RESUMO
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.
RESUMO
BACKGROUND/AIM: Uterine leiomyosarcomas (uLMS) are the most common mesenchymal tumors of the female genital tract. uLMS genetics encompass complex karyotypes with no specific molecular alterations. The Hippo pathway has been implicated in the pathogenesis of epithelioid hemangio-endotheliomas and endometrial sarcomas. Hippo pathway effectors are YAP1 and TAZ co-transcriptional factors. PATIENTS AND METHODS: We studied Hippo pathway in a series of 32 uLMS patients and its association with clinicopathological parameters. MATERIALS AND METHODS: Immunohistochemical analysis of YAP1 and TAZ proteins accompanied with fluorescent in situ hybridization study of YAP1 gene was performed in patient samples. Age, sex, tumor size, stage at the time of diagnosis and treatment have been analyzed. Overall survival (OS) was calculated from the time of diagnosis until death, loss of follow up or data cut-off. RESULTS: Hippo signaling was found to be dysregulated in 20 (62.5%) patients with uLMS. Regarding OS we detected a trend of Hippo deregulation, designating it as a positive prognostic factor. CONCLUSION: The Hippo pathway is implicated in uLMS oncogenesis, since nuclear expression of YAP1 was detected in 17 (53.1%) of the 32 patients with immunohistochemistry and YAP1 amplification was found in 8 (25%) patients.