Pathogenesis of hepatitis B virus-associated hepatocellular carcinoma.

Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) remains the most common form of HCC in large areas of Asia and Africa. It remains common even in some countries where hepatitis C virus (HCV)-associated HCC has become the predominant form, such as Japan. Integration of HBV in HCC DNA is found at random sites in the host genome in nearly all patients with HBV-associated HCC. It is not clear how often this integration results in insertional mutagenesis, but previously unknown growth regulating genes and cancer-associated genes have been found frequently near HBV integration sites in HCC in recent studies. In addition, HBV encodes a transactivating protein, the X protein, which could enable the randomly integrated HBV to alter the function of host genes that are not near the integration site. Mutations at two adjacent codons in HBV (1762(T)/1764(A) mutations) within the X gene are frequently found in HCC patients, and may play a role in the mutagenic or transactivational role of HBV in HCC. The presence of cirrhosis in most patients with HBV-associated HCC, and the presence of mutations in tumor suppressor genes in many, suggests that these are also factors in hepatocarcinogenesis. Few studies have examined the mutations of more than one gene in the same HCC patients. Fewstudies have evaluated the interactions between HBV mutations, host gene mutations, cirrhosis, and other potentially mutagenic stresses at the cellular level, with progression to HCC, and few studies have been conducted to determine whether these changes must accumulate in succession to lead to HCC. The recent availability of rapid sequencing methods and DNA microarray technologies has permitted expression profiling and permutation analysis of an array of genes to explore the pattern and succession of molecular changes leading to HBV-associated HCC. To date, these methods have been used to show patterns of molecular changes that differ in HBV-associated HCC (compared to HCV-associated HCC or to HCC in patients lacking either virus) and patterns that can predict survival (and hence may directly indicate different mechanisms of disease), and may soon make possible a universally accepted clinical classification scheme for HCC.