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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.

Clinical impact of EZH2 and its antagonist SMARCA4 in ovarian cancer