Genetics of Hepatocellular Carcinoma: Approaches to Explore Molecular Diversity

Hepatocellular carcinomas (HCCs) are highly heterogeneous malignancies with different risk factors, including alcohol abuse, chronic hepatitis B (HBV) and C (HCV) infection, fatty liver disease and other genetic disorders. Despite recent progress in HCC management, most are diagnosed at advanced stages, when therapeutic options are limited. Currently, multikinase inhibitors (sorafenib, lenvatinib, cabozantinib and regorafenib), human monoclonal antibodies (ramucirumab), and immune checkpoint inhibitors (nivolumab, pembrolizumab) are the only systemic therapies approved for the treatment of unresectable HCC (1). However, these drugs show low response rates and limited survival benefit of 2-3 months. Tumor heterogeneity, characterized by distinct molecular alterations in different sub-clones within each tumor or among tumors from different patients, contributes to drug resistance (2). Consequently, improved understanding of tumor heterogeneity and mechanisms of resistance to systemic treatments is required. Advances in next-generation sequencing have increased our understanding of the molecular complexity of HCC, delineating a molecular landscape which includes recurrent genetic alterations that drive tumor expansion, as well as inherited variants that increase HCC risk. This review provides an overview of the genetic changes during HCC development and progression, with a special focus on the role of the tumor heterogeneity. We also discuss the latest advances in the establishment of preclinical models to investigate the molecular diversity of HCC and their use for developing effective personalized therapies.