The molecular characteristics of DNA damage and repair related to P53 mutation for predicting the recurrence and immunotherapy response in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally, owing to its high recurrence rate of 50 to 70% within five years. Despite known associations of certain DNA damage and repair (DDR) genes with tumor recurrence and drug resistance, a comprehensive understanding of DDR pathways' role in predicting HCC recurrence and therapeutic responses remains elusive. Addressing this gap could offer significant advancements in prognostic and therapeutic strategies for HCC. This study used 769 RNA sequencing samples from public datasets and 53 samples from Xiangya Hospital for DDR model training and validation. It came out that DDR pathways were significantly enriched in samples with P53 mutations. Next, among the 173 combinations of algorithms and parameters, CoxBoost + RSF, Lasso [fold = 10] + RSF, and Lasso [fold = 50] + RSF demonstrated the best performance. The average AUC values of 1 to 5 years and the average concordance index (C-index) value were around 0.7. The risk scores were increased in tumors with recurrence, P53 mutation, and higher TNM stages. High-risk groups, characterized by enriched DDR pathways, exhibited lower CD8 + T cell infiltration and poorer responses to immunotherapy using atezolizumab and bevacizumab, emphasizing the potential of DDR signatures as valuable prognostic and therapeutic biomarkers. In conclusion, the DDR signatures associated with P53 mutations can predict recurrence and therapeutic response in HCC, highlighting their potential as prognostic and therapeutic biomarkers.