Functional polymorphisms in cell death pathway genes FAS and FASL contribute to risk of lung cancer

Abstract

Background: The FAS and FASL system plays a key role in regulating apoptotic cell death and corruption of this signalling pathway has been shown to participate in immune escape and tumorigenesis. There is reduced expression of FAS but elevated expression of FASL in many types of human cancers including lung cancer. We recently reported an association between functional polymorphisms in FAS (21377GRA) and FASL (2844TRC) and risk of oesophageal cancer. Objective: To examine the contribution of these polymorphisms to risk of developing lung cancer. Methods: Genotypes of 1000 lung cancer patients and 1270 controls were analysed by PCR based restriction fragment length polymorphism. Associations with risk of lung cancer were estimated by logistic regression. Results: Compared with non-carriers, there was a 1.6 fold excess risk of developing lung cancer for carriers of the FAS 21377AA genotype (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.21 to 2.10; p = 0.001), and 1.8 fold excess risk (OR 1.79, 95% CI 1.26 to 2.52; p = 0.001) for carriers of FASL 2844CC. Gene-gene interaction of FAS and FASL polymorphisms increased risk of lung cancer in a multiplicative manner (OR for the carriers of both FAS 21377AA and FASL 2844CC genotypes 4.18, 95% CI 2.83 to 6.18). Gene-environment interaction of FAS or FASL polymorphism and smoking associated with increased risk of lung cancer was also found. Conclusion: These results are consistent with our initial findings in oesophageal cancer and further support the hypothesis that the FAS and FASL triggered apoptosis pathway plays an important role in human carcinogenesis.

Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer

“…Hypothetically the FasL polymorphism is important for progression to invasive cervical cancer but not for susceptibility to long-term HPV infection and cervical lesions. This is supported by reported associations of the FasL 2844 C-allele with other cancer sites, such as the esophagus, 52 lung 53 and bladder. 54 The C-allele increases expression of FasL 27 and many studies report increased expression of FasL by malignant cells in destruction of local tissue, invasion and metastasis.…”

Association between FAS polymorphism and prostate cancer development

“…7,8 In addition, polymorphisms in the FAS gene and perhaps also in the FASL gene that impair apoptotic signal transduction are associated with a high risk of cancer in various models. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] Thus, the FAS/FASL system appears to have a role in the development and progression of cancer.…”

A Polymorphic −844T/C in FasL Promoter Predicts Survival and Relapse in Non–Small Cell Lung Cancer

“…A series of epidemiologic studies conducted by Lin's group indicated that subjects with the FasL À844CC genotype have a higher cancer risk than those with the FasL À844TTþTC genotype, including increased risk of esophageal, cervical, lung, breast, and pancreatic carcinomas (18)(19)(20)(21)(22). However, the FasL À844T/C genotype was not associated with lung cancer risk in our case-control study (385 cases and 308 controls), which might be explained by differences in the studied case populations (FasL À844CC genotype: 61.2% for Chinese vs. 46.4% for Taiwanese).…”

“…A series of case-controlled studies from Lin's group indicated that the functional FasL À844T/C polymorphism in a Chinese population was associated with an increased risk of different human cancers, including those of the cervix, lung, esophagus, breast, and pancreas (18)(19)(20)(21)(22).…”