Genetic Landscape of Multistep Hepatocarcinogenesis

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. As the complex genetic landscape of HCC is considered to compromise the antitumor efficacy of targeted therapy, genetic landscape of hepatocarcinogenesis is necessary to be understood in detail. Here, we summarize the landscape of the liver cancer genome and its intratumor heterogeneity. Recent insight on early genetic alterations in hepatocarcinogenesis, especially those in early HCC and noncancerous liver tissues are also introduced. Importantly recent studies demonstrated that noncancerous liver tissues already possess a variety of somatic mutations. Finally, we summarize recent findings on the multistep accumulation of genetic aberrations throughout liver cancer progression. These genetic aberrations have been used for subtyping of liver cancers, which can be applied for clinical practice in the future. 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.