MT1M and MT1G promoter methylation as biomarkers for hepatocellular carcinoma.
OBJECTIVE
To investigate the potential of promoter methylation of two tumor suppressor genes (TSGs) as biomarkers for hepatocellular carcinoma (HCC).


METHODS
A total of 189 subjects were included in this retrospective cohort, which contained 121 HCC patients without any history of curative treatment, 37 patients with chronic hepatitis B (CHB), and 31 normal controls (NCs). DNA samples were extracted from 400 μL of serum of each subject and then modified using bisulfite treatment. Methylation of the promoters of the TSGs (metallothionein 1M, MT1M; and metallothionein 1G, MT1G) was determined using methylation-specific polymerase chain reaction. The diagnostic value of combined MT1M and MT1G promoter methylation was evaluated using the area under the receiver operating characteristic curves.


RESULTS
Our results indicated that the methylation status of serum MT1M (48.8%, 59/121) and MT1G (70.2%, 85/121) promoters in the HCC group was significantly higher than that in the CHB group (MT1M 5.4%, 2/37, P < 0.001; MT1G 16.2%, 6/37, P < 0.001) and NC group (MT1M 6.5%, 2/31, P < 0.001; MT1G 12.9%, 4/27, P < 0.001). Aberrant serum MT1M promoter methylation gave higher specificity to discriminate HCC from CHB (94.6%) and NCs (93.5%), whereas combined methylation of serum MT1M and MT1G promoters showed higher diagnostic sensitivity (90.9%), suggesting that they are potential markers for noninvasive detection of HCC. Furthermore, MT1M promoter methylation was positively correlated with tumor size (rs = 0.321, P < 0.001), and HCC patients with both MT1M and MT1G promoter methylation tended to show a higher incidence of vascular invasion or metastasis (P = 0.018).


CONCLUSIONS
MT1M and MT1G promoter methylation may be used as serum biomarkers for noninvasive detection of HCC.
Xiang-Fen Ji, Shuai Gao, Yang Yang, Jian-Jun Zhang, Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
Xiang-Fen
XF
Ji
Xiang-Fen Ji, Shuai Gao, Yang Yang, Jian-Jun Zhang, Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
Yu-Chen
YC
Fan
Xiang-Fen Ji, Shuai Gao, Yang Yang, Jian-Jun Zhang, Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
Shuai
S
Gao
Xiang-Fen Ji, Shuai Gao, Yang Yang, Jian-Jun Zhang, Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
Yang
Y
Yang
Xiang-Fen Ji, Shuai Gao, Yang Yang, Jian-Jun Zhang, Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
Jian-Jun
JJ
Zhang
Xiang-Fen Ji, Shuai Gao, Yang Yang, Jian-Jun Zhang, Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
Kai
K
Wang
D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012372:ROC Curve; D012189:Retrospective Studies
D014408:Biomarkers, Tumor; C499629:MT1G protein, human; C000595829:MT1M protein, human; D008668:Metallothionein
Hepatocellular carcinoma; MT1G; MT1M; Methylation; Serum biomarker