The development of hepatocellular carcinoma (HCC) is a serious and feared malignancy, which is increasing in prevalence in the United States. HCC is associated with chronic liver damage secondary to viral infection by Hepatitis B or C Viruses (HBV and HCV) and/or alcohol. Clearly it would be desirable to discover the genes and genetic pathways that lead to HCC progression. Biomarkers that could be used to detect HCC and to predict tumor progression (invasion/metastasis) are desperately needed in the clinical management of patients at high risk for HCC. Furthermore, little is known about germline alterations that could predispose some patients to HCC. All of these goals address the mission of the National Cancer Institute's plan to create a comprehensive human cancer genome atlas. While some insight has been gained in the somatic changes that can occur in HCC, it is likely that much remains to be learned. An unbiased screen for somatic mutations that could cause HCC or accelerate malignancy after initiation by liver damage could provide a list of candidate genes to examine for alterations in human HCC. The identification of HCC cancer genes, and the patterns in which these mutations occur in individual cases, will certainly guide future therapies. It is the main goal of this grant to model HCC using a novel system for random, Sleeping Beauty (SB) transposon-based, somatic insertional mutagenesis developed by Drs. Largaespada and Dupuy. Methods to induce HCC by transposition of SB transposon vectors in hepatocytes and their precursors will be used to find genes consistently mutated by transposon insertion with and without background liver cirrhosis. Candidate HCC genes will be tested for their ability to cause cancer by SB mediated gene transfer into recipient mice. Cancer HCC genes will also be analyzed in human HCC samples for alterations in silico using public and published databases. Relevance: This project seeks to define what genes, when altered in liver cells, cause hepatocellular carcinoma (HCC). It is critical to know what genes cause HCC so that effective therapies for this cancer can be developed. A mouse model of HCC will be created in which all the mutated genes that cause the HCC can be identified.

Public Health Relevance

This proposal describes work done in mice to understand how certain tumors of the liver, called hepatocellular carcinomas (HCC), develop. We will discover what genes, when damaged, can cause these tumors. This will help us decide how best to treat this dangerous forms of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Genetics Study Section (CG)
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Read-Connole, Elizabeth Lee
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University of Minnesota Twin Cities
Schools of Arts and Sciences
United States
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Riordan, Jesse D; Feddersen, Charlotte R; Tschida, Barbara R et al. (2018) Chronic liver injury alters driver mutation profiles in hepatocellular carcinoma in mice. Hepatology 67:924-939
Tschida, Barbara R; Temiz, Nuri A; Kuka, Timothy P et al. (2017) Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors. Cancer Res 77:6576-6588
Gibson-Corley, Katherine N; Rogers, Laura M; Goeken, Adam et al. (2014) Keratoacanthoma Pathobiology in Mouse Models. Diseases 2:106-119
Riordan, Jesse D; Drury, Luke J; Smith, Ryan P et al. (2014) Sequencing methods and datasets to improve functional interpretation of sleeping beauty mutagenesis screens. BMC Genomics 15:1150
Lim, Lionel; Balakrishnan, Asha; Huskey, Noelle et al. (2014) MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer. Hepatology 59:202-15
Rogers, Laura M; Olivier, Alicia K; Meyerholz, David K et al. (2013) Adaptive immunity does not strongly suppress spontaneous tumors in a Sleeping Beauty model of cancer. J Immunol 190:4393-9
DeZwaan-McCabe, Diane; Riordan, Jesse D; Arensdorf, Angela M et al. (2013) The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis. PLoS Genet 9:e1003937
Riordan, Jesse D; Keng, Vincent W; Tschida, Barbara R et al. (2013) Identification of rtl1, a retrotransposon-derived imprinted gene, as a novel driver of hepatocarcinogenesis. PLoS Genet 9:e1003441
Rahrmann, Eric P; Largaespada, David A (2013) Retrotransposons: a new and credible source of inherited and somatically acquired hepatocellular carcinoma mutations. J Hepatol 59:616-7
Moriarity, Branden S; Rahrmann, Eric P; Keng, Vincent W et al. (2013) Modular assembly of transposon integratable multigene vectors using RecWay assembly. Nucleic Acids Res 41:e92

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