Functional genetic variations in cytotoxic T-lymphocyte antigen 4 and susceptibility to multiple types of cancer
Functional genetic variations in cytotoxic T-lymphocyte antigen 4 and susceptibility to multiple types of cancer
复制标题
细胞毒性 T 淋巴细胞抗原 4 的功能性遗传变异与多种癌症的易感性
DOI：
10.1158/0008-5472.can-08-0806
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Lin, Dongxin
中科院分区：
文献类型：
--
作者：
Sun, Tong;Zhou, Yifeng;Lin, Dongxin
抗肿瘤T淋巴细胞在恶性肿瘤的免疫监视中起关键作用。CTL抗原4（CTLA-4）是T细胞活化和增殖的重要负调节因子。本研究探讨了CTLA-4基因多态性是否与癌症易感性相关。采用单倍型标记单核苷酸多态性方法和多个独立病例对照分析进行两阶段调查，以评估CTLA-4基因型与癌症风险之间的关联。功能相关的多态性进行了检查，生化分析。我们发现CTLA-4前导序列中的49 G>A多态性导致（17）Ala到（17）Thr氨基酸取代与多种癌症的易感性增加相关，包括肺癌、乳腺癌、食道癌和贲门癌。对中国北方和南方人群的5，832名癌症患者和5，831名对照受试者进行的基因分型显示，与49 GG基因型相比，CTLA-4 49 AA基因型患癌症的优势比为1.72（95%置信区间，1.50-2.10; P = 3.4 x 10（-7））。生化分析表明，CTLA-4-（17）Thr与B7.1结合能力强于CTLA-4-（17）Ala，对T细胞活化的抑制作用强于CTLA-4-（17）Ala。与携带49 GG基因型的T细胞相比，携带49 AA基因型的T细胞在刺激后具有显著较低的活化和增殖率。这些结果与我们的假设一致，表明影响T细胞活化的遗传多态性改变癌症易感性。
Antitumor T lymphocytes play a pivotal role in immunosurveillance of malignancy. The CTL antigen 4 (CTLA-4) is a vital negative regulator of T-cell activation and proliferation. This study examined whether genetic polymorphisms in CTLA-4 are associated with cancer susceptibility. A two-stage investigation using haplotype-tagging single nucleotide polymorphism approach and multiple independent case-control analyses was performed to assess the association between CTLA-4 genotypes and cancer risk. Functional relevance of the polymorphisms was examined by biochemical assays. We found that the 49G>A polymorphism in the CTLA-4 leading sequence causing (17)Ala to (17)Thr amino acid substitution is associated with increased susceptibility to multiple cancers, including lung, breast, esophagus, and gastric cardia cancers. Genotyping in 5,832 individuals with cancer and 5,831 control subjects in northern and southern Chinese populations showed that the CTLA-4 49AA genotype had an odds ratio of 1.72 (95% confidence interval, 1.50-2.10; P = 3.4 x 10(-7)) for developing cancer compared with the 49GG genotype. Biochemical analyses showed that CTLA-4-(17)Thr had higher capability to bind B7.1 and stronger inhibitory effect on T-cell activation compared with CTLA-4-(17)Ala. T cells carrying the 49AA genotype had significantly lower activation and proliferation rates compared with T cells carrying the 49GG genotype upon stimulation. These results are consistent with our hypothesis and indicate that genetic polymorphisms influencing T-cell activation modify cancer susceptibility.