Hepatitis B virus DNA integration in hepatocellular carcinoma after interferon-induced disappearance of hepatitis C virus.
OBJECTIVE
Hepatocellular carcinoma (HCC) has been reported in patients in whom hepatitis C virus (HCV) was eliminated by interferon (IFN) therapy. We examined the pathogenesis of HCC in patients with sustained viral response.


METHODS
Operable HCC developed in 7 of 342 patients cured of HCV infection by IFN monotherapy. No patient abused alcohol or had diabetes mellitus or obesity. Resected specimens of HCC were histologically evaluated. DNA extracted from HCC was examined by polymerase chain reaction (PCR) to locate hepatitis B virus (HBV) DNA. HBV integration sites in human genome were identified by cassette-ligation-mediated PCR.


RESULTS
HBV DNA was not amplified in serum samples from any of the seven patients with HCC and was found in liver in four patients. In the latter four patients, HBV DNA was integrated into the human genome of HCC. In two of these patients, covalently closed circular HBV (cccHBV) was also detected. The patients with HBV DNA integration were free of HCV for more than 3 yr. In two of the three patients without HBV DNA integration, the surrounding liver showed cirrhosis. The liver of HCC with HBV DNA integration had not progressed to cirrhosis. Three of the four tumors with HBV integration had one integration site each, located at chromosomes 11q12, 11q22-23, and 22q11, respectively. The other tumor had two integration sites, situated at chromosomes 11q13 and 14q32. At chromosome 11q12, HBV DNA was integrated into protein-coding genome, the function of which remains unclear.


CONCLUSIONS
Integrated HBV DNA may play a role in hepatocarcinogenesis after the clearance of HCV by IFN treatment.
Tamori
Akihiro
A
Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Nishiguchi
Shuhei
S
Shiomi
Susumu
S
Hayashi
Takehiro
T
Kobayashi
Sawako
S
Habu
Daiki
D
Takeda
Tadashi
T
Seki
Shuichi
S
Hirohashi
Kazuhiro
K
Tanaka
Hiromu
H
Kubo
Shoji
S
D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D004279:DNA, Viral / Q000032:analysis*; D016174:Hepacivirus / Q000302:isolation & purification*; D006509:Hepatitis B / Q000150:complications / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D008099:Liver / Q000821:virology; D008113:Liver Neoplasms / Q000821:virology*; D008297:Male; D008875:Middle Aged; D016662:Virus Integration
D000998:Antiviral Agents; D004279:DNA, Viral; D007372:Interferons