Methylated cyclin D2 gene circulating in the blood as a prognosis predictor of hepatocellular carcinoma.
BACKGROUND
Prognosis of hepatocellular carcinoma (HCC) remains poor because of high recurrence rate. We examined preoperatively the methylated CCND2 gene levels present in the serum following release from HCC cells as a prognosis predictor in patients undergoing curative hepatectomy.


METHODS
Quantitative real-time RT-PCR and quantitative methylation-specific PCR were used to measure methylated CCND2 gene and its mRNA levels.


RESULTS
The CCND2 mRNA levels were down-regulated in HCC with early intrahepatic recurrence (IHR) within 1year of curative hepatectomy. We also identified that this down-regulation was due to promoter hypermethylation. In 70 HCC patients who underwent curative hepatectomy, 39 patients sero-positive for the methylated CCND2 gene (>70pg/ml serum) exhibited a significantly shorter disease-free survival (DFS) period (P=0.02) than the 31 patients who were sero-negative for the methylated CCND2 gene. None of the sero-negative patients demonstrated early IHR, and this method of serum testing did not produce any false-negative predictions for early IHR. Multivariate analysis showed that the serum level of methylated CCND2 was an independent risk factor for DFS (hazard ratio of 1.866, 95% CI: 1.106-3.149).


CONCLUSIONS
Methylated CCND2 gene in the serum serves as a prognosis predictor of HCC after curative hepatectomy.
Tsutsui
Masahito
M
Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Iizuka
Norio
N
Moribe
Toyoki
T
Miura
Toshiaki
T
Kimura
Naoki
N
Tamatsukuri
Shigeru
S
Ishitsuka
Hideo
H
Fujita
Yusuke
Y
Hamamoto
Yoshihiko
Y
Tsunedomi
Ryouichi
R
Iida
Michihisa
M
Tokuhisa
Yoshihiro
Y
Sakamoto
Kazuhiko
K
Tamesa
Takao
T
Sakaida
Isao
I
Oka
Masaaki
M
D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000175:diagnosis* / Q000235:genetics; D056742:Cyclin D2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood* / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008745:Methylation; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
D056742:Cyclin D2; D012333:RNA, Messenger