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Carcinogenesis. 2015 May;36(5):509-20. doi: 10.1093/carcin/bgv013. Epub 2015 Mar 4.

Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome.

Author information

1
Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan, 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, earai@ncc.go.jp.
3
Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
4
Bioscience Department, Business Development Division, Mitsui Knowledge Industry Co., Ltd., Tokyo 105-6215, Japan.
5
Department of Translational Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
6
Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
7
Department of Pathology and Clinical Laboratories, Pathology Division, National Cancer Center Hospital, Tokyo 104-0045, Japan and.
8
Department of Gastric Surgery, National Cancer Center Hospital, Tokyo 104-0045, Japan.
9
Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.

Abstract

The aim of this study was to clarify the significance of DNA methylation alterations during gastric carcinogenesis. Single-CpG resolution genome-wide DNA methylation analysis using the Infinium assay was performed on 109 samples of non-cancerous gastric mucosa (N) and 105 samples of tumorous tissue (T). DNA methylation alterations in T samples relative to N samples were evident for 3861 probes. Since N can be at the precancerous stage according to the field cancerization concept, unsupervised hierarchical clustering based on DNA methylation levels was performed on N samples (βN) using the 3861 probes. This divided the 109 patients into three clusters: A (n = 20), B1 (n = 20), and B2 (n = 69). Gastric carcinomas belonging to Cluster B1 showed tumor aggressiveness more frequently than those belonging to Clusters A and B2. The recurrence-free and overall survival rates of patients in Cluster B1 were lower than those of patients in Clusters A and B2. Sixty hallmark genes for which βN characterized the epigenetic clustering were identified. We then focused on DNA methylation levels in T samples (βT) of the 60 hallmark genes. In 48 of them, including the ADAM23, OLFM4, AMER2, GPSM1, CCL28, DTX1 and COL23A1 genes, βT was again significantly correlated with tumor aggressiveness, and the recurrence-free and/or overall survival rates. Multivariate analyses revealed that βT was a significant prognostic factor, being independent of clinicopathological parameters. These data indicate that DNA methylation profiles at the precancerous stage may be inherited by gastric carcinomas themselves, thus determining tumor aggressiveness and patient outcome.

PMID:
25740824
PMCID:
PMC4417340
DOI:
10.1093/carcin/bgv013
[Indexed for MEDLINE]
Free PMC Article

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