Anti-tumor T lymphocytes play a pivotal role in immune surveillance of cancer cells. The cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a vital negative regulator of T lymphocyte activation and proliferation, which may influence immune surveillance of malignancies. We tested whether genetic variantsin the CTLA-4 gene are associated with cancer susceptibility. Using a haplotype-tagging SNP approach, we found that the 49G>A polymorphism in the CTLA-4leading sequence causing Ala17 to Thr17 amino acid substitution, is associated with increased risk of lung cancer. Biochemical analyses showed thatCTLA-4-Thr17 had higher affinity to bind B7.1 molecule and had stronger inhibitory effect on T lymphocyte activation compared with CTLA-4-Ala17. T lymphocytes carrying the 49AA genotype had significantly lower activation and proliferation rates compared with T lymphocytes carrying the 49GG genotype upon stimulated with PHA ex vivo. Case-control analyses of 4,446 individuals with cancer and 4,433 controls in a Chinese population showed that this genetic variant is associated with increased susceptibility to multiple types of cancer, including lung, esophageal, gastric cardia, pancreatic, breast, and cervical cancers, acting in an allele dose-dependent manner. The odds ratios of overall cancer were 1.92 (95% CI = 1.64-2.25) for the 49AA genotype and 1.26 (95% CI = 1.15-1.37) for the 49GA genotype. These results support the hypothesis that genetic variants influencing T lymphocyte activation and proliferation modify cancer susceptibility.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA