{"title":"Severe induction of aberrant DNA methylation by nodular gastritis in adults.","authors":"Akiko Sasaki, Hideyuki Takeshima, Satoshi Yamashita, Chikamasa Ichita, Jun Kawachi, Wataru Naito, Yui Ohashi, Chihiro Takeuchi, Masahide Fukuda, Yumi Furuichi, Nobutake Yamamichi, Takayuki Ando, Hideki Kobara, Tohru Kotera, Takao Itoi, Chihiro Sumida, Akinobu Hamada, Kazuya Koizumi, Toshikazu Ushijima","doi":"10.1007/s00535-024-02094-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Nodular gastritis (NG) is characterized by marked antral lymphoid follicle formation, and is a strong risk factor for diffuse-type gastric cancer in adults. However, it is unknown whether aberrant DNA methylation, which is induced by atrophic gastritis (AG) and is a risk for gastric cancer, is induced by NG. Here, we analyzed methylation induction by NG.</p><p><strong>Methods: </strong>Gastric mucosal samples were obtained from non-cancerous antral tissues of 16 NG and 20 AG patients with gastric cancer and 5 NG and 6 AG patients without, all age- and gender-matched. Genome-wide methylation analysis and expression analysis were conducted by a BeadChip array and RNA-sequencing, respectively.</p><p><strong>Results: </strong>Clustering analysis of non-cancerous antral tissues of NG and AG patients with gastric cancer was conducted using methylation levels of 585 promoter CpG islands (CGIs) of methylation-resistant genes, and a large fraction of NG samples formed a cluster with strong methylation induction. Promoter CGIs of CDH1 and DAPK1 tumor-suppressor genes were more methylated in NG than in AG. Notably, methylation levels of these genes were also higher in the antrum of NG patients without cancer. Genes related to lymphoid follicle formation, such as CXCL13/CXCR5 and CXCL12/CXCR4, had higher expression in NG, and genes involved in DNA demethylation TET2 and IDH1, had only half the expression in NG.</p><p><strong>Conclusions: </strong>Severe aberrant methylation, involving multiple tumor-suppressor genes, was induced in the gastric antrum and body of patients with NG, in accordance with their high gastric cancer risk.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"442-456"},"PeriodicalIF":6.9000,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Gastroenterology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00535-024-02094-y","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Nodular gastritis (NG) is characterized by marked antral lymphoid follicle formation, and is a strong risk factor for diffuse-type gastric cancer in adults. However, it is unknown whether aberrant DNA methylation, which is induced by atrophic gastritis (AG) and is a risk for gastric cancer, is induced by NG. Here, we analyzed methylation induction by NG.
Methods: Gastric mucosal samples were obtained from non-cancerous antral tissues of 16 NG and 20 AG patients with gastric cancer and 5 NG and 6 AG patients without, all age- and gender-matched. Genome-wide methylation analysis and expression analysis were conducted by a BeadChip array and RNA-sequencing, respectively.
Results: Clustering analysis of non-cancerous antral tissues of NG and AG patients with gastric cancer was conducted using methylation levels of 585 promoter CpG islands (CGIs) of methylation-resistant genes, and a large fraction of NG samples formed a cluster with strong methylation induction. Promoter CGIs of CDH1 and DAPK1 tumor-suppressor genes were more methylated in NG than in AG. Notably, methylation levels of these genes were also higher in the antrum of NG patients without cancer. Genes related to lymphoid follicle formation, such as CXCL13/CXCR5 and CXCL12/CXCR4, had higher expression in NG, and genes involved in DNA demethylation TET2 and IDH1, had only half the expression in NG.
Conclusions: Severe aberrant methylation, involving multiple tumor-suppressor genes, was induced in the gastric antrum and body of patients with NG, in accordance with their high gastric cancer risk.
背景：结节性胃炎（NG）以明显的前胃淋巴滤泡形成为特征，是成人弥漫型胃癌的一个重要危险因素。然而，萎缩性胃炎（AG）诱导的异常 DNA 甲基化是胃癌的一个风险因素，NG 是否会诱导异常 DNA 甲基化尚不清楚。在此，我们分析了 NG 的甲基化诱导作用：方法：从 16 例 NG 和 20 例 AG 胃癌患者以及 5 例 NG 和 6 例 AG 非胃癌患者的非癌前组织中获取胃黏膜样本，所有样本的年龄和性别均匹配。通过 BeadChip 阵列和 RNA 序列分别进行了全基因组甲基化分析和表达分析：结果：利用甲基化耐药基因的585个启动子CpG岛（CGIs）的甲基化水平对NG和AG胃癌患者的非癌前组织进行了聚类分析，结果发现大部分NG样本形成了一个具有强甲基化诱导的聚类。与 AG 相比，NG 中 CDH1 和 DAPK1 肿瘤抑制基因启动子 CGI 的甲基化程度更高。值得注意的是，在没有癌症的 NG 患者的胃窦中，这些基因的甲基化水平也更高。与淋巴滤泡形成相关的基因，如 CXCL13/CXCR5 和 CXCL12/CXCR4 在 NG 中的表达量更高，而参与 DNA 去甲基化的基因 TET2 和 IDH1 在 NG 中的表达量仅为 AG 的一半：结论：NG 患者的胃窦和胃体中存在严重的甲基化异常，涉及多个肿瘤抑制基因，这与他们的高胃癌风险相符。
期刊介绍：
The Journal of Gastroenterology, which is the official publication of the Japanese Society of Gastroenterology, publishes Original Articles (Alimentary Tract/Liver, Pancreas, and Biliary Tract), Review Articles, Letters to the Editors and other articles on all aspects of the field of gastroenterology. Significant contributions relating to basic research, theory, and practice are welcomed. These publications are designed to disseminate knowledge in this field to a worldwide audience, and accordingly, its editorial board has an international membership.
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