The evolving role of TP53 mutation in hepatocellular carcinoma (HCC)

Hepatocellular carcinoma (HCC) is one of the most common cancer types globally, which is characteristically aggressive, with a poor prognosis and a high mortality rate. The pathways leading to the development and progression of this fatal disease have been studied at the macro and micromolecular levels, where the interplay of multiple factors has been observed in multistep processes. Invariably, all factors at some point trigger mutations in specific genes that contribute to the development and progression of hepatic tumors. Decades of research have demonstrated that, among all genetic variations, mutation in the TP53 gene is the most frequent phenomenon, attracting global interest in cancer research. Driven by certain external and internal factors, the mutation transforms TP53 into an active oncogene with both gain-of-function (GOF) and loss-of-function (LOF) properties, collectively exerting a robust carcinogenic effect. The key mechanisms involved in this process include the P53-MDM2 negative feedback loop, the CDK4/cyclin D1-PIN1-FBW7a-c-Myc axis, profound immune modulation, and the development of cancer stemness, collectively shaping tumor behavior. Given that patients with p53 mutations often present with advanced-stage, it is crucial to adopt mutation-centric subgroup stratification to achieve prognostic precision and therapeutic success. However, emerging techniques are facing significant challenges due to the diverse heterogeneity and immune modulation caused by the mutation, making it difficult to design an effective management scheme. In recent years, several strategies have shown promising results in preclinical and early clinical settings, and combining them with established frontline therapies or incorporating them into preventive measures may open new possibilities. Existing studies largely highlight the mutation from molecular and clinicopathological perspectives, rather than undertaking an inclusive examination and meaningful translation for prospective clinical advancement. This review attempts to fully capture the unfolding role of p53 mutations, primarily based on the literature from the last 10 years, and provides a comprehensive perspective on both mechanistic insights and translational aspects.