Functional Genetic Variations in Cytotoxic T-Lymphocyte Antigen 4 and Susceptibility to Multiple Types of Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 68; no. 17; pp. 7025 - 7034
• Main Authors: Sun, Tong, Zhou, Yifeng, Yang, Ming, Hu, Zhibin, Tan, Wen, Han, Xiaohong, Shi, Yuankai, Yao, Jiarui, Guo, Yongli, Yu, Dianke, Tian, Tian, Zhou, Xiaoyi, Shen, Hongbing, Lin, Dongxin
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2008
• Subjects: Antigens, CD - genetics; Antineoplastic agents; Biological and medical sciences; Case-Control Studies; CTLA-4 Antigen; Genetic Variation; Genotype; Haplotypes; Humans; Interleukin-2 - biosynthesis; Lymphocyte Activation; Medical sciences; Neoplasms - genetics; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Tumors; Genetic variability; Risk factor; Genotype; Malignant tumor; Cancer; Polymorphism; Cytotoxic T lymphocyte antigen 4
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-0806

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 17Ala to 17Thr 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 × 10−7) for developing cancer compared with the 49GG genotype. Biochemical analyses showed that CTLA-4−17Thr had higher capability to bind B7.1 and stronger inhibitory effect on T-cell activation compared with CTLA-4−17Ala. 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. [Cancer Res 2008;68(17):7025–34]