Severe induction of aberrant DNA methylation by nodular gastritis in adults. Severe induction of aberrant DNA methylation by nodular gastritis in adults

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. Overall design: Genome-wide DNA methylation analysis was conducted by an Infinium HumanMethylationEPIC BeadChip array of FFPE samples. ***Please note that the records have been updated with IDAT files on Oct 8, 2024.

背景：结节性胃炎（Nodular gastritis, NG）以胃窦淋巴滤泡显著形成为特征，是成人弥漫型胃癌的明确高危因素。目前已知萎缩性胃炎（atrophic gastritis, AG）可诱导异常DNA甲基化，而该表观遗传改变亦是胃癌的危险因素，但结节性胃炎是否同样可诱导此类甲基化异常，尚不明确。本研究针对结节性胃炎的甲基化诱导效应展开分析。

方法：本研究共纳入47例按年龄与性别匹配的受试者，其中伴胃癌的结节性胃炎患者16例、萎缩性胃炎患者20例，不伴胃癌的结节性胃炎患者5例、萎缩性胃炎患者6例。所有受试者的非癌性胃窦组织均被采集为胃黏膜样本。分别采用微珠芯片（BeadChip array）阵列与RNA测序（RNA-sequencing）完成全基因组甲基化分析与基因表达分析。

结果：针对伴胃癌的结节性胃炎与萎缩性胃炎患者的非癌性胃窦组织，本研究以585个甲基化抵抗基因的启动子CpG岛（CpG islands, CGIs）的甲基化水平进行聚类分析，结果显示大部分结节性胃炎样本形成了一个甲基化诱导程度显著的聚类簇。抑癌基因CDH1与DAPK1的启动子CpG岛在结节性胃炎中的甲基化程度显著高于萎缩性胃炎。值得注意的是，上述基因的甲基化水平在不伴胃癌的结节性胃炎患者的胃窦组织中同样处于较高水平。与淋巴滤泡形成相关的基因（如CXCL13/CXCR5、CXCL12/CXCR4）在结节性胃炎中表达上调，而参与DNA去甲基化过程的TET2与IDH1基因在结节性胃炎中的表达量仅为对照组的一半。

结论：结节性胃炎患者的胃窦与胃体组织中存在涉及多个抑癌基因的严重异常DNA甲基化，这与其较高的胃癌发病风险相符。

整体实验设计：本研究通过Infinium HumanMethylationEPIC微珠芯片阵列对福尔马林固定石蜡包埋（FFPE）样本开展全基因组DNA甲基化分析。

***请注意：本数据集的记录已于2024年10月8日更新了IDAT文件。