Genetic Landscape of Multistep Hepatocarcinogenesis

Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Although several targeted therapy agents are available for advanced HCC, their antitumor efficacy remains limited. As the complex genetic landscape of HCC would compromise the antitumor efficacy of targeted therapy, a deeper understanding of the genetic landscape of hepatocarcinogenesis is necessary. Recent comprehensive genetic analyses have revealed the driver genes of HCC, which accumulate during the multistage process of hepatocarcinogenesis, facilitating HCC genetic heterogeneity. In addition, as early genetic changes may represent key therapeutic targets, the genetic landscapes of early HCC and precancerous liver tissues have been characterized in recent years, in parallel with the advancement of next-generation sequencing analysis. In this review article, we first summarize the landscape of the liver cancer genome and its intratumor heterogeneity. We then introduce recent insight on early genetic alterations in hepatocarcinogenesis, especially those in early HCC and noncancerous liver tissues. Finally, we summarize the multistep accumulation of genetic aberrations throughout cancer progression and discuss the future perspective towards the clinical application of this genetic information.

Keywords: early HCC; genetic analysis; hepatocellular carcinoma; intratumor heterogenerity; liver cirrhosis; molecular targeted therapy; whole-genome sequencing.

Figure 1

Oncogenic pathways associated with hepatocarcinogenesis. The upper panel shows the major oncogenic pathways elucidated via comprehensive genome analysis projects. The lower heatmap indicates the genes which have been reported as putative liver cancer driver genes in at least two publications of ICGC/TCGA projects. The top row shows each publication, and the second row shows the number of liver cancer samples analyzed. The major pathways and representative cancer-related genes for each pathway are listed on the left. The mutation frequency of each gene (percentage of the cases with mutated genes among all cases analyzed in each cohort) is shown as a heatmap. WES: whole-exome sequencing; WGS: whole-genome sequencing.

Figure 2

Scheme of the multistep evolution of typical hepatocellular carcinoma (HCC) The upper scheme is a phylogenetic tree showing a scenario of the progression from a normal cell to an advanced HCC. Examples of trunk and branch mutations in addition to shared as well as unique mutations are shown by red arrows. The middle scheme depicts the evolutionary progression from parental cancer cell to dysplastic nodule (DN), early HCC, classical HCC, and, finally, metastatic HCC. Each colored dot indicates a tumor cell with a different mutational profile, and each nodule consists of various tumor cells with distinct genetic alterations, contributing to intratumoral heterogeneity. The red dots indicate progressive tumor cells. This scheme omits nonepithelial cells such as vessels and fibrotic tissues. The lower scheme describes the typical radiological change of liver nodules during multistep hepatocarcinogenesis via nodule-in-nodule HCC, shown in the early arterial phase of contrast-enhanced dynamic computed tomography (CT) imaging. The black areas indicate nodules described as hypovascular areas in the early arterial phase of dynamic CT, whereas white circles mark hypervascular nodules in the early arterial phase of dynamic CT.