Background: Bromodomain and extra-terminal (BET) domain proteins that bind to acetylated lysine residues of histones serve as the “readers” of DNA acetylation. BRD4 is the most thoroughly studied member of the BET family and regulates the expression of key oncogenes. BRD4 gene amplification has been identified in ovarian cancer (~18–19%) according toThe Cancer Genome Atlas(TCGA) analysis. BET inhibitors are novel small molecules that displace BET proteins from acetylated histones and are currently tested in Phase I/II trials. We here aim to explore the prognostic role of the BRD4 gene and protein expression in the ascitic fluid of patients with advanced FIGO III/IV high-grade serous ovarian carcinoma (HGSC). Methods: Ascitic fluid was obtained from 28 patients with advanced stage (FIGO III/IV) HGSC through diagnostic/therapeutic paracentesis or laparoscopy before the initiation of chemotherapy. An amount of ~200 mL of ascitic fluid was collected from each patient and peripheral blood mononuclear cells (PBMCs) were isolated. Each sample was evaluated for BRD4 and GAPDH gene expression through RT-qPCR and BRD4 protein levels through enzyme-linked immunosorbent assay (ELISA). The study protocol was approved by the Institutional Review Board of Alexandra University Hospital and the Committee on Ethics and Good Practice (CEGP) of the National and Kapodistrian University of Athens (NKUA). Results: Low BRD4 gene expression was associated with worse prognosis at 12 months compared to intermediate/high expression (95% CI; 1.75–30.49;p= 0.008). The same association was observed at 24 months although this association was not statistically significant (95% CI; 0.96–9.2;p= 0.065). Progression-free survival was shorter in patients with low BRD4 gene expression at 12 months (5.6 months; 95% CI; 2.6–8.6) compared to intermediate/high expression (9.8 months; 95% CI; 8.3–11.3) (95% CI; 1.2–16.5;p= 0.03). The same association was confirmed at 24 months (6.9 months vs. 13.1 months) (95% CI; 1.1–8.6;p= 0.048). There was a trend for worse prognosis in patients with high BRD4 protein levels versus intermediate/low BRD4 protein expression both at 12 months (9.8 months vs. 7.6 months;p= 0.3) and at 24 months (14.2 months vs. 16.6 months;p= 0.56) although not statistically significant. Again, there was a trend for shorter PFS in patients with high BRD4 protein expression although not statistically significant both at 12 months (p= 0.29) and at 24 months (p= 0.47). Conclusions: There are contradictory data in the literature over the prognostic role of BRD4 gene expression in solid tumors. In our study, intermediate/high BRD4 gene expression was associated with a favorable prognosis in terms of overall survival and progression-free survival compared to low BRD4 gene expression.
背景：溴结构域和超末端结构域（BET）蛋白作为DNA乙酰化的“阅读器”，可与组蛋白的乙酰化赖氨酸残基结合。BRD4是BET家族中被研究最深入的成员，调控关键癌基因的表达。根据癌症基因组图谱（TCGA）分析，卵巢癌中已发现BRD4基因扩增（约18–19%）。BET抑制剂是一类新型小分子药物，可将BET蛋白从乙酰化组蛋白上置换下来，目前正处于I/II期临床试验阶段。本研究旨在探讨BRD4基因及其蛋白表达在晚期FIGO III/IV高级别浆液性卵巢癌（HGSC）患者腹水中的预后作用。 方法：在化疗开始前，通过诊断性/治疗性腹腔穿刺或腹腔镜手术，从28例晚期（FIGO III/IV期）HGSC患者获取腹水样本。每例患者采集约200 mL腹水，并分离外周血单个核细胞（PBMCs）。通过实时定量聚合酶链反应（RT-qPCR）检测各样本中BRD4和GAPDH基因表达，通过酶联免疫吸附试验（ELISA）检测BRD4蛋白水平。本研究方案已获亚历山德拉大学医院机构审查委员会及雅典国立卡波季斯特里安大学（NKUA）伦理与良好实践委员会（CEGP）批准。 结果：与中/高表达相比，低BRD4基因表达在12个月时与较差的预后相关（95% CI；1.75–30.49；p=0.008）。在24个月时观察到相同关联，但无统计学意义（95% CI；0.96–9.2；p=0.065）。低BRD4基因表达患者在12个月时的无进展生存期（5.6个月；95% CI；2.6–8.6）较中/高表达患者（9.8个月；95% CI；8.3–11.3）更短（95% CI；1.2–16.5；p=0.03）。该关联在24个月时得到确认（6.9个月 vs. 13.1个月）（95% CI；1.1–8.6；p=0.048）。高BRD4蛋白水平患者与中/低BRD4蛋白表达患者相比，在12个月（9.8个月 vs. 7.6个月；p=0.3）和24个月（14.2个月 vs. 16.6个月；p=0.56）均显示出预后较差的趋势，但无统计学意义。同样，高BRD4蛋白表达患者的无进展生存期有缩短趋势，但在12个月（p=0.29）和24个月（p=0.47）均无统计学意义。 结论：关于BRD4基因表达在实体瘤中的预后作用，现有文献数据存在矛盾。本研究发现，与低BRD4基因表达相比，中/高BRD4基因表达在总生存期和无进展生存期方面均与良好预后相关。
The Prognostic Role of BRD4 Expression in High-Grade Serous Ovarian Cancer
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