Brief Article
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World J Gastroenterol. Apr 28, 2014; 20(16): 4723-4729
Published online Apr 28, 2014. doi: 10.3748/wjg.v20.i16.4723
MT1M and MT1G promoter methylation as biomarkers for hepatocellular carcinoma
Xiang-Fen Ji, Yu-Chen Fan, Shuai Gao, Yang Yang, Jian-Jun Zhang, Kai Wang
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 Fan, Kai Wang, Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
Yu-Chen Fan, Kai Wang, Institute of Hepatology, Shandong University, Jinan 250012, Shandong Province, China
Author contributions: Ji XF designed the study, carried out the experiments and drafted the manuscript; Fan YC revised the manuscript; Yang Y performed part of experiments; Gao S and Zhang JJ interpreted the data; Wang K revised the paper critically for important intellectual content.
Supported by National Natural Science Foundation of China, No. 81171579, No. 81201287 and No. 81371832
Correspondence to: Kai Wang, MD, PhD, Department of Hepatology, Qilu Hospital of Shandong University and Institute of Hepatology, Shandong University, No. 107, Wenhuaxi Road, Jinan 250012, Shandong Province, China. wangdoc876@126.com
Telephone: +86-531-86630809 Fax: +86-531-8692754
Received: November 24, 2013
Revised: January 10, 2014
Accepted: February 17, 2014
Published online: April 28, 2014
Abstract

AIM: 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).

CONCLUSION: MT1M and MT1G promoter methylation may be used as serum biomarkers for noninvasive detection of HCC.

Keywords: MT1M, MT1G, Methylation, Serum biomarker, Hepatocellular carcinoma

Core tip: DNA methylation of tumor suppressor gene promoter regions appears to be a valuable biomarker in many tumors, including hepatocellular carcinoma (HCC). We found that aberrant serum metallothionein 1M (MT1M) promoter methylation gave higher specificity to discriminate HCC from chronic hepatitis B and normal controls. In contrast, combined methylation of serum MT1M and metallothionein 1G promoters showed higher diagnostic sensitivity. This indicates that they may be used as potential biomarkers for noninvasive detection of HCC.