The Mutational and Transcriptional Landscapes of Hepatocarcinogenesis in a Rat Model

Zhiao Chen; Shengli Li; Mengting Shen; Xinyuan Lu; Chunyang Bao; Di Chen; Jie Ding; Qifeng Wang; Shenglin Huang; Wenming Cong; Leng Han; Xianghuo He

doi:10.1016/j.isci.2020.101690

The Mutational and Transcriptional Landscapes of Hepatocarcinogenesis in a Rat Model

iScience. 2020 Oct 15;23(11):101690. doi: 10.1016/j.isci.2020.101690. eCollection 2020 Nov 20.

Authors

Zhiao Chen¹, Shengli Li^{2

3}, Mengting Shen¹, Xinyuan Lu⁴, Chunyang Bao¹, Di Chen¹, Jie Ding¹, Qifeng Wang¹, Shenglin Huang¹, Wenming Cong⁴, Leng Han², Xianghuo He^{1

5}

Affiliations

¹ Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
² Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
³ Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
⁴ Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
⁵ Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.

Abstract

Hepatocellular 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.

Keywords: Cancer; Cancer Systems Biology; Genomics; Transcriptomics.