Integrative genomic analysis of mouse and human hepatocellular carcinoma

Michelle Dow, Rachel M. Pyke, Brian Y. Tsui, Ludmil B. Alexandrov, Hayato Nakagawa, Koji Taniguchi, Ekihiro Seki, Olivier Harismendy, Shabnam Shalapour, Michael Karin, Hannah Carter, Joan Font-Burgada

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among the most complex cancers. This complexity is paralleled by dozens of mouse models that generate histologically similar tumors but have not been systematically validated at the molecular level. Accurate models of the molecular pathogenesis of HCC are essential for biomedical progress; therefore we compared genomic and transcriptomic profiles of four separate mouse models [MUP transgenic, TAK1-knockout, carcinogen-driven diethylnitrosamine (DEN), and Stelic Animal Model (STAM)] with those of 987 HCC patients with distinct etiologies. These four models differed substantially in their mutational load, mutational signatures, affected genes and pathways, and transcriptomes. STAM tumors were most molecularly similar to human HCC, with frequent mutations in Ctnnb1, similar pathway alterations, and high transcriptomic similarity to high-grade, proliferative human tumors with poor prognosis. In contrast, TAK1 tumors better reflected the mutational signature of human HCC and were transcriptionally similar to low-grade human tumors. DEN tumors were least similar to human disease and almost universally carried the Braf V637E mutation, which is rarely found in human HCC. Immune analysis revealed that strain-specific MHC-I genotype can influence the molecular makeup of murine tumors. Thus, different mouse models of HCC recapitulate distinct aspects of HCC biology, and their use should be adapted to specific questions based on the molecular features provided here.

Original languageEnglish
Pages (from-to)E9879-E9888
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number42
DOIs
Publication statusPublished - 2018 Oct 16

Keywords

  • Cancer mutational landscapes
  • Comparative genomics
  • Hepatocellular carcinoma
  • Immune analysis
  • Mouse models

ASJC Scopus subject areas

  • General

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  • Cite this

    Dow, M., Pyke, R. M., Tsui, B. Y., Alexandrov, L. B., Nakagawa, H., Taniguchi, K., Seki, E., Harismendy, O., Shalapour, S., Karin, M., Carter, H., & Font-Burgada, J. (2018). Integrative genomic analysis of mouse and human hepatocellular carcinoma. Proceedings of the National Academy of Sciences of the United States of America, 115(42), E9879-E9888. https://doi.org/10.1073/pnas.1811029115