## Molecular Alterations in HCC **Key Point:** TP53 mutations are the most frequent genetic alterations in hepatocellular carcinoma, occurring in approximately 20–50% of cases depending on etiology and geographic region. ### Frequency of Major Mutations in HCC | Mutation | Frequency | Association | | --- | --- | --- | | TP53 | 20–50% | HBV-related, aflatoxin exposure, poor prognosis | | CTNNB1 (β-catenin) | 15–40% | HCV-related, better prognosis | | AXIN1 | 5–15% | HBV-related | | PTEN | 5–10% | Rare, associated with PI3K/AKT activation | | MYC | <5% | Uncommon primary event | **High-Yield:** TP53 inactivation leads to loss of cell cycle control and apoptosis, driving hepatocarcinogenesis. It is particularly common in HBV-related HCC and aflatoxin-exposed cases. **Clinical Pearl:** TP53 mutations are associated with more aggressive tumours, higher grade, and worse overall survival compared to CTNNB1 mutations, which tend to occur in better-differentiated HCCs. ### Pathogenic Mechanism TP53 ("guardian of the genome") normally: 1. Detects DNA damage 2. Triggers cell cycle arrest (via p21) 3. Initiates apoptosis if damage is irreparable Loss of TP53 function removes this brake, allowing accumulation of additional mutations and uncontrolled proliferation. 
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.