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Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4262-7. Epub 2004 Mar 3.

Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes.

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  • 1Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.

Abstract

Hepatitis C virus (HCV) is a nonretroviral oncogenic RNA virus, which is frequently associated with hepatocellular carcinoma (HCC) and B cell lymphoma. We demonstrated here that acute and chronic HCV infection caused a 5- to 10-fold increase in mutation frequency in Ig heavy chain, BCL-6, p53, and beta-catenin genes of in vitro HCV-infected B cell lines and HCV-associated peripheral blood mononuclear cells, lymphomas, and HCCs. The nucleotide-substitution pattern of p53 and beta-catenin was different from that of Ig heavy chain in HCV-infected cells, suggesting two different mechanisms of mutation. In addition, the mutated protooncogenes were amplified in HCV-associated lymphomas and HCCs, but not in lymphomas of nonviral origin or HBV-associated HCC. HCV induced error-prone DNA polymerase zeta, polymerase iota, and activation-induced cytidine deaminase, which together, contributed to the enhancement of mutation frequency, as demonstrated by the RNA interference experiments. These results indicate that HCV induces a mutator phenotype and may transform cells by a hit-and-run mechanism. This finding provides a mechanism of oncogenesis for an RNA virus.

PMID:
14999097
[PubMed - indexed for MEDLINE]
PMCID:
PMC384729
Free PMC Article
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