Genomic profiling in hepatocellular carcinoma: a real-world retrospective analysis

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with limited molecular characterization due to reliance on radiological diagnosis. This study aims to characterize the genomic landscape of advanced HCC and assess the prognostic and predictive roles of genetic alterations (GAs). Patients and methods: This study used a de-identified nationwide (USA-based) HCC clinico-genomic database to retrospectively analyze patients with advanced HCC who received systemic therapies and underwent comprehensive genomic profiling via tissue or liquid biopsy. GAs were identified using Foundation Medicine, Inc.'s next-generation sequencing tests. Time to progression (TTP) was assessed using Kaplan-Meier analysis and Cox proportional hazards models. Results: In total, 370 patients were analyzed. The most frequent GAs in the tissue cohort (n = 291) involved TERT promoter (TERTp, 61.5%), CTNNB1 (34.0%), and TP53 (33.0%). Key affected pathways were cell cycle and apoptosis (56%), DNA damage and control (43%), WNT (40.9%), and p53 (38.1%). Viral etiology was significantly associated with alterations in TERTp, CTNNB1, and the WNT pathway, while non-viral HCC was associated with alterations in the RTK/RAS pathway. TTP analysis revealed a trend toward improved outcomes with atezolizumab + bevacizumab (A + B) compared with tyrosine kinase inhibitors. TP53, p.V157F, and p.R249S mutations were associated with significantly shorter TTP. MYC seemed to be a negative predictor for A + B versus tyrosine kinase inhibitors, but statistical significance was not reached. Conclusions: This study highlights the genomic landscape of advanced HCC, identifying cell cycle and apoptosis, DNA damage and control, WNT, and p53 as the key affected pathways. Further research is warranted to confirm such findings.