Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and a leading cause of cancer-related deaths worldwide. Ninety percent of HCC cases arise from cirrhosis, during which liver cells undergo chronic cycles of necrosis and regeneration. The complex genomic landscape of HCC has been extensively investigated to draw correlations between recurrently mutated pathways and patient prognosis. However, our limited success with targeted therapy shows that knowing the presence of somatic mutations alone is insufficient for us to gauge the full spectrum of their functional consequences in the context of tumor evolution. In addition, the current molecular classification of HCC offers little information on the relationship between the molecular features and immunological properties of HCC tumors and their immune microenvironment. This review introduces current challenges and advancements made in HCC surveillance, diagnosis, and treatment. We also discuss the suite of HCC-associated genetic changes and describe recent studies that provide evidence for an evolving functional model and its implications for understanding and targeting HCC progression. Liver cancer: Call to explore evolving mutations within tumors Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide, but despite advances in understanding disease genetics, successful targeted therapies are limited. Eunsun Kim at Stanford University and Patrick Viatour at the University of Pennsylvania reviewed current HCC surveillance, diagnostics and treatments, focusing on genetic changes and their influence on disease progression. Novel methods for HCC diagnosis, including analysis of cancer-derived materials in blood, will complement existing diagnostics and help identify more early stage cases. Extensive studies of HCC tumor ecosystems will inform the development of novel immunotherapies. More studies involving genetic sequencing of mutations within tumors over time should further advance our understanding of HCC progression and help explain varying treatment responses.
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