Clonal analysis of regenerative nodules in hepatitis C virus-induced liver cirrhosis

Abstract

Background/aims: Based on histological criteria, regenerative nodules in cirrhotic liver have been generally considered to result from hyperplastic proliferation of hepatocytes. Whether these nodules are hyperplastic or neoplastic has not been determined definitively. This study examined the issue by clonal analysis of each nodule.

Methods: The method for clonal analysis was based on restriction fragment length polymorphism of the X chromosome-linked phosphoglycerokinase gene and on random inactivation of the gene by methylation.

Results: Clonality of hepatocellular carcinoma (n = 7) and regenerative nodules (n = 76) induced by hepatitis C virus infection was analyzed. All carcinomas were monoclonal. Clonal analysis of regenerative nodules showed that 43% (33 of 76) were monoclonal in origin. Adjacent monoclonal nodules showed inactivation of the same allele of phosphoglycerokinase gene. Because the gene allele is inactivated at random, it is unlikely that each nodule happens to inactivate the same allele; it is more likely that monoclonal cell expansion is initiated before the nodule is established by septum formation.

Conclusions: Monoclonal cell expansion is seen in a considerable number of regenerative nodules in cirrhotic liver. The results indicate that certain genetic changes, which are required for hepatocarcinogenesis, have already occurred in these nodules.