Overexpression of enhance of Zeste homolog 2 (EZH2) in endometrial carcinoma: An NRG Oncology/Gynecologic Oncology Group Study

Abstract

Objectives: Enhancer of zeste homolog 2 (EZH2) is a histone methyl transferase that mediates epigenetic silencing of tumor suppressor genes. It is commonly over-expressed in several solid tumors and has been shown to be a prognostic biomarker. We investigated patterns of EZH2 expression in endometrial cancer.

Methods: Evaluation of EZH2 expression was completed on both early and advanced stage endometrioid adenocarcinoma tissues and a subset of matched normal mullerian tissue samples, from participants enrolled in Gynecologic Oncology Group (GOG) protocol 210, using real time reverse transcription polymerase chain reaction (RT-PCR) and western blot (WB) analysis. Non-parametric methods were used to assess differences in mRNA and protein expression respectively with known clinical/pathologic prognostic factors. Survival analysis was performed using techniques including Cox proportional hazards (PH) model to evaluate differences in progression free survival (PFS) and overall survival (OS) based on EZH2 expression.

Results: Eighty-seven patient samples were analyzed that included 60 tumors and 27 matched-normal tissue specimens. EZH2 mRNA (p < .0001) and protein expression (p < .0001) in tumor specimens were significantly higher than in matched-normal tissue. In primary tumors, EZH2 protein expression was associated with lympho-vascular space invasion (LVSI, p = .044), and EZH2 mRNA expression was associated with age (p = .037). Differences in EZH2 expression between primary tumors and matched normal tissue were not associated with other known clinical and pathologic factors. However, there did appear to be a trend toward decreased progression-free survival among patients with high EZH2 expression levels.

Conclusions: Our results confirm the differential expression of EZH2 in uterine cancers compared to normal tissues. However, there were no statistically significant differences in survival associated with EZH2 expression in patients with endometrial cancer. NCT #: NCT00340808.

Keywords: EZH2; Endometrial carcinoma; Prognosis.

Conflict of interest statement

Declaration of competing interest The authors have no competing interests to disclose.

Copyright © 2019. Published by Elsevier Inc.

Figures

Fig. 1.

EZH2 mRNA expression difference and protein expression between tumor tissue and matched normal tissue by patient ID.

Fig. 2.

AKaplan-Meier curve forprogression-free survival (PFS) by EZH2 mRNAexpression level in tumor tissue (Hazard Ratio (HR) = 0.59,95% CI = 0.178–1.769; log-rank test p-value = .3611 ) (EZH2 mRNA: Low [≤median] vs High [>median]) B. Kaplan-Meier curve for PFS by EZH2 protein expression in tumor tissue (HR = 0.307,95% CI 0.047–1.143; log-ranktest p-value 0.117) (EZH2 protein: negative vs positive) C. Kaplan-Meier curve for overall survival (OS) by EZH2 mRNAexpression level in tumor tissue (HR = 1.292,95% CI 0.285–6.556; log-ranktest p-value 0.737) D. Kaplan-Meier curve for OS by EZH2 protein expression in tumor tissue (HR = 0.289,95% CI 0.015–1.692; log-rank test p-value 0.221 ).

Fig. 3.

A Kaplan-Meier curve for PFS by EZH2 mRNA expression difference between tumor tissue and matched normal tissue B. Kaplan-Meier curve for PFS by EZH2 protein expression (WB) difference between tumor tissue and matched normal tissue.