胰腺癌的OR分别为0.73（95%CI，0.57-0.94）和0.35（95%CI，0.19-0.63），CASP8 -652 6N ins/del和del/del携带者的OR分别为0.65（95%CI，0.50-0.85）和0.56（95%CI，0.33-0.98）。FasL和CASP8变异之间基因-基因相互作用以相乘方式进一步降低了癌症风险（同时存在FasL -844TT和CASP8 -652 6N del/del基因型的OR为0.10；95%CI，0.01-0.75）。另一方面，FasL -844CC或CASP8 -652 6N ins/ins基因型与吸烟或糖尿病之间在增加胰腺癌风险方面的相乘联合效应也很明显。
这些结果表明，死亡途径基因FasL和CASP8的遗传变异与胰腺癌易感性有关。
