摘要：SummaryHepatocellular carcinoma (HCC) initiation is characterized by stepwise accumulation of molecular alterations, during which the early events are largely unknown. Here, we presented a comprehensive genomic and transcriptomic landscape at stages of hepatitis, cirrhosis, and HCC by using a diethylnitrosamine-induced rat HCC model. We observed the early occurrence of gene instability and aberrant cancer associated signaling pathways in liver hepatitis. We further characterized the progressive molecular changes during hepatocarcinogenesis, wherein the intense rivalry between tumor-suppressive and oncogenic strengths occurred in cirrhosis stage. Despite the significant pathological difference, mutation signatures and expression landscape are highly similar between hepatitis and cirrhosis stages. Furthermore, we identified PI3K-Akt signaling pathway as a key pathway in the process of hepatocarcinogenesis through integrative analysis, and PIK3CD is a potential biomarker indicating HCC recurrence. The dynamic immune response during hepatocarcinogenesis, such as continuous decline of monocytes, suggests an immunological intervention strategy beyond chemoprevention for liver cancer.Graphical AbstractDisplay OmittedHighlights•Genome instability and cancer-related signaling aberrance occurred in liver hepatitis•The rivalry between tumor-suppressive and oncogenic strengths peaked in liver cirrhosis•PI3K-Akt plays a key role in the process of hepatocarcinogenesis•Hepatocarcinogenesis witnessed dynamic changes of monocytes and natural killer cellsGenomics; Cancer Systems Biology; Cancer; Transcriptomics
