Epigenetic clustering of gastric carcinomas based on dna methylation profiles at the precancerous stage

Its correlation with tumor aggressiveness and patient outcome

Kazuhiro Yamanoi, Eri Arai, Ying Tian, Yoriko Takahashi, Sayaka Miyata, Hiroki Sasaki, Fumiko Chiwaki, Hitoshi Ichikawa, Hiromi Sakamoto, Ryoji Kushima, Hitoshi Katai, Teruhiko Yoshida, Michiie Sakamoto, Yae Kanai

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 (β<inf>N</inf>) 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 β<inf>N</inf> characterized the epigenetic clustering were identified. We then focused on DNA methylation levels in T samples (β<inf>T</inf>) of the 60 hallmark genes. In 48 of them, including the ADAM23, OLFM4, AMER2, GPSM1, CCL28, DTX1 and COL23A1 genes, β<inf>T</inf> was again significantly correlated with tumor aggressiveness, and the recurrence-free and/or overall survival rates. Multivariate analyses revealed that β<inf>T</inf> 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.

Original languageEnglish
Pages (from-to)509-520
Number of pages12
JournalCarcinogenesis
Volume36
Issue number5
DOIs
Publication statusPublished - 2015 May 1

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DNA Methylation
Epigenomics
Methylation
Cluster Analysis
Stomach
Carcinoma
Neoplasms
Survival Rate
Genes
Recurrence
Gastric Mucosa
Carcinogenesis
Multivariate Analysis
Genome

ASJC Scopus subject areas

  • Cancer Research

Cite this

Epigenetic clustering of gastric carcinomas based on dna methylation profiles at the precancerous stage : Its correlation with tumor aggressiveness and patient outcome. / Yamanoi, Kazuhiro; Arai, Eri; Tian, Ying; Takahashi, Yoriko; Miyata, Sayaka; Sasaki, Hiroki; Chiwaki, Fumiko; Ichikawa, Hitoshi; Sakamoto, Hiromi; Kushima, Ryoji; Katai, Hitoshi; Yoshida, Teruhiko; Sakamoto, Michiie; Kanai, Yae.

In: Carcinogenesis, Vol. 36, No. 5, 01.05.2015, p. 509-520.

Research output: Contribution to journalArticle

Yamanoi, Kazuhiro ; Arai, Eri ; Tian, Ying ; Takahashi, Yoriko ; Miyata, Sayaka ; Sasaki, Hiroki ; Chiwaki, Fumiko ; Ichikawa, Hitoshi ; Sakamoto, Hiromi ; Kushima, Ryoji ; Katai, Hitoshi ; Yoshida, Teruhiko ; Sakamoto, Michiie ; Kanai, Yae. / Epigenetic clustering of gastric carcinomas based on dna methylation profiles at the precancerous stage : Its correlation with tumor aggressiveness and patient outcome. In: Carcinogenesis. 2015 ; Vol. 36, No. 5. pp. 509-520.
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AU - Sakamoto, Hiromi

AU - Kushima, Ryoji

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AB - 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.

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