TERT Promoter Mutation: A Molecular Link Between HCV and Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) ranks sixth among cancers globally and is the third leading cause of cancer-related mortality. Hepatitis C virus (HCV) infection accounts for approximately 25–30% of HCC cases worldwide. Although direct-acting antiviral agents (DAAs) now achieve viral eradication in over 95% of patients, HCC risk persists even after viral clearance, making it essential to understand the molecular mechanisms linking HCV to tumor development. Among the most significant molecular alterations in HCC are TERT promoter mutations, occurring in 54–60% of all cases. The two predominant mutations, C228T and C250T, create novel ETS transcription factor binding sites including GABPα driving persistent TERT activation and conferring replicative immortality upon cancer cells. HCV promotes these mutations through interconnected mechanisms: virus-induced oxidative stress damages the TERT promoter region; HCV proteins NS3/4A and NS5A enhance telomerase stability; the core protein remodels chromatin architecture; and chronic inflammation elevates IL-6 and TNF-α, activating STAT3 and NF-κB pathways that further upregulate TERT expression. Clinically, TERT promoter mutations correlate with tumor aggressiveness, elevated AFP levels, microvascular invasion, and poor prognosis. Importantly, these mutations are detectable in patient plasma, offering a promising avenue for non-invasive HCC diagnosis.