The Role of Chronic Liver Diseases in the Emergence and Recurrence of Hepatocellular Carcinoma: An Omics Perspective

Abstract

Hepatocellular carcinoma (HCC) typically develops from a background of cirrhosis resulting from chronic inflammation. This inflammation is frequently associated with chronic liver diseases (CLD). The advent of next generation sequencing has enabled extensive analyses of molecular aberrations in HCC. However, less attention has been directed to the chronically inflamed background of the liver, prior to HCC emergence and during recurrence following surgery. Hepatocytes within chronically inflamed liver tissues present highly activated inflammatory signaling pathways and accumulation of a complex mutational landscape. In this altered environment, cells may transform in a stepwise manner toward tumorigenesis. Similarly, the chronically inflamed environment which persists after resection may impact the timing of HCC recurrence. Advances in research are allowing an extensive epigenomic, transcriptomic and proteomic characterization of CLD which define the emergence of HCC or its recurrence. The amount of data generated will enable the understanding of oncogenic mechanisms in HCC from the CLD perspective and provide the possibility to identify robust biomarkers or novel therapeutic targets for the treatment of primary and recurrent HCC. Importantly, biomarkers defined by the analysis of CLD tissue may permit the early detection or prevention of HCC emergence and recurrence. In this review, we compile the current omics based evidence of the contribution of CLD tissues to the emergence and recurrence of HCC.

Keywords: chronic liver disease; epigenetics; genomics; hepatocellular carcinoma; metabolomics; proteomics; transcriptomics.

Figure 1

Chronic liver inflammation predisposes potential genetic changes for selective clonal expansion during HCC development. Inflammation triggered by chronic liver diseases, such as fatty liver disease or hepatitis viral infections, can eventually develop into fibrosis which can subsequently lead to cirrhosis. In cirrhotic tissues, hepatocarcinogenesis is a multistep process whereby the repeated cycles of cell damage and hepatocyte regeneration may predispose the accumulation of various multi-omic changes. Therefore, this chronic inflammatory microenvironment sets up a scenario that promotes the hepatocytes with an advantageous mutational burden for clonal expansion and eventually selects for HCC lesions. Created with www.BioRender.com.

Figure 2

The multi-omic landscape of inflammation-induced liver injury during HCC emergence and recurrence. Most HCCs (>90%) arise on the background of chronic liver inflammation. Molecular alterations analyzed by omic profiling are detectable in the non-tumoral and CLD tissues of inflamed livers prior to HCC (emergence). Upon recurrence, certain genetic mutations or altered protein expression are associated with an increased risk of malignant transformation. Created with www.BioRender.com.