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.