Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Author:
Andrikopoulou Angeliki
Dissertation committee:
Ζαγουρή Φλώρα, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Δημόπουλος Μελέτιος-Αθανάσιος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Χαϊδόπουλος Δημήτριος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μπάμιας Αριστοτέλης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Λιόντος Μιχαήλ, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Θωμάκος Νικόλαος, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Παπαδημητρίου Χρήστος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Προγνωστική και προβλεπτική σημασία μορίων επιγενετικής τροποποίησης σε ασθενείς με καρκίνο ωοθηκών
Translated title:
“Prognostic and predictive value of epigenetic molecules in high grade serous carcinoma of the ovaries”
Summary:
BACKGROUND: Histone acetylation is one of the main epigenetic modifications and is mediated by histone acetyltransferases (HATs), histone deacetylases (HDACs) and bromodomain and extra-terminal (BET) domain proteins that serve as the ‘readers’ of DNA acetylation. BRD4 is the most thoroughly studied member of BET protein family that regulates the expression of key oncogenes including MYC and DNA repair genes like BRCA1 and RAD51. BRD4 catalyzes the initiation of transcription via recruiting positive transcription elongation factor (PTEF-b) to sites of active transcription and thus indirectly activating RNA PoLII. The catalytic role of BET proteins to tumori¬genesis led to the development of BET inhibitors that are currently under investigation in Phase I/II clinical trials. The purpose of this study was to investigate the prognostic role of BRD4 gene and protein expression in patients with advanced high grade ovarian carcinoma (HGSC).
METHODS: Ascitic fluid was obtained from 28 patients with HGSC FIGO stage IIIC / IV during diagnostic/therapeutic paracentesis or laparoscopy performed at “Alexandra University Hospital” before the initiation of chemotherapy. Ascitic fluid was centri-fuged and analyzed for BRD4 and GAPDH gene expression via RT-qPCR. BRD4 protein level was then quantified via ELISA immunoassay. Kaplan Meier curves were performed to explore the association of BRD4 gene and protein expression with survival in terms of OS and PFS.
RESULTS: Patients with intermediate/high BRD4 gene expression demonstrated better one-year overall survival compared to those with low expression (10.4 months (95% CI; 9.0 – 11.8) versus 6.3 months μήνες (95% CI; 3.3 – 9.3) (P = 0,008). The same trend was noted at two-year survival although not statistically significant (18.5 months (95% CI; 14.8 – 22.2) versus 10.3 months (95% CI; 3.3 – 17.3) (P = 0,065). In terms of PFS, intermediate/high BRD4 gene expression was associated with a favorable prognosis both at one-year analysis (9.8 versus 5.6 months; P = 0,03) and at two years (13.1 versus 6.9 months; P = 0,048). In contrast, high BRD4 protein expression was associated with an adverse prognosis at one-year survival (P=0.3) and at two-year survival analysis (P=0.56). Of note, BRD4 gene expression was found to be inversely associated to BRD4 protein level although this association was not significant.
CONCLUSION: In conclusion, intermediate/high BRD4 gene expression was asso-ciated with better survival in advanced HGSC. In contrast, high BRD4 protein expres-sion was associated to an adverse prognosis compared to intermediate / low protein expression in the same setting. It seems that BRD4 gene and protein expression both correlate to survival in ovarian cancer and are potentially druggable targets with BET inhibitors.
Main subject category:
Health Sciences
Keywords:
Ovarian cancer, Epigenetic modifications, Histone acetylation, BET proteins, BET inhibitors, BRD4 gene
