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

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

SUBMITTER: Yamanoi K

PROVIDER: S-EPMC4417340 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Yamanoi Kazuhiro K Arai Eri E Tian Ying Y Takahashi Yoriko Y Miyata Sayaka S Sasaki Hiroki H Chiwaki Fumiko F Ichikawa Hitoshi H Sakamoto Hiromi H Kushima Ryoji R Katai Hitoshi H Yoshida Teruhiko T Sakamoto Michiie M Kanai Yae Y

Carcinogenesis 20150304 5

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 hi ...[more]

PMID: 25740824

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Project description:Background Published multi-gene classifiers suggested outcome prediction for patients with stage UICC II colon cancer based on different gene expression signatures. However, there is currently no translation of these classifiers for application in routine diagnostic. Therefore, we aimed at validating own and published gene expression signatures employing methods which enable RNA and protein detection in routine diagnostic specimens. Results Immunohistochemistry was applied to 68 stage UICC II colon cancers to determine the protein expression of five selected previously published classifier genes (CDH17, LAT, CA2, EMR3, and TNFRSF11A). Correlation of protein expression data with clinical outcome within a 5-year post-surgery course failed to separate patients with a disease-free follow-up [Group DF] and relapse [Group R]). In addition, RNA from macrodissected tumor samples from 53 of these 68 patients was profiled on Affymetrix GeneChips (HG-U133 Plus 2.0). Prognostic signatures were generated by Nearest Shrunken Centroids with cross-validation. Although gene expression profiling allowed the identification of differentially expressed genes between the groups DF and R, a stable classification and prognosis signature was not discernable in our data. Furthermore, the application of previously published gene signatures consisting of 22 and 19 genes, respectively, to our gene expression data set using ‘global tests’ and leave-one-out cross-validation was unable to predict clinical outcome (prediction rate 75.5% and 64.2%; n.s.). T-stage was the only independent prognostic factor for relapse in multivariate analysis with established clinical and pathological parameters including microsatellite status. Conclusions Our protein and gene expression analyses currently do not support application of molecular classifiers for prediction of clinical outcome in routine diagnostic as a basis for patient-orientated therapy in stage UICC II colon cancer. Further studies are needed to develop prognosis signatures applicable in patient care.

Dataset Information

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

Publications

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

Similar Datasets

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