Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome.
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.
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.
Kazuhiro
K
Yamanoi
Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan, earai@ncc.go.jp.
Eri
E
Arai
Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Ying
Y
Tian
Bioscience Department, Business Development Division, Mitsui Knowledge Industry Co., Ltd., Tokyo 105-6215, Japan.
Yoriko
Y
Takahashi
Bioscience Department, Business Development Division, Mitsui Knowledge Industry Co., Ltd., Tokyo 105-6215, Japan.
Sayaka
S
Miyata
Department of Translational Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Hiroki
H
Sasaki
Department of Translational Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Fumiko
F
Chiwaki
Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Hitoshi
H
Ichikawa
Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Hiromi
H
Sakamoto
Department of Pathology and Clinical Laboratories, Pathology Division, National Cancer Center Hospital, Tokyo 104-0045, Japan and.
Ryoji
R
Kushima
Department of Gastric Surgery, National Cancer Center Hospital, Tokyo 104-0045, Japan.
Hitoshi
H
Katai
Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Teruhiko
T
Yoshida
Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Michiie
M
Sakamoto
Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Yae
Y
Kanai
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011230:Precancerous Conditions / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate
D014408:Biomarkers, Tumor; D012333:RNA, Messenger