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Carcinogenesis. 2017 Mar 1;38(3):261-270. doi: 10.1093/carcin/bgx005.

Genome-wide DNA methylation analysis during non-alcoholic steatohepatitis-related multistage hepatocarcinogenesis: comparison with hepatitis virus-related carcinogenesis.

Author information

1
Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
2
Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
3
Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655Japan.
4
Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
5
Biomedical Department, Cloud Service Division, IT Infrastructure Services Unit, Mitsui Knowledge Industry Co., Ltd., Tokyo 105-6215, Japan.
6
Department of Pathology and Clinical Laboratories, Pathology Division, National Cancer Center Hospital, Tokyo 104-0045, Japan and.
7
Weight loss and Metabolic Surgery Center, Yotsuya Medical Cube, Tokyo 102-0084, Japan.

Abstract

The aim of this study was to clarify the significance of DNA methylation alterations during non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Single-CpG-resolution genome-wide DNA methylation analysis was performed on 264 liver tissue samples using the Illumina Infinium HumanMethylation450 BeadChip. After Bonferroni correction, 3331 probes showed significant DNA methylation alterations in 113 samples of non-cancerous liver tissue showing NASH (NASH-N) as compared with 55 samples of normal liver tissue (NLT). Principal component analysis using the 3331 probes revealed distinct DNA methylation profiles of NASH-N samples that were different from those of NLT samples and 37 samples of non-cancerous liver tissue showing chronic hepatitis or cirrhosis associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (viral-N). Receiver operating characteristic curve analysis identified 194 probes that were able to discriminate NASH-N samples from viral-N samples with area under the curve values of more than 0.95. Jonckheere-Terptsra trend test revealed that DNA methylation alterations in NASH-N samples from patients without hepatocellular carcinoma (HCC) were inherited by or strengthened in NASH-N samples from patients with HCC, and then inherited by or further strengthened in 22 samples of NASH-related HCC (NASH-T) themselves. NASH- and NASH-related HCC-specific DNA methylation alterations, which were not evident in viral-N samples and 37 samples of HCC associated with HBV or HCV infection, were observed in tumor-related genes, such as WHSC1, and were frequently associated with mRNA expression abnormalities. These data suggested that NASH-specific DNA methylation alterations may participate in NASH-related multistage hepatocarcinogenesis.

PMID:
28426876
PMCID:
PMC5862314
DOI:
10.1093/carcin/bgx005
[Indexed for MEDLINE]
Free PMC Article

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