Functional genetic variations in cytotoxic T-lymphocyte antigen 4 and susceptibility to multiple types of cancer.
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.
Sun
Tong
T
Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Zhou
Yifeng
Y
Yang
Ming
M
Hu
Zhibin
Z
Tan
Wen
W
Han
Xiaohong
X
Shi
Yuankai
Y
Yao
Jiarui
J
Guo
Yongli
Y
Yu
Dianke
D
Tian
Tian
T
Zhou
Xiaoyi
X
Shen
Hongbing
H
Lin
Dongxin
D