Abstract
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 (CNAs), 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 CNAs and changes in gene expression in the mouse liver (normal, tumor, and nontumor fibrotic tissues). Additionally, we compared our findings to DNA CNAs 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 CNAs, highly frequently occurring DNA CNAs are found in mouse tumors, which is indicative of a profound increase in chromosomal instability in HCC. The cross‐species gene‐level comparison of CNAs identified shared regions of CNAs between human fibrosis‐ and cirrhosis‐associated liver tumors and mouse fibrosis‐associated HCC. Our results suggest that CNAs 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.
Highlights
Hepatocellular carcinoma (HCC) is a prevalent and life- threatening human cancer [1]
We found that epigenetic alterations indicative of genomic instability were prevalent in both tumors and nontumor fibrotic tissues of mice treated with DEN+CCl4 compared with liver tissue of vehicle-treated control animals [12]
Of the chromosomal gains and losses found in our analysis, many are known to be frequent in HCC, such as loss of 1p, 8p, and 17p and gain of 1q, 6p, 8q, and 20q [30]; we show that these effects are independent of whether HCC arises in the background of fibrosis or cirrhosis
Summary
Hepatocellular carcinoma (HCC) is a prevalent and life- threatening human cancer [1]. The incidence of HCC continues to increase, while the incidence and death rates of many other cancers are steadily declining [1, 2]. The majority (70–90%) of HCC cases are concomitant with advanced liver fibrosis or cirrhosis [3]. The incidence of HCC in noncirrhotic liver is estimated to be approximately 15–20% of all HCC cases, and only 10–12% in healthy livers. Liver fibrosis and cirrhosis associated with HCC are typically the consequence of toxic insults, disturbances in metabolism, and/or viral infection [4]. Copy Number Alterations in Human and Mouse HCC
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