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


METHODS
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.
Yang
Ming
M
Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China.
Sun
Tong
T
Wang
Li
L
Yu
Dianke
D
Zhang
Xuemei
X
Miao
Xiaoping
X
Liu
Junniao
J
Zhao
Dan
D
Li
Hui
H
Tan
Wen
W
Lin
Dongxin
D
D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects; D017209:Apoptosis / Q000235:genetics*; D016022:Case-Control Studies; D053181:Caspase 8 / Q000235:genetics*; D003920:Diabetes Mellitus; D053222:Fas Ligand Protein / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D019014:fas Receptor / Q000235:genetics
D053222:Fas Ligand Protein; D019014:fas Receptor; D053181:Caspase 8