Tumor Mutational Burden as a Prognostic Biomarker for Relapse-Free Survival in Hepatocellular Carcinoma: Insights...

Hepatocellular carcinoma (HCC) has a high recurrence rate even after curative resection. Although the tumor mutational burden (TMB) has emerged as a potential biomarker for survival outcomes in HCC, its clinical significance remains unclear.

A retrospective analysis of 204 patients who underwent an initial liver resection was performed. Patients were classified into TMB-high (≥4.8 mutations/Mb) or TMB-low groups based on whole-exome sequencing. We assessed relapse-free survival (RFS), overall survival (OS), and performed subgroup analyses focusing on patients without recurrence within the first two postoperative years. Gene expression profiling and mutational signature analyses were also conducted.

Patients with TMB-high tumors showed significantly shorter RFS compared to the TMB-low group (median 24.2 vs. 37.1 months; p = 0.008), whereas OS was not significantly different. Multivariate analysis identified TMB-high status as an independent prognostic factor for RFS (hazard ratio [HR], 1.72; p = 0.011). In the subgroup without early recurrence, TMB-high status was the only independent factor associated with late recurrence (HR, 2.45; p = 0.005). TMB-high tumors correlated with advanced liver fibrosis and specific somatic mutations (CTNNB1, TTN, MUC16). Additionally, mutational signatures associated with chronic inflammation and alcohol consumption were enriched in the TMB-high group.

High TMB is associated with shorter RFS in HCC, particularly among patients with long-term follow-up, indicating an increased risk for multicentric recurrence. TMB may serve as a valuable prognostic biomarker for recurrence risk stratification. The associations between TMB, liver fibrosis, and inflammation suggest potential therapeutic strategies targeting the hepatic microenvironment to reduce recurrence risk in patients undergoing liver resection for HCC.