Clinical impact of EZH2 and its antagonist SMARCA4 in ovarian cancer

• Published in: Scientific reports 2020-11, Vol.10 (1), p.20412-20412, Article 20412
• Main Authors: Leitner, Katharina, Tsibulak, Irina, Wieser, Verena, Knoll, Katharina, Reimer, Daniel, Marth, Christian, Fiegl, Heidi, Zeimet, Alain G.
• Format: Article
• Language: English
• Subjects: 631/337/100/102; 631/67/1517/1709; 692/4028/67/1517/1709; Adult; Aged; Aged, 80 and over; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - mortality; Carcinoma, Ovarian Epithelial - pathology; Carcinoma, Ovarian Epithelial - surgery; Case-Control Studies; Cell differentiation; Chromatin remodeling; DNA Helicases - genetics; DNA Helicases - metabolism; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Fallopian Tubes - pathology; Fallopian Tubes - surgery; Female; Gene expression; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Hypersensitivity; Mad2 Proteins - genetics; Mad2 Proteins - metabolism; Middle Aged; multidisciplinary; Neoplasm Grading; Neoplasm Staging; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - mortality; Ovarian Neoplasms - pathology; Ovarian Neoplasms - surgery; Ovary - pathology; Ovary - surgery; Platinum; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Polymerase chain reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; ROC Curve; Science; Science (multidisciplinary); Signal Transduction; Survival; Survival Analysis; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-77532-x

SMARCA4 and EZH2 are two functional key players of their respective antagonizing chromatin remodeling complexes SWI/SNF and PRC2. EZH2 inhibitory drugs may abrogate pro-oncogenic features of PRC2 and turn the balance to cell differentiation via SWI/SNF activity in cancers. SMARCA4 and EZH2 expression was assessed by RT-PCR in 238 epithelial ovarian cancers (OCs) and put in relation to clinico-pathological parameters and patients’ outcome. Optimal thresholds for high and low expression of both variables were calculated by the Youden’s index based on receiver operating characteristic (ROC) curves. High SMARCA4 mRNA expression was independently associated with favorable progression-free survival (PFS) ( P  = 0.03) and overall survival (OS) ( P  = 0.018). As Youden’s threshold determination for EZH2 yielded a S-shaped ROC-curve, two cut-off points (29th and 94th percentile) predicting opposite features were defined. Whereas EZH2 mRNA levels beyond the 29th percentile independently predicted poor PFS ( P  = 0.034), Cox-regression in EZH2 transcripts above the 94th percentile revealed a conversion from unfavorable to favorable PFS and OS ( P  = 0.009 and P  = 0.032, respectively). High SMARCA4 expression associates with improved survival, whereas moderate/high EZH2 expression predicts poor outcome, which converts to favorable survival in ultra-high expressing OCs. This small OC subgroup could be characterized by REV7-abrogated platinum hypersensitivity but concomitant PARP-inhibitor resistance.