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A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers

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.

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Figure 1: Fine mapping of the CFLAR/CASP10/CASP8 gene cluster and SNPs associated with lung cancer in the promoter of CASP8.
Figure 2: Association between CASP8 −652 6N ins/del polymorphism and the expression of caspase-8.
Figure 3: Abolishment of an Sp1 binding site in the CASP8 promoter by the six-nucleotide deletion and reduction of promoter activity.
Figure 4: Differential levels of caspase-8 activity and rates of T lymphocyte apoptosis in PBMCs from healthy individuals carrying different CASP8 −652 genotypes.

References

  1. 1

    de Visser, K.E., Eichten, A. & Coussens, L.M. Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer 6, 24–37 (2006).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Green, D.R., Droin, N. & Pinkoski, M. Activation-induced cell death in T cells. Immunol. Rev. 193, 70–81 (2003).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Chappell, D.B. & Restifo, N.P. T cell-tumor cell: a fatal interaction? Cancer Immunol. Immunother. 47, 65–71 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Maher, S., Toomey, D., Condron, C. & Bouchier-Hayes, D. Activation-induced cell death: the controversial role of FAS and FAS ligand in immune privilege and tumor counterattack. Immunol. Cell Biol. 80, 131–137 (2002).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Yu, P. & Fu, Y.X. Tumor-infiltrating T lymphocytes: friends or foes? Lab. Invest. 86, 231–245 (2006).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Aggarwal, B.B. Signalling pathways of the TNF superfamily: a double-edged sword. Nat. Rev. Immunol. 3, 745–756 (2003).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Siegel, R.M. Caspases at the crossroads of immune-cell life and death. Nat. Rev. Immunol. 6, 308–317 (2006).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Ho, P.K. & Hawkins, C.J. Mammalian initiator apoptotic caspases. FEBS J. 272, 5436–5453 (2005).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Thorburn, A. Death receptor-induced cell killing. Cell. Signal. 16, 139–144 (2004).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Sun, T. et al. Polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma. J. Natl. Cancer Inst. 96, 1030–1036 (2004).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Sun, T. et al. FASL-844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer. J. Exp. Med. 202, 967–974 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Zhang, X. et al. Functional polymorphisms in cell death pathway genes FAS and FASL contribute to risk of lung cancer. J. Med. Genet. 42, 479–484 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Krippl, P., Langsenlehner, U., Renner, W., Koppel, H. & Samonigg, H. Re: Polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma. J. Natl. Cancer Inst. 96, 1478–1479 (2004).

    Article  PubMed  Google Scholar 

  14. 14

    Sibley, K. et al. Functional FAS promoter polymorphisms are associated with increased risk of acute myeloid leukemia. Cancer Res. 63, 4327–4330 (2003).

    CAS  PubMed  Google Scholar 

  15. 15

    MacPherson, G. et al. Association of a common variant of the CASP8 gene with reduced risk of breast cancer. J. Natl. Cancer Inst. 96, 1866–1869 (2004).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Frank, B. et al. Re: Association of a common variant of the CASP8 gene with reduced risk of breast cancer. J. Natl. Cancer Inst. 97, 1012 (2005).

    Article  PubMed  Google Scholar 

  17. 17

    Frank, B. et al. Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant. Carcinogenesis 27, 606–609 (2006).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Cox, A. et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat. Genet. 39, 352–358 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Couzin, J. Genomics. The HapMap gold rush: researchers mine a rich deposit. Science 312, 1131 (2006).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Bond, G.L. et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119, 591–602 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Medema, J.P. et al. FLICE is activated by association with the CD95 death-inducing signaling complex (Drosoph. Inf. Serv.C). EMBO J. 16, 2794–2804 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Boldin, M.P., Goncharov, T.M., Goltsev, Y.V. & Wallach, D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85, 803–815 (1996).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Muzio, M. et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death–inducing signaling complex. Cell 85, 817–827 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Teitz, T. et al. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat. Med. 6, 529–535 (2000).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Soung, Y.H. et al. CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas. Cancer Res. 65, 815–821 (2005).

    CAS  PubMed  Google Scholar 

  26. 26

    Soung, Y.H. et al. Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas. Oncogene 24, 141–147 (2005).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Kim, H.S. et al. Inactivating mutations of caspase-8 gene in colorectal carcinomas. Gastroenterology 125, 708–715 (2003).

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Liedtke, C., Groger, N., Manns, M.P. & Trautwein, C. The human caspase-8 promoter sustains basal activity through SP1 and ETS-like transcription factors and can be up-regulated by a p53-dependent mechanism. J. Biol. Chem. 278, 27593–27604 (2003).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Scaffidi, C., Medema, J.P., Krammer, P.H. & Peter, M.E. FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b. J. Biol. Chem. 272, 26953–26958 (1997).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Breckenridge, D.G., Nguyen, M., Kuppig, S., Reth, M. & Shore, G.C. The procaspase-8 isoform, procaspase-8L, recruited to the BAP31 complex at the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA 99, 4331–4336 (2002).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Himeji, D. et al. Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade. Blood 99, 4070–4078 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Ju, S.T. et al. FAS (CD95)/FASL interactions required for programmed cell death after T-cell activation. Nature 373, 444–448 (1995).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Evan, G.I. & Vousden, K.H. Proliferation, cell cycle and apoptosis in cancer. Nature 411, 342–348 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Lowe, S.W. & Lin, A.W. Apoptosis in cancer. Carcinogenesis 21, 485–495 (2000).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Lee, S.H. et al. Alteration of Fas (APO-1/CD95) gene in non-small cell lung cancer. Oncogene 18, 3754–3760 (1999).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Gratas, C. et al. Up-regulation of Fas (APO-1/CD95) ligand and down-regulation of Fas expression in human esophageal cancer. Cancer Res. 58, 2057–2062 (1998).

    CAS  PubMed  Google Scholar 

  37. 37

    Reesink-Peters, N. et al. Death receptors and ligands in cervical carcinogenesis: an immunohistochemical study. Gynecol. Oncol. 96, 705–713 (2005).

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Gutierrez, L.S., Eliza, M., Niven-Fairchild, T., Naftolin, F. & Mor, G. The Fas/Fas-ligand system: a mechanism for immune evasion in human breast carcinomas. Breast Cancer Res. Treat. 54, 245–253 (1999).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Shin, M.S. et al. Mutation of tumor necrosis factor-related apoptosis-inducing ligand receptor 1(TRAIL-R1) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers. Cancer Res. 61, 4942–4946 (2001).

    CAS  PubMed  Google Scholar 

  40. 40

    Park, W.S. et al. Inactivating mutations of KILLER/DR5 gene in gastric cancers. Gastroenterology 121, 1219–1225 (2001).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Kase, C. et al. Expression of Fas and Fas ligand in esophageal tissue mucosa and carcinomas. Int. J. Oncol. 20, 291–297 (2002).

    CAS  PubMed  Google Scholar 

  42. 42

    Zhang, X. et al. Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer. Gastroenterology 129, 565–576 (2005).

    CAS  PubMed  Google Scholar 

  43. 43

    Liu, F. et al. Genetic variants in cyclooxygenase-2: expression and risk of gastric cancer and its precursors in a Chinese population. Gastroenterology 130, 1975–1984 (2006).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Sun, T. et al. Functional Phe31Ile polymorphism in Aurora A and risk of breast carcinoma. Carcinogenesis 25, 2225–2230 (2004).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Tan, W. et al. Association of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer. Carcinogenesis published online 6 December 2006 (doi:10.1093/carcin/bgl242).

    Google Scholar 

  46. 46

    Carlson, C.S., Eberle, M.A., Kruglyak, L. & Nickerson, D.A. Mapping complex disease loci in whole-genome association studies. Nature 429, 446–452 (2004).

    CAS  Article  Google Scholar 

  47. 47

    Buetow, K.H. et al. High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Proc. Natl. Acad. Sci. USA 98, 581–584 (2001).

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

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.).

Author information

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Authors

Contributions

T.S. performed most of the experiments and the data analyses and wrote the manuscript; Y. Gao, S.M. and Q.Z. contributed to SNP discovery and Sequenom genotyping; Z.C. supervised SNP discovery and Sequenom genotyping; W.T., Y. Guo, M.Y. and X.Z. managed DNA samples and clinical information; Y.S. and J.Y. performed flow cytometry analyses and D.L. performed the data analyses, prepared the manuscript and supervised this study.

Corresponding authors

Correspondence to Changqing Zeng or Dongxin Lin.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

LD block of the CFLAR-CASP8-CASP10 region. (PDF 65 kb)

Supplementary Table 1

Characteristics of individuals with lung cancer and control subjects. (PDF 34 kb)

Supplementary Table 2

Association between tag SNPs and lung cancer risk. (PDF 25 kb)

Supplementary Table 3

Activation of T lymphocytes in PBMCs. (PDF 15 kb)

Supplementary Table 4

Distribution of characteristics of affected individuals and controls. (PDF 19 kb)

Supplementary Table 5

Primer sequences. (PDF 65 kb)

Supplementary Methods (PDF 256 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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