Caspases are important in the life and death of immune cells and therefore influence immune surveillance of malignancies. We tested whether genetic variants in CASP8, CASP10 and CFLAR, three genes important for death receptor–induced cell killing residing in tandem order on chromosome 2q33, are associated with cancer susceptibility. Using a haplotype-tagging SNP approach, we identified a six-nucleotide deletion (−652 6N del) variant in the CASP8 promoter associated with decreased risk of lung cancer. The deletion destroys a stimulatory protein 1 binding site and decreases CASP8 transcription. Biochemical analyses showed that T lymphocytes with the deletion variant had lower caspase-8 activity and activation-induced cell death upon stimulation with cancer cell antigens. Case-control analyses of 4,995 individuals with cancer and 4,972 controls in a Chinese population showed that this genetic variant is associated with reduced susceptibility to multiple cancers, including lung, esophageal, gastric, colorectal, cervical and breast cancers, acting in an allele dose–dependent manner. These results support the hypothesis that genetic variants influencing immune status modify cancer susceptibility.
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This work was supported by National Natural Science Foundation grant 30530710 and State Key Basic Research Program grant 2004CB518701 (D.L.) and by grant 2002AA232031 from the Mega-Projects of Science Research for the 10th Five-Year Plan and the Hundred Talents Program of the Chinese Academy of Sciences (C.Z.).
The authors declare no competing financial interests.
LD block of the CFLAR-CASP8-CASP10 region. (PDF 65 kb)
Characteristics of individuals with lung cancer and control subjects. (PDF 34 kb)
Association between tag SNPs and lung cancer risk. (PDF 25 kb)
Activation of T lymphocytes in PBMCs. (PDF 15 kb)
Distribution of characteristics of affected individuals and controls. (PDF 19 kb)
Primer sequences. (PDF 65 kb)
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Sun, T., Gao, Y., Tan, W. et al. A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nat Genet 39, 605–613 (2007). https://doi.org/10.1038/ng2030
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