Decoding Genomic Diversity to Guide Tumor Lesion‐Specific Treatment of Multifocal Hepatocellular Carcinoma

Abstract

ABSTRACT

Background

Hepatocellular carcinoma (HCC) is a primary liver cancer often associated with chronic liver disease and characterized by multifocal tumor lesions with synchronous and metachronous lesions, which poses treatment challenges due to potential genomic heterogeneity. This study aims to assess the consistency of actionable mutation profiles across synchronous and metachronous lesions in HCC patients.

Methods

This study analyzed 68 patients with multifocal HCC, including 193 tumor lesions (82 synchronous, 111 metachronous). Genomic profiling of 72 HCC‐related genes was performed using next‐generation sequencing. We collected clinical and pathological data, including tumor size, grade, fibrosis, and etiology. Patients were categorized into two groups based on the consistency of actionable mutations among multifocal HCC. Statistical analyses compared clinicopathological features between these groups.

Results

A total of 252 and 445 somatic mutations were identified in synchronous and metachronous tumors, respectively. Synchronous tumors had an average of 3.1 somatic mutations and 0.7 actionable mutations per lesion. Metachronous tumors had 4.0 somatic mutations and 1.0 actionable mutations per lesion. Actionable variants were found in 12 (36.4%) of 33 patients and 20 (24.4%) of 82 nodules in the synchronous tumors, and 23 (65.7%) of 35 patients and 42 (37.8%) of 111 nodules in the metachronous tumors. Compared to synchronous tumors, metachronous tumors exhibited significantly aberrant signaling pathways including the Wnt/β‐catenin (p = 0.009) and KEAP1/NRF2 (p = 0.022) pathways. There was no correlation with significant clinical differences in tumor characteristics between the consistent and divergent actionable mutation groups. Notably, divergent actionable mutations were identified in 45.6% of patients, which may be beneficial for changing potential therapies for individual tumors.

Conclusion

The study shows substantial inter‐tumoral heterogeneity in multifocal HCC, indicating the necessity for comprehensive molecular profiling for tailored treatment strategies. Divergent actionable mutations across lesions suggest that a uniform treatment approach may not be effective in some patients with multifocal HCC.