FASL polymorphism is associated with response to bacillus Calmette-Guerin immunotherapy in bladder cancer

Objective: Deregulation of FAS/FASL system may lead to immune escape and influence bacillus Calmette-Guerin (BCG) immunotherapy outcome, which is currently the gold standard adjuvant treatment for high-risk non muscle invasive bladder tumors. Among other events, functional promoter polymorphisms of FAS and FAST, genes may alter their transcriptional activity. Therefore, we aim to evaluate the role of FAS and FASL polymorphisms in the context of BCG therapy, envisaging the validation of these biomarkers to predict response. Patients and methods: DNA extracted from peripheral blood from 125 patients with bladder cancer treated with BCG therapy was analyzed by Polymerase Chain Reaction Restriction Fragment Length Polymorphism for FAS-670 A/G and FASL-844 T/C polymorphisms. FAST. mRNA expression was analyzed by real-time Polymerase Chain Reaction. Results: Carriers of FAS-L-844 CC genotype present a decreased recurrence-free survival after BCG treatment when compared with TASL-844 T allele carriers (mean 71.5 vs. 97.8 months, P = 0.030) and have an increased risk of BCG treatment failure (Hazard Ratio = 1.922; 95% Confidence Interval: [1.064-3.471]; P = 0.030). Multivariate analysis shows that FASL-844 TIC and therapeutics scheme are independent predictive markers of recurrence after treatment. The evaluation of FAST, gene mRNA levels demonstrated that patients carrying FAST-844 CC genotype had higher FASL. expression in bladder tumors (P = 0.0027). Higher FAST; levels were also associated with an increased risk of recurrence after BCG treatment (Hazard Ratio = 2.833; 95% Confidence Interval: [1.012-7.9291; P = 0.047). FAS-670 A/G polymorphism analysis did not reveal any association with BCG therapy outcome. Conclusions: Our results suggest that analysis of FASL-844 T/C, but not FAS-670 A/G polymorphisms, may be used as a predictive marker of response to BCG immunotherapy. (C) 2014 Elsevier Inc. All rights reserved.