Functional Interpretation of Recurrent Genetic Variants in Hepatocellular Carcinoma: Molecular Consequences and Clinical Relevance.

Hepatocellular carcinoma (HCC) is characterized by substantial molecular heterogeneity shaped by recurrent genetic alterations. Large-scale genomic studies have defined the mutational landscape of HCC, but the biological interpretation and clinical utility of these variants remain incompletely established. Increasing evidence suggests that key driver alterations influence tumor behavior not only through direct pathway dysregulation but also through downstream transcriptional programs, epigenetic remodeling, proteomic changes, metabolic adaptation, and tumor-immune interactions. Therefore, variant interpretation in HCC requires a framework that extends beyond mutation frequency and integrates functional annotation, multiomics profiling, experimental validation, and clinical evidence. In this review, we summarize major recurrent genetic alterations in HCC, including variants affecting telomere maintenance, cell cycle control, WNT/β-catenin signaling, and chromatin remodeling. We then discuss how these alterations shape molecular phenotypes across transcriptomic, proteomic, metabolic, and immune layers. Particular attention is given to distinguishing well-supported variant-phenotype relationships from emerging or exploratory associations. We further evaluate the translational relevance of recurrent variants in diagnosis, prognosis, liquid biopsy, and therapeutic stratification while emphasizing that most variant-informed applications in HCC remain investigational rather than clinically validated. Finally, we discuss current challenges and future directions, including functional genomics, single-cell and spatial profiling, and prospective clinical validation. This review proposes a variant-centered interpretive framework for understanding how recurrent genetic alterations contribute to HCC biology and how they may inform future precision oncology strategies.