The Coding and Non-Coding Genomic Landscape of Hepatocellular Carcinoma: Etiological Risk Factors and their Current Clinical Implications

Abstract

Hepatocellular carcinoma (HCC) is the most common liver malignancy and a leading cause of cancer mortality, with burden projected to rise substantially by 2040. Its poor prognosis reflects the timing of diagnosis: HCC develops silently against chronic liver disease, and six-monthly ultrasound with alpha-fetoprotein remains insensitive in the early stages. Two developments have reshaped molecular understanding of this heterogeneous cancer. Large-scale sequencing established that the somatic landscape is not etiology-agnostic. The driver hierarchy is dominated by TERT, TP53, and CTNNB1; exposure-specific mutational signatures; and structural events such as hepatitis B virus integration, all of which differ systematically by upstream cause. In parallel, a dense non-coding regulatory layer has been shown to intersect with the core processes of hepatocarcinogenesis. These layers have largely been reviewed in isolation. Here, we integrate them, organize the coding and non-coding genomic architecture of HCC by etiological risk factor, and appraise the contributions of each to clinical decision-making. Etiological patterning is asymmetric – well-established at the coding layer but not yet demonstrated at the non-coding layer, where assignments derive from single-etiology cohorts compared across studies, platforms, and normalization strategies. Cutting across both layers are convergent nodes shared by all causes, most clearly depletion of the hepatoprotective microRNA-122, a marker of convergence rather than specificity. We then assess the clinical interface: multi-analyte serum scores and methylation-based cell-free DNA now outperform ultrasound for early detection in prospective cohorts, yet none is guideline-endorsed, and no circulating non-coding RNA has reached prospective validation. The near-term clinical yield of this field lies in risk stratification, not molecularly guided therapy.