Genetic alterations in hepatocellular carcinoma: An update

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.

Keywords: Chromosomal instability; Genetic alterations; Hepatocellular carcinoma; Signaling pathways; Somatic mutations.

Figure 1

The impact of genetic alterations on hepatocarcinogenesis. Genetic alterations in hepatocarcinogenesis are connected to underlying etiologies, such as HBV, HCV, dietary AFB1 exposure and alcohol intake. Genomic instability accumulates slowly in a limited number of genes during the early preneoplastic stage, such as the development of cirrhosis, and the accumulation of genetic and epigenetic alterations accelerates throughout the formation of preneoplastic lesions, such as LGDNs and HGDNs, and into the development HCC; HBV: Hepatitis B virus; HCV: Hepatitis C virus; AFB1: Aflatoxin B1; LGDN: Low grade dysplastic nodule; HGDN: High grade dysplastic nodule; HCC: Hepatocellular carcinoma; CIN: Chromosomal instability; MSI: Microsatellite instability; TERT: Telomerase reverse-transcriptase; ARID1A: AT-rich interactive domain-containing protein 1A; ARID2: AT-rich interactive domain-containing protein 2; NFE2L2 or NRF2: Nuclear factor erythroid-derived 2-like 2; KEAP1: Kelch-like ECH-associated protein 1; JAK1: Janus kinase 1; RPS6KA3: Ribosomal protein S6 kinase polypeptide 3.