Prognostic Significance of EZH2-Related Gene Variants in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy

Abstract

Background/aim: Prostate cancer remains a major global health burden, with treatment resistance posing a significant challenge. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), a histone methyltransferase, is frequently overexpressed in prostate cancer, contributing to tumor progression and castration resistance. Clinical trials of EZH2 inhibitors may have therapeutic benefits. This study aimed to evaluate the impact of genetic variants in EZH2-related genes on survival outcomes in prostate cancer.

Patients and methods: We conducted a genetic association study evaluating 76 single nucleotide polymorphisms (SNPs) across 10 EZH2-related genes in 630 patients with prostate cancer undergoing androgen deprivation therapy (ADT). Functional analyses, including gene ontology and pathway enrichment assessments, were performed to elucidate the biological significance of key genes across multiple datasets.

Results: DNMT3A rs77993651 was significantly associated with both cancer-specific survival [hazard ratio (HR)=0.82, p=0.042] and overall survival (HR=0.80, p=0.011). Functional annotation indicated that rs77993651 resides within enhancer histone marks, potentially regulating DNMT3A expression. Elevated DNMT3A expression was observed in prostate tumor tissues and correlated with more aggressive features and shorter progression-free survival. Gene set enrichment analysis revealed that DNMT3A expression was strongly associated with cell cycle G₂/M checkpoint regulation, implicating a role in prostate cancer progression.

Conclusion: The prognostic significance of DNMT3A and its genetic variant rs77993651 in prostate cancer is herein highlighted. Targeting DNMT3A-mediated pathways may offer novel therapeutic strategies for prostate cancer management.

Keywords: EZH2; Prostate cancer; epigenetic regulation; gene set enrichment analysis; survival.