Hit-and-run mechanism of HBV-mediated progression to hepatocellular carcinoma.
OBJECTIVE
Hepatitis B virus is implicated in the development of hepatocellular caracinoma. No oncogenes have been identified within the viral genome. Furthermore, it frequently fragments after integration into the hepatocyte genome. Simultaneous investigations of hepatitis B virus integration patterns and genetic changes in precancerous tissues are important to understand the role played by hepatitis B virus integration in hepatocellular caracinoma.


METHODS
We used a combination approach of dual characterization of highly polymorphic loci and the change in hepatitis B virus-DNA integration pattern. Large regenerative nodules were dissected from 6 explanted hepatitis B virus infected cirrhotic livers. Nodules within each liver segment were schematically mapped and histopathologically analyzed. Genomic DNA from each nodule was analyzed for hepatitis B virus integration and the genetic stability of 12 microsatellite loci including D3S2321, D8S1022, D17S1159, D4S2281, D5S1/2, D16S675, D16S685, D16S490, D16S526, D16S673, D16S677 and D16S690.


RESULTS
Data from different liver segments revealed few viral integrations and average allele loss. The most exciting results came from a segment containing a set of clonally and spatially related nodules having similar histologic features, a progressive lineage of allele loss, HBV integration and loss of integration.


CONCLUSIONS
This model portrait, a scenario of genetic events that precede tumor formation where the acquisition and loss of hepatitis B virus integrations in clonally related regenerative nodules, might explain how the virus acts as a hit-and-run mutagen.
Hessein
Mohamed
M
Marion Bessin Liver Research Center, Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA. M-hessien-M@maktoob.com
Saad
El Gendy
el G
Mohamed
Attallah A
AA
Kamel
El Awaday M
el AM
Abdel Hady
A M
AM
Amina
Medhat
M
Rogler
Charles E
CE
D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000503:physiopathology* / Q000821:virology*; D002471:Cell Transformation, Neoplastic; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D006509:Hepatitis B / Q000150:complications*; D006515:Hepatitis B virus / Q000472:pathogenicity*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000503:physiopathology* / Q000821:virology*; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D016296:Mutagenesis; D011110:Polymorphism, Genetic; D014407:Tumor Cells, Cultured; D016662:Virus Integration
D004279:DNA, Viral