Clonal expansion in evolution of chronic hepatitis to hepatocellular carcinoma as seen at an X-chromosome locus

Clonal analysis has shown that hepatocellular carcinoma arises from a singl e cell. However, the clonality of precancerous lesions and adjacent nonneop lastic tissues is not clear. We analyzed a human androgen receptor locus to elucidate the clonal state of liver tissues including post-hepatitic lesio ns associated with hepatocarcinogenesis, The analysis was based on a restri ction fragment length polymorphism involving an androgen receptor locus on the X chromosome, taking advantage of physiologic random inactivation by me thylation of 1 of 2 X chromosomes in females during embryogenesis. Clonalit y was assessed in 79 randomly located tissue samples microdissected from no ncirrhotic liver, including a total of 40 morphologically normal sites in 4 normal livers and 39 sites from a single HCV-infected liver. In addition, 51 regenerative nodules, 4 areas of adenomatous hyperplasia, and 18 hepatoc ellular carcinomas were sampled. All samples were obtained from livers invo lved by various neoplasms, Eight of forty samples (20.0%) from the four nor mal livers and 20 of the 39 samples (51.3%) from the single HCV-infected li ver showed a monoclonal pattern. Moreover,: 30 of 51 regenerative nodules ( 58.9%) showed a monoclonal pattern. No histologic differences were evident between mono- and polyclonal nodules, On the other hand, the 18 carcinomas and 4 areas of adenomatous hyperplasia all were monoclonal, Mean calculated monoclonal areas of normal liver and liver with chronic hepatitis were 1.1 and 3.3 mm(2), Our results suggest that areas representing a single clone of hepatocytes are present in normal liver, and these progressively expand as changes advance from chronic hepatitis to hepatocellular carcinoma.