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DNA integration sites and hepatocellular carcinoma

This study is part of an ongoing analysis of woodchuck hepatitis virus integration sites in the host genome of hepatocellular carcinomas. The study of woodchuck hepatitis virus‐DNA integration sites may shed light on the oncogenic mechanisms involved in cellular transformation and tumor formation. Viral integration enhancing cellular proto‐oncogene expression is one such mechanism and has been well documented for oncogenic retroviruses such as mouse mammary tumor virus and interleukin‐1. By cloning a woodchuck hepatitis virus integration site from a woodchuck hepatocellular carcinoma the authors were able to identify a new member of the myc gene family, N‐myc‐2. Examination of 30 additional woodchuck hepatomas revealed viral integration commonly occurred near N‐myc loci with an additional five woodchuck hepatitis virus integrants near the N‐myc‐2 gene and one viral integrant near N‐myc‐1. Three of these N‐myc‐2 viral integrations were further evaluated and found to be localized within 200 bp of the translation stop codon. This 3′ noncoding region has recently been identified as a common site of murine leukemia virus integration in virally induced T‐cell lymphomas and results in increased expression of the N‐myc gene. Similar mechanisms can be proposed for hepatocellular carcinoma formation. Woodchuck hepatitis virus integration near cell‐growth related protooncogenes, such as N‐myc, can juxtapose viral enhancer elements and growth‐regulatory genes. Virally induced overexpression of proto‐oncogene messenger RNA could result from enhanced transcription or increased messenger RNA stability. To search for such effects the authors analyzed N‐myc‐2 RNA levels in 30 woodchuck hepatitis virus‐related hepatomas. Increased levels of N‐myc‐2 RNA were found in 18 of 30 tumors, whereas nontumorous portions of the same livers had no detectable N‐myc‐2 RNA. Taken together these findings suggest that woodchuck hepatitis virus integration can result in altered N‐myc‐2 gene expression in a significant proportion of woodchuck hepatocellular carcinomas. The deregulation of N‐myc gene expression could result in cellular transformation and ultimately tumor formation. Such examples of hepadnavirus‐specific oncogenic mechanisms lend credence to theories of hepatitis B virus‐induced tumorigenesis and provide models to design molecular investigations of human hepatocellular carcinoma formation.