{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T14:14:50Z","timestamp":1761920090756},"reference-count":53,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,1,18]],"date-time":"2016-01-18T00:00:00Z","timestamp":1453075200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P42 ES005948"],"award-info":[{"award-number":["P42 ES005948"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hepatocellular carcinoma (<jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>) is a prevalent human cancer with rising incidence worldwide. Human <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> 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 <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>, we used a human disease\u2010relevant mouse model of fibrosis\u2010associated hepatocarcinogenesis. In this model, marked liver tumor response caused by the promutagenic chemical <jats:italic>N<\/jats:italic>\u2010nitrosodiethylamine in the presence of liver fibrosis was associated with epigenetic events indicative of genomic instability. Therefore, we hypothesized that <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> copy number alterations (<jats:styled-content style=\"fixed-case\">CNA<\/jats:styled-content>s), a feature of genomic instability and a common characteristic of cancer, are concordant between human <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> and mouse models of fibrosis\u2010associated hepatocarcinogenesis. We evaluated <jats:styled-content style=\"fixed-case\">DNA CNA<\/jats:styled-content>s and changes in gene expression in the mouse liver (normal, tumor, and nontumor fibrotic tissues). Additionally, we compared our findings to <jats:styled-content style=\"fixed-case\">DNA CNA<\/jats:styled-content>s in human <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> cases (tumor and nontumor cirrhotic\/fibrotic tissues) using publicly available data from The Cancer Genome Atlas (<jats:styled-content style=\"fixed-case\">TCGA<\/jats:styled-content>). We observed that while fibrotic liver tissue is largely devoid of <jats:styled-content style=\"fixed-case\">DNA CNA<\/jats:styled-content>s, highly frequently occurring <jats:styled-content style=\"fixed-case\">DNA CNA<\/jats:styled-content>s are found in mouse tumors, which is indicative of a profound increase in chromosomal instability in <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>. The cross\u2010species gene\u2010level comparison of <jats:styled-content style=\"fixed-case\">CNA<\/jats:styled-content>s identified shared regions of <jats:styled-content style=\"fixed-case\">CNA<\/jats:styled-content>s between human fibrosis\u2010 and cirrhosis\u2010associated liver tumors and mouse fibrosis\u2010associated <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>. Our results suggest that <jats:styled-content style=\"fixed-case\">CNA<\/jats:styled-content>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 <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>.<\/jats:p>","DOI":"10.1002\/cam4.606","type":"journal-article","created":{"date-parts":[[2016,1,18]],"date-time":"2016-01-18T05:28:43Z","timestamp":1453094923000},"page":"574-585","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Characterization of copy number alterations in a mouse model of fibrosis\u2010associated hepatocellular carcinoma reveals concordance with human disease"],"prefix":"10.1002","volume":"5","author":[{"given":"Grace","family":"Chappell","sequence":"first","affiliation":[{"name":"Department of Veterinary Integrative Biosciences Texas A&amp;M University  College Station Texas 77843"},{"name":"Department of Environmental Sciences and Engineering University of North Carolina  Chapel Hill North Carolina 27599"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace O.","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Genetics University of North Carolina  Chapel Hill North Carolina 27599"},{"name":"Curriculum in Bioinformatics and Computational Biology University of North Carolina  Chapel Hill North Carolina 27599"},{"name":"Lineberger Comprehensive Cancer Center University of North Carolina  Chapel Hill North Carolina 27599"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeki","family":"Uehara","sequence":"additional","affiliation":[{"name":"Department of Environmental Sciences and Engineering University of North Carolina  Chapel Hill North Carolina 27599"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor P.","family":"Pogribny","sequence":"additional","affiliation":[{"name":"Division of Biochemical Toxicology National Center for Toxicological Research United States Food and Drug Administration  Jefferson Arkansas 72079"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Rusyn","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences Texas A&amp;M University  College Station Texas 77843"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,1,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-11-0643"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-2107"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1934"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.09.014"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-012-0931-2"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1590-8658(10)60511-7"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1247135"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61347-0"},{"key":"e_1_2_7_10_1","first-page":"4253","article-title":"Kinetics of diethylnitrosamine hepatocarcinogenesis in the infant mouse","volume":"43","author":"Vesselinovitch S. 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