A 55-year-old man with chronic HCV develops hepatocellular carcinoma (HCC). AFP is 1200 ng/mL. Imaging shows a 4 cm arterially enhancing nodule with washout on portal phase (LI-RADS 5). Which molecular event in HCV-related hepatocarcinogenesis most directly promotes cell cycle progression?

• A HCV NS5A protein activating beta-catenin pathway by Wnt-independent mechanism
• B HCV core protein suppressing p53 function and promoting CCND1 (cyclin D1) overexpression
• C TERT promoter mutation — most frequent somatic mutation in HCC regardless of etiology, enabling unlimited cell division ✓
• D HCV NS3-NS4A protease cleaving MAVS to prevent innate antiviral immune response enabling persistent viral replication

Explanation

TERT (telomerase reverse transcriptase) promoter mutations (C228T and C250T hotspots) are the most frequent somatic mutations in hepatocellular carcinoma across all etiologies (HCV, HBV, alcoholic, NASH-associated), occurring in ~60% of cases. These mutations create new ETS binding sites, enabling TERT transcription in normally TERT-silent hepatocytes and conferring replicative immortality. HCV core protein and NS5A have roles in early dysplasia, and NS3-NS4A cleavage of MAVS is an important immune evasion mechanism, but TERT promoter mutation is the single most frequent driver across HCC etiologies.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.