Abstract
Objective: Enhancer of zeste homologue 2 (EZH2) serves as the enzymatic component of polycomb repressive complex 2, while SMARCB1/INI-1 is an essential subunit of the SWI/SNF chromatin remodeling complex; both function as epigenetic regulators with proposed roles in hepatocarcinogenesis. This study aimed to evaluate the expression of EZH2 and INI-1 by immunohistochemistry (IHC) in hepatocellular carcinoma (HCC) and to determine their association with clinicopathological features and survival outcomes.
Material and Methods: We retrospectively studied 103 patients with histologically proven HCC who were treated at a single center between 2011 and 2019. EZH2 and INI-1 were evaluated by IHC in archival, paraffin-embedded specimens, with a case considered positive when at least 1% of tumor nuclei showed distinct staining. Relationships with clinicopathological variables were tested using the chi-square test or Fisher’s exact test, and overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier estimation and Cox proportional hazards modeling.
Results: EZH2 positivity occurred in 45 patients (43.7%), whereas INI-1 loss occurred in 11 (10.7%). Over a median follow-up of 42.0 months, 71 deaths and 86 progression events were observed. EZH2-positive cases exhibited significantly shorter median OS (8.0 vs. 27.0 months; p=0.007) and PFS (5.0 vs. 9.0 months; p=0.012). In univariate Cox regression analysis, EZH2 positivity was a significant risk factor for both mortality [hazard ratio (HR): 1.88; 95% confidence interval (CI): 1.17-3.02; p=0.009] and disease progression (HR: 1.69; 95% CI: 1.10-2.60; p=0.018). However, EZH2 did not retain independent prognostic significance in multivariate analysis adjusted for Barcelona Clinic Liver Cancer (BCLC) stage for either OS (HR: 1.55; 95% CI: 0.95-2.53; p=0.078) or PFS (HR: 1.39; 95% CI: 0.89-2.17; p=0.146). INI-1 loss showed a trend toward longer PFS (22.0 vs. 6.0 months; p=0.051) and OS (30.0 vs. 15.0 months; p=0.097), but these differences did not reach statistical significance.
Conclusion: EZH2 positivity is associated with inferior survival in HCC; however, this association does not remain independent of BCLC stage, indicating a stage-dependent rather than independent prognostic effect. INI-1 loss showed only borderline exploratory associations with survival that require validation in larger series. Together, these observations support the biological relevance of epigenetic regulators in HCC.