Functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer

摘要

The FAS–FASL system plays crucial role in counterattack of cancer cell against immune system. This study examined the effects of FAS (?1377G/A and ?670A/G) and FASL (?844T/C and 7896G/C) polymorphisms on breast cancer risk and apoptosis of T lymphocytes. The effect on breast cancer risk was determined by case–control analysis of 840 patients and 840 controls. The effects on T-lymphocyte apoptosis were determined by activation-induced cell death (AICD) of T cells ex vivo and by analyzing apoptotic tumor-infiltrating lymphocytes (TILs) in breast cancer tissue. We found moderately increased risk associated with FAS ?1377AG [odds ratio (OR), 1.29; 95% confidence interval (CI), 1.05–1.59] and ?1377AA (OR, 1.36; 95% CI, 1.01–1.82) genotypes compared with the ?1377GG genotype and decreased risk associated with FASL ?844CT (OR, 0.76; 95% CI, 0.62–0.94) and ?844TT (OR, 0.66; 95% CI, 0.43–1.00) genotypes compared with the ?844CC genotype. T lymphocytes with the FASL ?844CC genotype had heightened FASL expression that is associated with increased AICD of the T cells stimulated by MCF-7 cells or phytohemagglutinin compared with the FASL ?844TT genotype (10.38 ± 4.09% and 24.29 ± 1.50% versus 6.03 ± 0.41% and 17.96 ± 3.66%; P < 0.05 and 0.001). Breast cancer patients with the FASL ?844CC genotype had higher apoptotic TILs in their cancer tissues than those with the FASL ?844TT genotype (33.7 ± 1.2% versus 19.1 ± 2.0%; P = 0.007). These findings indicate that functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer.