Sun Tong, Gao Yang, Tan Wen, Ma Sufang, Shi Yuankai, Yao Jiarui, Guo Yongli, Yang Ming, Zhang Xuemei, Zhang Qingrun, Zeng Changqing, Lin Dongxin
Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Nat Genet. 2007 May;39(5):605-13. doi: 10.1038/ng2030. Epub 2007 Apr 22.
Caspases are important in the life and death of immune cells and therefore influence immune surveillance of malignancies. We tested whether genetic variants in CASP8, CASP10 and CFLAR, three genes important for death receptor-induced cell killing residing in tandem order on chromosome 2q33, are associated with cancer susceptibility. Using a haplotype-tagging SNP approach, we identified a six-nucleotide deletion (-652 6N del) variant in the CASP8 promoter associated with decreased risk of lung cancer. The deletion destroys a stimulatory protein 1 binding site and decreases CASP8 transcription. Biochemical analyses showed that T lymphocytes with the deletion variant had lower caspase-8 activity and activation-induced cell death upon stimulation with cancer cell antigens. Case-control analyses of 4,995 individuals with cancer and 4,972 controls in a Chinese population showed that this genetic variant is associated with reduced susceptibility to multiple cancers, including lung, esophageal, gastric, colorectal, cervical and breast cancers, acting in an allele dose-dependent manner. These results support the hypothesis that genetic variants influencing immune status modify cancer susceptibility.
半胱天冬酶在免疫细胞的生死过程中起着重要作用，因此影响着对恶性肿瘤的免疫监视。我们测试了位于2号染色体q33上串联排列的、对死亡受体诱导的细胞杀伤至关重要的三个基因CASP8、CASP10和CFLAR中的遗传变异是否与癌症易感性相关。我们采用单倍型标签单核苷酸多态性方法，在CASP8启动子中鉴定出一个六核苷酸缺失（-652 6N del）变异，该变异与肺癌风险降低相关。该缺失破坏了一个刺激蛋白1结合位点，并降低了CASP8的转录。生化分析表明，具有缺失变异的T淋巴细胞在用癌细胞抗原刺激时，半胱天冬酶-8活性较低，且激活诱导的细胞死亡减少。对中国人群中4995例癌症患者和4972例对照进行的病例对照分析表明，这种遗传变异与多种癌症（包括肺癌、食管癌、胃癌、结直肠癌、宫颈癌和乳腺癌）的易感性降低相关，且呈等位基因剂量依赖性。这些结果支持了影响免疫状态的遗传变异会改变癌症易感性这一假说。
