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 single cell. However, the clonality of precancerous lesions and adjacent nonneoplastic tissues is not clear. We analyzed a human androgen receptor locus to elucidate the clonal state of liver tissues including post-hepatitic lesions associated with hepatocarcinogenesis. The analysis was based on a restriction fragment length polymorphism involving an androgen receptor locus on the X chromosome, taking advantage of physiologic random inactivation by methylation of 1 of 2 X chromosomes in females during embryogenesis. Clonality was assessed in 79 randomly located tissue samples microdissected from noncirrhotic 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 hepatocellular carcinomas were sampled. All samples were obtained from livers involved by various neoplasms. Eight of forty samples (20.0%) from the four normal livers and 20 of the 39 samples (51.3%) from the single HCV-infected liver 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.
Ochiai
T
T
Department of Surgery, Kyoto Prefectural Yosanoumi Hospital, Otokoyama, Iwataki-cho, Yosa-gun, Kyoto, Japan. tochiai@mxa.nkansai.ne.jp
Urata
Y
Y
Yamano
T
T
Yamagishi
H
H
Ashihara
T
T
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002999:Clone Cells; D004247:DNA / Q000032:analysis; D005260:Female; D006521:Hepatitis, Chronic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011944:Receptors, Androgen / Q000235:genetics; D014960:X Chromosome
D011944:Receptors, Androgen; D004247:DNA