Functional variants in cell death pathway genes and risk of pancreatic cancer

Clin Cancer Res. 2008 May 15;14(10):3230-6. doi: 10.1158/1078-0432.CCR-08-0177.


Purpose: Fas-Fas ligand (FasL)-mediated death pathway is important in the life and death of immune cells and, therefore, influences immune surveillance of carcinogenesis. This study examined the association between functional variants of Fas (-1377G-->A and -670A-->G), FasL (-844T-->C), and caspase-8 (CASP8) six-nucleotide deletion polymorphism (-652 6N ins-->del) and risk of pancreatic cancer.

Experimental design: Genotypes were determined in 397 cases with pancreatic cancer and 907 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression, and all statistical tests were two sided.

Results: We found a significant decrease in risk of pancreatic cancer associated with FasL and CASP8 but not Fas polymorphisms. Compared with noncarriers, the ORs of developing pancreatic cancer for FasL -844CT and TT carriers were 0.73 (95% CI, 0.57-0.94) and 0.35 (95% CI, 0.19-0.63), and for CASP8 -652 6N ins/del and del/del carriers were 0.65 (95% CI, 0.50-0.85) and 0.56 (95% CI, 0.33-0.98), respectively. Gene-gene interaction between the FasL and CASP8 variants further reduced the cancer risk in a multiplicative manner (OR for the presence of both FasL -844TT and CASP8 -652 6N del/del genotype, 0.10; 95% CI, 0.01-0.75). On the other hand, a multiplicative joint effect between the FasL -844CC or CASP8 -652 6N ins/ins genotype and smoking or diabetes mellitus in intensifying risk of pancreatic cancer was also evident.

Conclusions: These results suggest that genetic variations in the death pathway genes FasL and CASP8 are involved in susceptibility to developing pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alcohol Drinking / adverse effects
  • Apoptosis / genetics*
  • Case-Control Studies
  • Caspase 8 / genetics*
  • Diabetes Mellitus
  • Fas Ligand Protein / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Middle Aged
  • Pancreatic Neoplasms / genetics*
  • Polymorphism, Restriction Fragment Length
  • Risk Factors
  • Smoking / adverse effects
  • fas Receptor / genetics


  • Fas Ligand Protein
  • fas Receptor
  • Caspase 8