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

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:26778414", "kind": "science-record", "revision": 6, "content_hash": "sha256:fb278b2ac11ceb386240c1f4ae4ec5a33649a92e84e5313b16cae78ac87bcf2c", "created_at": "2026-11-01T15:40:15Z", "updated_at": "2026-11-01T21:20:23Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Characterization of copy number alterations in a mouse model of fibrosis-associated hepatocellular carcinoma reveals concordance with human disease.", "doi": "10.1002/cam4.606", "pmid": "26778414", "authors": ["Grace Chappell", "Grace O Silva", "Takeki Uehara", "Igor P Pogribny", "Ivan Rusyn"], "journal": "Cancer medicine", "year": 2016, "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.", "claims": [{"id": "claim-method", "statement": "To evaluate the significance of these findings relative to the expected outcome of a randomly chosen set of genes among all expressed transcripts (17,021), we conducted a permutation‐based analysis with the gene set sizes corresponding to the number of significantly down‐ and up‐regulated genes (2374 and 3063, respectively).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26778414", "locator": "sections[12] \"Gene expression analysis\" paragraph 4", "quote": "To evaluate the significance of these findings relative to the expected outcome of a randomly chosen set of genes among all expressed transcripts (17,021), we conducted a permutation‐based analysis with the gene set sizes corresponding to the number of significantly down‐ and up‐regulated genes (2374 and 3063, respectively)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "For the human copy number data, publically available circular binary segmented (CBS) 25 copy number data obtained from Affymetrix 6.0 SNP arrays were downloaded through The Cancer Genome Atlas (TCGA) data portal (https://tcga-data.nci.nih.gov/tcga/). The following inclusion criteria were applied to select the samples for the analysis: (1) a diagnosis of either cirrhosis or fibrosis as detailed in the pathology report of the patient and (2) available circular binary segmented copy number data for both a tumor and a nontumor liver specimen.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26778414", "locator": "sections[5] \"Normalization and segmentation of array data\" paragraph 3", "quote": "For the human copy number data, publically available circular binary segmented (CBS) 25 copy number data obtained from Affymetrix 6.0 SNP arrays were downloaded through The Cancer Genome Atlas (TCGA) data portal (https://tcga-data.nci.nih.gov/tcga/). The following inclusion criteria were applied to select the samples for the analysis: (1) a diagnosis of either cirrhosis or fibrosis as detailed in the pathology report of the patient and (2) available circular binary segmented copy number data for both a tumor and a nontumor liver specimen."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The paper reports that a cross-species, gene-level copy-number comparison using SWITCHplus identified shared CNA regions between human fibrosis- or cirrhosis-associated liver tumors and mouse fibrosis-associated HCC; human CNA data came from publicly available TCGA data, while mouse data came from the controlled in vivo experiment.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:26778414", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "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."}, {"asset": "source:pmid:26778414", "locator": "sections[6] \"Identification of group‐specific CNAs and species‐conserved CNAs\" paragraph 2", "quote": "SWITCHplus uses the identified copy number–altered segments from SWITCHdna and/or any other copy number change point detection tools, species‐specific genomic annotations, and categorical information (e.g., tissue type or disease state) to identify frequent CNAs that are significantly associated with a group (e.g., tumors) compared against all other samples (e.g., nontumor liver)."}, {"asset": "source:pmid:26778414", "locator": "sections[6] \"Identification of group‐specific CNAs and species‐conserved CNAs\" paragraph 2", "quote": "Conserved CNAs are identified by SWITCHplus using gene‐level copy number data and remapping of orthologous genes (i.e., mouse genes remapped in human genomic order) to highlight overlapping features (i.e., CNAs that occur at a high frequency and are altered in the same direction of copy number gain or loss)."}, {"asset": "source:pmid:26778414", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "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)."}, {"asset": "source:pmid:26778414", "locator": "sections[1] \"Introduction\" paragraph 6", "quote": "In this study, publicly available data from human HCC patients and data collected from a controlled in vivo mouse experiment were utilized in the analysis of CNAs."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "The paper reports that a cross-species, gene-level copy-number comparison using SWITCHplus identified shared CNA regions between human fibrosis- or cirrhosis-associated liver tumors and mouse fibrosis-associated HCC; human CNA data came from publicly available TCGA data, while mouse data came from the controlled in vivo experiment.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:26778414"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. 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