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Abstract：
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 to The 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.
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.
摘要：
背景：与组蛋白的乙酰化赖氨酸残基结合的溴结构域和末端外（BET）结构域蛋白充当DNA乙酰化的“读取器”。BRD4是BET家族中研究最彻底的成员,并且调节关键癌基因的表达。根据癌症基因组图谱(TCGA)分析,已经在卵巢癌中鉴定了BRD4基因扩增(~18-19%)。BET抑制剂是新的小分子,其从乙酰化组蛋白取代BET蛋白,并且目前在I/II期试验中进行测试。我们在这里旨在探讨BRD4基因和蛋白质表达在晚期FIGOIII/IV高级别浆液性卵巢癌（HGSC）患者腹水中的预后作用。
方法：在开始化疗之前，通过诊断/治疗性穿刺或腹腔镜检查，从28例晚期（FIGOIII/IV）HGSC患者中获取腹水。从每个患者收集〜200mL量的腹水,并分离外周血单核细胞(PBMC)。通过RT-qPCR评估每个样品的BRD4和GAPDH基因表达，并通过酶联免疫吸附测定（ELISA）评估BRD4蛋白水平。该研究方案得到了亚历山德拉大学医院的机构审查委员会和雅典国立和Kapodistrian大学（NKUA）的伦理和良好实践委员会（CEGP）的批准。
结果：与中/高表达相比，低BRD4基因表达与12个月时的预后较差相关（95％CI；1.75-30.49；p=0.008）。在24个月时观察到相同的关联，尽管这种关联没有统计学意义（95％CI;0.96-9.2;p=0.065）。与中/高表达（9.8个月；95％CI；8.3-11.3）相比，BRD4基因低表达患者在12个月（5.6个月；95％CI；2.6-8.6）的无进展生存期较短（95％CI；1.2-16.5；p=0.03）。在24个月时确认了相同的关联（6.9个月vs.13.1个月）（95%CI；1.1-8.6；p=0.048）。在12个月时，高BRD4蛋白水平与中/低BRD4蛋白表达的患者的预后均有恶化的趋势（9.8个月与7.6个月；p=0.3）和24个月时（14.2个月与16.6个月；p=0.56），尽管没有统计学意义。再一次,BRD4蛋白高表达患者的PFS有较短的趋势,但在12个月(p=0.29)和24个月(p=0.47)时均无统计学意义.
结论：文献中关于BRD4基因表达在实体瘤中的预后作用存在矛盾的数据。在我们的研究中,与BRD4基因低表达相比,BRD4基因中/高表达与总生存期和无进展生存期的良好预后相关.
方法：在开始化疗之前，通过诊断/治疗性穿刺或腹腔镜检查，从28例晚期（FIGOIII/IV）HGSC患者中获取腹水。从每个患者收集〜200mL量的腹水,并分离外周血单核细胞(PBMC)。通过RT-qPCR评估每个样品的BRD4和GAPDH基因表达，并通过酶联免疫吸附测定（ELISA）评估BRD4蛋白水平。该研究方案得到了亚历山德拉大学医院的机构审查委员会和雅典国立和Kapodistrian大学（NKUA）的伦理和良好实践委员会（CEGP）的批准。
结果：与中/高表达相比，低BRD4基因表达与12个月时的预后较差相关（95％CI；1.75-30.49；p=0.008）。在24个月时观察到相同的关联，尽管这种关联没有统计学意义（95％CI;0.96-9.2;p=0.065）。与中/高表达（9.8个月；95％CI；8.3-11.3）相比，BRD4基因低表达患者在12个月（5.6个月；95％CI；2.6-8.6）的无进展生存期较短（95％CI；1.2-16.5；p=0.03）。在24个月时确认了相同的关联（6.9个月vs.13.1个月）（95%CI；1.1-8.6；p=0.048）。在12个月时，高BRD4蛋白水平与中/低BRD4蛋白表达的患者的预后均有恶化的趋势（9.8个月与7.6个月；p=0.3）和24个月时（14.2个月与16.6个月；p=0.56），尽管没有统计学意义。再一次,BRD4蛋白高表达患者的PFS有较短的趋势,但在12个月(p=0.29)和24个月(p=0.47)时均无统计学意义.
结论：文献中关于BRD4基因表达在实体瘤中的预后作用存在矛盾的数据。在我们的研究中,与BRD4基因低表达相比,BRD4基因中/高表达与总生存期和无进展生存期的良好预后相关.
