CTNNB1 mutations and β-catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1

Authors

  • Theodora R. Devereux,

    Corresponding author
    1. Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
    • MD D4-04, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709.
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  • Mariana C. Stern,

    1. Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
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  • Gordon P. Flake,

    1. Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
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  • Mimi C. Yu,

    1. Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, California
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  • Zhen-Quan Zhang,

    1. Cancer Insitute of Guangxi, Nanning, Guangxi, People's Republic of China
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  • Stephanie J. London,

    1. Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
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  • Jack A. Taylor

    1. Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
    2. Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
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  • This article is a US Government work and, as such, is in the public domain in the United States of America.

Abstract

β-Catenin plays a key role in the Wnt signaling pathway, and mutations of CTNNB1, the gene that encodes β-catenin, have been identified in about one-fourth of human hepatocellular carcinomas from regions of low aflatoxin B1 exposure. In this study 62 hepatocellular carcinomas (HCCs) from people highly exposed to aflatoxin B1 in Guangxi, People's Republic of China, were laser-capture microdissected and examined for CTNNB1 mutations. In addition, 41 of the HCCs were evaluated for the presence of the β-catenin protein by immunohistochemical methods. Twenty of the HCCs showed positive results for β-catenin, with strong membrane staining, while adjacent non-neoplastic liver tissue lacked or showed only weak membrane staining. One HCC, in which a CTNNB1 mutation was not detected, showed nuclear staining for the β-catenin protein. Mutations of CTNNB1 were identified in five HCCs. These consisted of four point mutations in the glycogen serine kinase-3β phosphorylation region of codons 32–45 and one deletion of codons 32–38. These mutations were similar to those previously reported for human HCC, although at a lower frequency. A signature mutation profile associated with aflatoxin B1 exposure could not be identified. The immunohistochemical findings indicate a role for accumulation of β-catenin and possibly increased Wnt signaling in aflatoxin B1–associated HCC. The low frequency of CTNNB1 mutations, however, suggests that mutation of another Wnt signaling component, such as the Wnt scaffolding protein axin or the adenomatous polyposis coli protein, both of which modulate β-catenin stability, also may be involved in aflatoxin-associated HCC. Published 2001 Wiley-Liss, Inc.

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