A 55-year-old man with 20-year history of chronic HCV cirrhosis develops a 3 cm arterially enhancing liver mass with washout appearance on portal-venous phase MRI. AFP is 450 ng/mL. Core biopsy is not performed; LI-RADS 5 diagnosis is made. Which molecular pathway is most frequently dysregulated in hepatocellular carcinoma arising on HCV-associated cirrhosis, and which targeted therapy exploits this?
- A Wnt/β-catenin pathway (CTNNB1 activating mutations and AXIN1/APC loss) is the most frequently mutated oncogenic pathway; downstream targets include cyclin D1, c-MYC, and AFP gene itself; while there is no approved direct β-catenin inhibitor, sorafenib (VEGFR/PDGFR/RAF inhibitor) is standard systemic therapy exploiting the VEGF-driven angiogenesis universally present in HCC ✓
- B TP53 and RB1 mutations drive autonomous S-phase entry; CDK4/6 inhibitors (palbociclib) are first-line therapy
- C KRAS activation and MEK-ERK signaling dominate HCV-related HCC; binimetinib (MEK inhibitor) is approved for first-line HCC treatment
- D IDH1/IDH2 mutations producing oncometabolite 2-hydroxyglutarate cause HCC; IDH inhibitors (enasidenib) are first-line therapy
Explanation
In HCC, the Wnt/β-catenin pathway is the most commonly activated oncogenic pathway, with CTNNB1 (β-catenin) gain-of-function mutations in ~30% and AXIN1 loss-of-function in ~8–15% of cases. Active β-catenin translocates to the nucleus, transactivating TCF/LEF targets including CCND1 (cyclin D1), MYC, and GLUL (glutamine synthetase — a diagnostic IHC marker for CTNNB1-mutant HCC). AFP is a fetal liver gene also regulated by Wnt signaling. Sorafenib (multi-kinase inhibitor targeting VEGFR1-3, PDGFR-β, RAF) is approved first-line systemic therapy, exploiting HCC's critical dependence on VEGF-driven angiogenesis; atezolizumab+bevacizumab has become current preferred first-line.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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