Article abstract
Nature Genetics 39, 605 - 613 (2007)
Published online: 22 April 2007 | doi:10.1038/ng2030
A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers
Tong Sun1,4, Yang Gao2,4, Wen Tan1, Sufang Ma2, Yuankai Shi3, Jiarui Yao3, Yongli Guo1, Ming Yang1, Xuemei Zhang1, Qingrun Zhang2, Changqing Zeng2 & Dongxin Lin1
Abstract
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.
- Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- Beijing Genomics Institute, Chinese Academy of Sciences, Beijing, China.
- Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- These authors contributed equally to this work.
Correspondence to: Dongxin Lin1 e-mail: dlin@public.bta.net.cn
Correspondence to: Changqing Zeng2 e-mail: czeng@genomics.org.cn
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