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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&amp;gt;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\u22122.10; P = 3.4 \u00d7 10\u22127) for developing cancer compared with the 49GG genotype. Biochemical analyses showed that CTLA-4\u221217Thr had higher capability to bind B7.1 and stronger inhibitory effect on T-cell activation compared with CTLA-4\u221217Ala. 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\u201334]<\/jats:p>","DOI":"10.1158\/0008-5472.can-08-0806","type":"journal-article","created":{"date-parts":[[2008,8,29]],"date-time":"2008-08-29T00:53:55Z","timestamp":1219971235000},"page":"7025-7034","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":136,"title":["Functional Genetic Variations in\n                    <i>Cytotoxic T-Lymphocyte Antigen 4<\/i>\n                    and Susceptibility to Multiple Types of Cancer"],"prefix":"10.1158","volume":"68","author":[{"given":"Tong","family":"Sun","sequence":"first","affiliation":[{"name":"1Etiology and Carcinogenesis and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"1Etiology and Carcinogenesis and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Yang","sequence":"additional","affiliation":[{"name":"1Etiology and Carcinogenesis and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibin","family":"Hu","sequence":"additional","affiliation":[{"name":"3Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Tan","sequence":"additional","affiliation":[{"name":"1Etiology and Carcinogenesis and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Han","sequence":"additional","affiliation":[{"name":"2Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuankai","family":"Shi","sequence":"additional","affiliation":[{"name":"2Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiarui","family":"Yao","sequence":"additional","affiliation":[{"name":"2Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongli","family":"Guo","sequence":"additional","affiliation":[{"name":"1Etiology and Carcinogenesis and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianke","family":"Yu","sequence":"additional","affiliation":[{"name":"1Etiology and Carcinogenesis and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Tian","sequence":"additional","affiliation":[{"name":"3Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"3Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbing","family":"Shen","sequence":"additional","affiliation":[{"name":"3Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxin","family":"Lin","sequence":"additional","affiliation":[{"name":"1Etiology and Carcinogenesis and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1086","published-online":{"date-parts":[[2008,8,28]]},"reference":[{"key":"2022061700294663500_B1","doi-asserted-by":"crossref","unstructured":"Egen JG, Kuhns MS, Allison JP. 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