A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers.
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.
Sun
Tong
T
Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Gao
Yang
Y
Tan
Wen
W
Ma
Sufang
S
Shi
Yuankai
Y
Yao
Jiarui
J
Guo
Yongli
Y
Yang
Ming
M
Zhang
Xuemei
X
Zhang
Qingrun
Q
Zeng
Changqing
C
Lin
Dongxin
D
D044466:Asian People; D001665:Binding Sites / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D002681:China; D047369:Chromatin Immunoprecipitation; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics*; D008156:Luciferases; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014162:Transfection
D008156:Luciferases; C505530:CASP8 protein, human; D053181:Caspase 8