Lima Luís, Ferreira José A, Tavares Ana, Oliveira Daniela, Morais António, Videira Paula A, Medeiros Rui, Santos Lúcio
Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Rua Dr. António Bernardino de Almeida, Porto, Portugal; ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal; Nucleo de Investigação em Farmácia-Centro de Investigação em Saúde e Ambiente (CISA), School of Allied Health Sciences-Polytechnic Institute of Oporto, Porto, Portugal; LPCC, Research Department-Portuguese League Against Cancer (NRNorte), Porto, Portugal.
Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Rua Dr. António Bernardino de Almeida, Porto, Portugal; QOPNA, Mass Spectrometry Center of the University of Aveiro, Campus de Santiago, Aveiro, Portugal.
Urol Oncol. 2014 Jan;32(1):44.e1-7. doi: 10.1016/j.urolonc.2013.05.009. Epub 2013 Aug 12.
Deregulation of FAS/FASL system may lead to immune escape and influence bacillus Calmette-Guérin (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 FASL 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.
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. FASL mRNA expression was analyzed by real-time Polymerase Chain Reaction.
Carriers of FASL-844 CC genotype present a decreased recurrence-free survival after BCG treatment when compared with FASL-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 T/C and therapeutics scheme are independent predictive markers of recurrence after treatment. The evaluation of FASL gene mRNA levels demonstrated that patients carrying FASL-844 CC genotype had higher FASL expression in bladder tumors (P = 0.0027). Higher FASL levels were also associated with an increased risk of recurrence after BCG treatment (Hazard Ratio = 2.833; 95% Confidence Interval: [1.012-7.929]; P = 0.047). FAS-670 A/G polymorphism analysis did not reveal any association with BCG therapy outcome.
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.
FAS/FASL系统失调可能导致免疫逃逸，并影响卡介苗（BCG）免疫治疗的效果，而BCG免疫治疗是目前高危非肌层浸润性膀胱肿瘤的金标准辅助治疗方法。在其他事件中，FAS和FASL基因的功能性启动子多态性可能会改变它们的转录活性。因此，我们旨在评估FAS和FASL多态性在BCG治疗中的作用，期望验证这些生物标志物以预测反应。
采用聚合酶链反应-限制性片段长度多态性方法，对125例接受BCG治疗的膀胱癌患者外周血提取的DNA进行FAS-670 A/G和FASL-844 T/C多态性分析。通过实时聚合酶链反应分析FASL mRNA表达。
与FASL-844 T等位基因携带者相比，FASL-844 CC基因型携带者在BCG治疗后的无复发生存期缩短（平均71.5个月对97.8个月，P = 0.030），且BCG治疗失败风险增加（风险比=1.922；95%置信区间：[1.064 - 3.471]；P = 0.030）。多因素分析表明，FASL-844 T/C和治疗方案是治疗后复发的独立预测标志物。对FASL基因mRNA水平的评估表明，携带FASL-844 CC基因型的患者膀胱肿瘤中FASL表达较高（P = 0.0027）。较高的FASL水平也与BCG治疗后复发风险增加相关（风险比=2.833；95%置信区间：[1.012 - 7.929]；P = 0.047）。FAS-670 A/G多态性分析未发现与BCG治疗结果有任何关联。
我们的结果表明，分析FASL-844 T/C多态性而非FAS-670 A/G多态性，可作为BCG免疫治疗反应的预测标志物。
