Polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma.
BACKGROUND
The FAS receptor-ligand system is a key regulator of apoptotic cell death, and loss of FAS expression and gain of FAS ligand (FASL) expression play important roles in the development and progression of cancer. Single-nucleotide polymorphisms in the promoter region of the FAS (G or A at position -1377 [FAS -1377G/A] and A or G at position -670 [FAS -670A/G]) and FASL (T or C at position -844 [FASL -844T/C]) genes alter the transcriptional activity of these genes. We examined the association between these polymorphisms and risk of the development and metastasis of esophageal squamous-cell carcinoma.


METHODS
Genotypes of 588 case patients with esophageal squamous-cell carcinoma and 648 control subjects were determined by polymerase chain reaction-based restriction fragment length polymorphism. Associations with the risk of esophageal squamous-cell carcinoma were estimated by logistic regression. All statistical tests were two-sided.


RESULTS
We observed a statistically significantly increased risk of esophageal squamous-cell carcinoma associated with the FAS -1377AA (odds ratio [OR] = 1.79, 95% confidence interval [CI] = 1.29 to 2.48; P<.001) or FAS -670GG (OR = 1.72, 95% CI = 1.26 to 2.34; P<.001) genotype, which are in strong linkage disequilibrium compared with the FAS -1377GA or GG or the FAS -670AG or AA genotype, respectively. An increased risk of esophageal squamous-cell carcinoma was also associated with the FASL -844CC genotype (OR = 2.06, 95% CI = 1.64 to 2.59; P<.001) compared with the FASL -844CT or TT genotype. Gene-gene interactions of FAS and FASL polymorphisms increased the risk of esophageal squamous-cell carcinoma in a multiplicative manner (OR for the presence of both FAS -1377AA and FASL -844CC genotypes = 4.55, 95% CI = 2.75 to 7.48; P =.001, test for homogeneity). Statistically significant interactions were found between these polymorphisms in FAS and FASL and tobacco smoking. None of the polymorphisms was associated with risk of differentiation or metastasis of esophageal squamous-cell carcinoma at diagnosis.


CONCLUSIONS
Genetic polymorphisms in the death pathway genes FAS and FASL appear to be associated with an increased risk of developing esophageal squamous-cell carcinoma.
Sun
Tong
T
Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Miao
Xiaoping
X
Zhang
Xuemei
X
Tan
Wen
W
Xiong
Ping
P
Lin
Dongxin
D
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D056970:Co-Repressor Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000032:analysis; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D053222:Fas Ligand Protein; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D017931:DNA Primers; D004273:DNA, Neoplasm; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins