Hepadnaviruses share properties of virion structure, genome structure and replication, epidemiologic behavior, and pathogenic effects, including an association with hepatocellular carcinoma (HCC). Epidemiologic evidence implicating hepadnavirus infection in HCC includes the observation that the geographic distributions of HBV infection and HCC are similar, that the incidence of HCC is much higher in hepadnavirus infected than uninfected hosts, and that viral DNA sequences are integrated in the cellular DNA of most (e.g., 80-90%) but not all hepadnavirus-associated HCC. Cirrhosis further increases the risk of HCC in HBV infected humans. The precise role of hepadnaviruses in development of most HCC is unclear, although the finding of viral integrations within or near protooncogenes in a few cases suggests the possibility that these integrations may play a direct role in these HCC. However, in the great majority of HCC associated with HBV infections, viral integrations are in different cellular DNA sites in different HCC, integrations are not within domains of known protooncogenes, and integrations are not found in some 10-15% hepadnavirus-associated HCC, suggesting that persisting viral sequences are not directly involved in the development of these HCC as viral sequences are for tumors caused by viruses with oncogenes or viruses that act by a "promoter-insertion" mechanism. It is possible, however, that oncogenic mutations could arise via other mutagenic mechanism that may operate in chronic hepatitis B and/or cirrhosis and which do not involve persisting viral integrations. For example, liver regeneration, which is a feature of the cirrhosis associated with chronic HBV infection (and sometimes with chronic hepatitis B) involves proliferation of many cells with HBV integrations, and such integrations have been shown to be unstable and may lead to mutations through post-integration rearrangements of cellular sequences at sites of viral integrations. Viral sequences appear to be lost or deleted at some such sites of rearranged cell DNA. Chronic HBV infection shares pathologic features of liver cell injury and reactive inflammation, liver regeneration, and in man sometimes cirrhosis with other important risk factors for HCC including chronic alcoholic liver disease, chronic non-A, non-B hepatitis, hemochromatosis, and crypogenic cirrhosis, suggesting that this common pathologic process may be carcinogenic by a mechanism that does not depend specifically on the factor which initiates liver cell injury. The pathogenetic role of chronic hepadnavirus infection in such a process would be in causing liver cell injury with reactive inflammation and hepatocyte proliferation (regeneration).(ABSTRACT TRUNCATED AT 400 WORDS)