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Molecular Pathology of Gastroenterological Cancer pp 219–243Cite as

Molecular Genetics of Hepatocellular Carcinoma

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Summary

The major exogenous agents underlying hepatocellular carcinoma have been identified and characterized in detail. These agents, which include hepatitis viruses and cirrhosis, function primarily as mitogens causing hepatocellular hyperplasia. Disorderly hepatocyte hyperplasia with concurrent mutagenesis may give rise to hepatocellular carcinoma. Little progress has been made in identifying either the somatic or germline mutations underlying the development of hepatocellular carcinoma. As such, the molecular genetics of hepatocellular carcinoma are not well understood. Hepatocyte mutagens include endogenous oxygen free radicals and H2O2, which may diffuse out of mitochondria and peroxisomes. Hepatocytes are also the location of cytochrome p450s, which catalase more than 60 different types of reaction concerned with the metabolism of steroids and fatty acids involved in hormone regulation and the metabolism of exogenous dietary-derived compounds. Hepatocyte microsomes are therefore the site of metabolic activation of many procarcinogens. Taken together, these reactions place the hepatocyte genome in a highly mutagenic environment. Hyperplasia greatly increases the rate at which mutations accumulate because the time for DNA repair is reduced, DNA replication has an intrinsic error, and cell division can result in rearrangements of the genome. However, no single tumor suppressor gene has been found to be preferentially inactivated or oncogene to be preferentially activated in hepatocellular carcinoma. The identified germline mutations predisposing to hepatocellular hyperplasia generally either increase hyperplasia (e.g., MHC) or the amount of endogenous mutagens produced in the hepatocyte (e.g., p450). Taken together, these data suggest that rather than being a genetic disease, hepatocellular carcinoma is a disease of a “chronically afflicted genome.”

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  1. Nuffield Department of Pathology and Bacteriology, John Radcliffe Hospital, Oxford University, Headington, Oxford, OX3 9DU, UK

    Christopher J. Bakkenist & James O’D. McGee

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  1. Faculty of Medicine, First Department of Pathology, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734, Japan

    Eiichi Tahara M.D., Ph.D. (Director, Professor and Chairman) (Director, Professor and Chairman)

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Bakkenist, C.J., McGee, J.O. (1997). Molecular Genetics of Hepatocellular Carcinoma. In: Tahara, E. (eds) Molecular Pathology of Gastroenterological Cancer. Springer, Tokyo. https://doi.org/10.1007/978-4-431-65915-0_16

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  • DOI: https://doi.org/10.1007/978-4-431-65915-0_16

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