Characterization of copy number alterations in a mouse model of fibrosis‐associated hepatocellular carcinoma reveals concordance with human disease

Hepatocellular carcinoma ( HCC ) is a prevalent human cancer with rising incidence worldwide. Human HCC is frequently associated with chronic liver inflammation and cirrhosis, pathophysiological processes that are a consequence of chronic viral infection, disturbances in metabolism, or exposure to chemical toxicants. To better characterize the pathogenesis of HCC , we used a human disease‐relevant mouse model of fibrosis‐associated hepatocarcinogenesis. In this model, marked liver tumor response caused by the promutagenic chemical N ‐nitrosodiethylamine in the presence of liver fibrosis was associated with epigenetic events indicative of genomic instability. Therefore, we hypothesized that DNA copy number alterations ( CNA s), a feature of genomic instability and a common characteristic of cancer, are concordant between human HCC and mouse models of fibrosis‐associated hepatocarcinogenesis. We evaluated DNA CNA s and changes in gene expression in the mouse liver (normal, tumor, and nontumor fibrotic tissues). Additionally, we compared our findings to DNA CNA s in human HCC cases (tumor and nontumor cirrhotic/fibrotic tissues) using publicly available data from The Cancer Genome Atlas ( TCGA ). We observed that while fibrotic liver tissue is largely devoid of DNA CNA s, highly frequently occurring DNA CNA s are found in mouse tumors, which is indicative of a profound increase in chromosomal instability in HCC . The cross‐species gene‐level comparison of CNA s identified shared regions of CNA s between human fibrosis‐ and cirrhosis‐associated liver tumors and mouse fibrosis‐associated HCC . Our results suggest that CNA s most commonly arise in neoplastic tissue rather than in fibrotic or cirrhotic liver, and demonstrate the utility of this mouse model in replicating the molecular features of human HCC .