Differences in molecular alterations of hepatocellular carcinoma between patients with a sustained virological response and those with hepatitis C virus infection.
OBJECTIVE
The mechanism of hepatocarcinogenesis remains unclear in patients in whom hepatitis C virus (HCV) disappears after interferon (IFN) therapy. We compared molecular alterations in hepatocellular carcinoma (HCC) between patients with a sustained virological response (SVR) to IFN and patients with HCV.


METHODS
The study group comprised 44 patients with HCV and 13 patients with SVR. One patient in the SVR group had two tumour nodules, both of which were examined. Mitochondrial DNA (mtDNA) mutations in displacement-loop lesions were directly sequenced. Mutation of the TP53 gene was examined by direct sequencing. The methylation status of p16, p15, p14, RB and PTEN genes was evaluated by a methylation-specific polymerase chain reaction.


RESULTS
The average number of mtDNA mutations was 4.2 in 44 HCCs with HCV and 2.0 in 14 HCCs with SVR (P=0.0021). mtDNA mutation was less frequently detected in HCCs from patients with SVR than in patients with HCV. TP53 mutations were detected in 12 (27%) of 44 HCCs with HCV and 2 (14%) of 14 SVR-HCCs. Hypermethylation of the p16, p15, p14, RB and PTEN promoters was, respectively, detected in 34, 13, 8, 12 and 11 of 44 HCCs from patients with HCV and 14, 0, 0, 2 and 2 of 14 HCCs from patients with SVR (P=0.049, 0.021, 0.085, 0.322 and 0.402). Hypermethylation of p16 was one of the most important alterations in SVR-HCC.


CONCLUSIONS
Molecular alterations in hepatocarcinogenesis of patients with SVR-HCC were different from those of patients with continuous HCV infection.
Hayashi
Takehiro
T
Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Tamori
Akihiro
A
Nishikawa
Manabu
M
Morikawa
Hiroyasu
H
Enomoto
Masaru
M
Sakaguchi
Hiroki
H
Habu
Daiki
D
Kawada
Norifumi
N
Kubo
Shoji
S
Nishiguchi
Shuhei
S
Shiomi
Susumu
S
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
D017931:DNA Primers; D004272:DNA, Mitochondrial; D007372:Interferons