Cooperative participation of epigenomic and genomic alterations in the clinicopathological diversity of gastric adenocarcinomas: significance of cell adhesion and epithelial–mesenchymal transition-related signaling pathways
| Autor: | Hitoshi Katai, Teruhiko Yoshida, Hiromi Sakamoto, Hirohiko Totsuka, Hirokazu Taniguchi, Suenori Chiku, Yoriko Takahashi, Yae Kanai, Menghan Yang, Eri Arai |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Adult Epigenomics Male Cancer Research Epithelial-Mesenchymal Transition AcademicSubjects/MED00710 Biology Adenocarcinoma MLH1 Biology Genetics and Epigenetics Polymorphism Single Nucleotide CDH1 Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine Stomach Neoplasms Exome Sequencing Gastric mucosa medicine Biomarkers Tumor Cell Adhesion Humans ERBB3 Gene Aged Aged 80 and over Transition (genetics) General Medicine DNA Methylation Middle Aged Prognosis Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Case-Control Studies DNA methylation Cancer research biology.protein Female Follow-Up Studies |
| Zdroj: | Carcinogenesis |
| ISSN: | 1460-2180 0143-3334 |
| Popis: | The present study was conducted to clarify the cooperative significance of epigenomic and genomic abnormalities during gastric carcinogenesis. Using 21 samples of normal control gastric mucosa (C), 109 samples of non-cancerous gastric mucosa (N) and 105 samples of cancerous tissue (T) from 109 patients with primary gastric adenocarcinomas, genome-wide DNA methylation analysis was performed using Infinium assay. Among these samples, 66 paired N and corresponding T samples were subjected to whole-exome and single nucleotide polymorphism array analyses. As had been shown in our previous study, 109 patients were clustered clinicopathologically into least aggressive Cluster A (n = 20), most aggressive Cluster B1 (n = 20) and Cluster B2 (n = 69). Most DNA methylation alterations in each cluster had already occurred even in N samples compared with C samples, and DNA methylation alterations at the precancerous N stage were inherited by the established cancers themselves. Recurrent single nucleotide variants and insertions/deletions resulting in functional disruption of the proteins encoded by the ABCA10, BNC2, CDH1, CTNNB1, SMAD4 and VAV2 genes were specific to Cluster B1, whereas those of the APC, EGFR, ERBB2, ERBB3, MLH1 and MUC6 genes were specific to Cluster A. MetaCore pathway analysis revealed that the epigenomically affected TWIST1 gene and genomically affected CDH1, CTNNB1, MMP9, TLN2, ROCK1 and SMAD4 genes were accumulated in signaling pathways related to cell adhesion, cytoskeleton remodeling and epithelial–mesenchymal transition in Cluster B1. These data indicate that epigenomic alterations at the precancerous stage are important in gastric carcinogenesis and that epigenomic and genomic alterations cooperatively underlie the aggressiveness of gastric adenocarcinomas. Genome-wide analyses have revealed that the epigenomically affected TWIST1 gene and genomically affected CDH1, CTNNB1, MMP9, TLN2, ROCK1, SMAD4 and VAV2 genes cooperatively accumulate in signaling pathways related to cell adhesion, cytoskeleton remodeling and epithelial–mesenchymal transition in aggressive gastric adenocarcinomas. |
| Databáze: | OpenAIRE |
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