Abstract
Prostate Cancer (PCa) screening using Prostate-Specific Antigen (PSA) has significantly improved early detection but has also led to substantial overdiagnosis and overtreatment, particularly of indolent tumors. While active surveillance and focal therapies have mitigated some harms, distinguishing aggressive from non-threatening disease remains a critical clinical challenge. Emerging evidence highlights the epigenetic regulation of the human Telomerase Reverse Transcriptase (hTERT) gene as a promising biomarker for risk stratification. Cancer-specific hypermethylation within the TERT Hypermethylated Oncological Region (THOR) and the broader CpG island termed "Acheron" correlates with hTERT reactivation, tumor progression, and adverse outcomes. Additionally, suppression of the long non-coding (lnc) RNA human TERT Antisense Promoter-Associated (hTAPAS) contributes to the derepression of hTERT, providing a mechanistic link between DNA methylation and telomerase activation. Collectively, these epigenetic signatures, referred to as EpihTERT, can be detected in tissue and liquid biopsies, offering non-invasive assessment of tumor aggressiveness. Integration of EpihTERT profiling into clinical practice may enhance early diagnosis, refine patient selection for intervention, and reduce unnecessary treatments, bridging the gap between overdiagnosis and timely identification of clinically significant disease. Prospective multicenter validation is warranted to establish EpihTERT as a robust, translational biomarker in PCa management.