Progressive accumulation of molecular aberrations contributing to stepwise liver cancer development

Early hepatocellular carcinoma (HCC) originates from chronic liver disease and can develop into overt HCC. To identify sequential molecular alterations that occur during stepwise hepatocarcinogenesis, we compared 52 early and 108 overt HCC specimens by genome sequencing. The unique mutational signatures that predominantly contribute to early and overt HCCs were identified. Despite the common somatic mutations in WNT and p53/RB pathways in early and overt HCC, WNT-targets were up-regulated only in overt HCC with CTNNB1 mutation in accordance with demethylation of CpG islands. Similarly, activation of cell cycle genes downstream of p53/RB pathway was the late event of stepwise hepatocarcinogenesis. On the other hand, TERT was the most frequently up-regulated gene in early HCC, and this study first identified three TERT gene fusions (e.g. SLC12A7-TERT fusions). Taken together, besides the driver gene mutations, additional molecular events cooperatively contribute to transcriptional activation of downstream targets as HCC progressed.