Molecular pathogenesis of hepatocellular carcinoma

Abstract

Hepatocarcinogenesis is a multistep process evolving from chronic liver diseases to hepatocellular carcinoma (HCC) and consists of progressive accumulation of molecular alterations pinpointing different molecular and cellular events. Recent advances in molecular methods have led to growing understanding of the underlying mechanisms of hepatocarcinogenesis. Chromosomal, genetic, and epigenetic abnormalities can lead to deregulation in many cell signaling pathways implicated in tumor proliferation, progression, and survival. Specific signaling cascades have consistently been found dysregulated in HCC. There is emerging evidence supporting the importance of cancer metabolism and tumor microenvironment in providing a favorable and supportive niche to expedite HCC development. Moreover, recent studies have identified distinct surface markers of cancer stem cell (CSC) in HCC. Significantly, the introduction of sophisticated genomics technologies has enhanced extensive research on its molecular pathogenesis. HCC has complicated and highly heterogeneous genomic, genetic and epigenetic profiles. Using different genomics analyses (whole genome, exome, and transcriptomic sequencing), recent remarkable advances have been made to provide comprehensive profiling data on mutational landscape. The molecular alterations in advanced HCCs are quite diverse. These mutations translate into different gene expression alterations as well as altered cell signaling pathways. Very recently, the cutting-edge technology of single cell analysis has provided important information of its intratumoral heterogeneity and is able to identify important sub-populations. Chronic HBV infection is a major etiological factor of HCC. HBV frequently integrates into the human genome, with TERT gene being the most frequent target of HBV integration in HBV-associated HCC. This presentation attempts to highlight the molecular mechanisms currently implicated in the pathogenesis of HCC. Dissection of hepatocarcinogenesis at multiple molecular levels potentially sheds light on alternative treatment options. Discoveries and insight into these complex pathways have created opportunities for targeted agents and new therapeutic approaches for this malignant disease. The ultimate goal of precision medicine is to utilize molecular information to assign patients to the most effective treatment.