Most hepatocellular carcinomas (HCCs) develop in a chronically injured liver, yet the extent to which this microenvironment promotes neoplastic transformation or influences selective pressures for genetic drivers of HCC remains unclear. We sought to determine the impact of hepatic injury in an established mouse model of HCC induced by Sleeping Beauty transposon mutagenesis. Chemically induced chronic liver injury dramatically increased tumor penetrance and significantly altered driver mutation profiles, likely reflecting distinct selective pressures. In addition to established human HCC genes and pathways, we identified several injury-associated candidates that represent promising loci for further study. Among them, we found that FIGN is overexpressed in human HCC and promotes hepatocyte invasion. We also validated Gli2's oncogenic potential in vivo, providing direct evidence that Hedgehog signaling can drive liver tumorigenesis in the context of chronic injury. Finally, we show that a subset of injury-associated candidate genes identifies two distinct classes of human HCCs. Further analysis of these two subclasses revealed significant trends among common molecular classification schemes of HCC. The genes and mechanisms identified here provide functional insights into the origin of HCC in a chronic liver damage environment. Conclusion: A chronically damaged liver microenvironment influences the genetic mechanisms that drive hepatocarcinogenesis. (Hepatology 2018;67:924–939).
Bibliographical noteFunding Information:
Supported by R01 CA132962 (National Cancer Institute) and P30 CA086862 (National Cancer Institute). D.A. Largaespada is an American Cancer Society Research Professor.
Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.29565/suppinfo. Supported by R01 CA132962 (National Cancer Institute) and P30 CA086862 (National Cancer Institute). D.A. Largaespada is an American Cancer Society Research Professor. Copyright VC 2017 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.29565 Potential conflict of interest: Dr. Largaespada consults for and received grants from Genentech. He owns stock in NeoClone Biotechnologies and Discovery Genomics. Dr. Linden consults for Bristol-Myers Squibb and received royalties from Cell Signaling Technology.
© 2017 by the American Association for the Study of Liver Diseases.