Polymorphisms of Death Pathway Genes FAS and FASL in Esophageal Squamous-Cell Carcinoma

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Abstract
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. Conclusion: Genetic polymorphisms in the death pathway genes FAS and FASL appear to be associated with an increased risk of developing esophageal squamous-cell carcinoma.