## Genetic Alterations in HCC **Key Point:** TP53 mutations are the most frequent genetic alterations in hepatocellular carcinoma, occurring in 20–50% of cases depending on the population and etiology. ### Frequency of Common Mutations | Mutation | Frequency | Clinical Significance | |----------|-----------|----------------------| | TP53 | 20–50% | Associated with poor prognosis, more common in HBV-related HCC | | CTNNB1 | 15–40% | Activates Wnt/β-catenin pathway; often mutually exclusive with TP53 | | PTEN | 5–15% | Loss leads to PI3K/AKT pathway activation | | RB1 | <5% | Rare in HCC; more common in other malignancies | **High-Yield:** TP53 mutations are particularly prevalent in HBV-related HCC, especially in regions with high HBV endemicity (East Asia, sub-Saharan Africa). The presence of TP53 mutations is associated with more aggressive tumors and worse overall survival. **Clinical Pearl:** CTNNB1 mutations, while common, are often associated with better differentiation and lower grade tumors compared to TP53-mutated HCCs. The two mutations are typically mutually exclusive, suggesting different pathogenic pathways. **Mnemonic:** **TP53 First** — Think "TP53 is the most Frequent" alteration in HCC. 
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