Hepatitis B virus integration site in hepatocellular carcinoma at chromosome 17;18 translocation.

Abstract

Integrated hepatitis B virus (HBV) DNA is almost invariably found in hepatocellular carcinomas (HCC) which develop in HBV carriers. Integrated HBV DNAs from two single-integration HCCs (C3 and C4) have been cloned, and the cellular integration sites have been analyzed. Integrated HBV DNA of C3 is present in chromosome 6 and contains a nearly complete linear HBV genome. The HBV DNA integration in tumor C3 was not associated with major rearrangements of cellular DNA. In contrast, the integrated HBV DNA in C4 contains a large inverted repeat of HBV DNA, in which each repeat consists of a linear HBV DNA segment similar to that present in C3. The C4 integration was also accompanied by a cellular DNA translocation at the HBV integration site. The translocation occurred between chromosomes 17 and 18, along with a deletion of at least 1. HCC (2,5,8). This is consistent with their potential action as tumor initiators (9). Hepadnaviruses so far have not been shown to contain a viral oncogene per se, nor has a common cellular integration site been identified in HCCs (7,(10)(11)(12). In addition, some human and woodchuck HCCs from carriers do not contain any integrated or free viral DNA (6, 7, 13). These findings raise the possibility that viral antigens are not required for the maintenance of HCC and may function only as tumor initiators. Additional studies are necessary to identify a unifying molecular mechanism to explain the strong epidemiological data linking chronic infection with HCC.Factors that stimulate the incidence of chromosome aberrations are associated with increased risk of neoplasia (9,14). In the case of chemical hepatocarcinogenesis in the mouse and rat, agents that damage DNA stimulate the occurrence of HCC (15-18). The ability of oncogenic viruses to damage DNA through integration and by increasing the mutation rate of cellular genes is probably an important factor in virusmediated multistage carcinogenesis (19). To investigate the possible role of HBV integrations in a general mechanism involving host DNA rearrangements, we have studied the structure of cellular DNA sequences at HBV integration sites. A previous study (20) reported a large deletion of cellular DNA at chromosome position 11p13 in association with an HBV integration. In this report we describe an HBV-induced translocation between chromosomes 17 and 18. We believe it is the first translocation to be directly linked to any viral DNA integration. The ability of HBV integrations to generate chromosome defects may be part of a multistep mechanism in the development of fully malignant HCC. METHODSPrimary HCCs were obtained from two HBV carriers at autopsy. The first tumor, C3, was obtained from a 62-year-old Japanese man and the second, C4, was obtained from a 37-year-old Japanese man. Both were HBsAg-positive, and both tumors had a trabecular phenotype.DNA was extracted from the tumors, and restriction endonuclease fragments containing integrated HBV DNA were identified by Southern blot analysis as previously reported (3). Tumors C3 ...

Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver.

“…Double transgenic mice carrying both the SAP-IFN-y gene and the HBV genome will be a useful mouse model of viral hepatitis, because the release of HBsAg by liver cell damage may enhance the immune response to viral antigen, leading to liver cell injury. On the other hand, it is shown that chromosomal changes linked to HBV DNA integration occur frequently in host DNA of human HCC (25,26). Furthermore, it was shown that HBV DNA has recombinogenic functions in the hepatitis-related proliferative state (27) and that DNA rearrangement is involved in hepatocarcinogenesis (28).…”

The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma.

“…Nineteen such structures, including unfinished ones (C6 and C1) that are too complex to analyze, are displayed in Figure 1. Because the major aim of this work is to obtain insights into general features of integrated HBV DNA, we also incorporated into the same figure 13 other reported cases (Dejean et al 1984;Koch et al 1984;Mizusawa et al 1985;Yaginuma et al 1985;Ziemer et al 1985;Hino et al 1986}.…”

“…Seven integrants have thus been studied and were assigned to chromosomes 3 (Dejean et al 1986), 6 (Hino et al 1986), 1 lp13-p14 (Rogler et al 1985), 11q22, 15q22-q23, 18q12 (Bowcock et al 1985, 17, and 18 (Hino et al 1986). Altogether, these results indicate that targets for HBV integration lie on at least 11 different chromosomes and suggest that HBV DNA does not show a strong preference for a particular chromosome for integration.…”

Genetic and expression analysis of the KCNRG gene in hepatocellular carcinomas

“…Despite of the fact that epidemiologic evidence indicates that the HBV is a major risk factor for the development of HCC (Robbins et al, 1994), the precise mechanisms of this association are unknown. The site of the cellular DNA at which the HBV integrates frequently undergoes rearrangement, resulting in a translocation, and deletion (Ogata et al,1990;Hino et al, 1996;Nakamura et al, 1998;Okabe et al, 2000). Furthermore, an allelic loss at 13q is significantly associated with an advanced tumor stage and a poor prognosis (Zondervan et al, 2000;Kusano et al, 2002;Wong et al, 2002).…”