Backgrounds: Epstein–Barr virus (EBV) is implicated in the pathogenesis of different B-cell lymphomas and lymphoproliferative disorders, including diffuse large B-cell lymphoma (DLBCL) arising in immunodeficiency settings. Despite its clinical significance, the mechanisms of EBV-mediated lymphomagenesis across different disease subtypes remain poorly understood. Global DNA methylation profiling can provide insight into tumor heterogeneity and disease mechanisms.Methods: To further characterize the underlying biology of EBV(+) DLBCL, we performed a global methylome analysis of a cohort of EBV(+)/(−) DLBCL. Illumina MethylationEPIC array data were generated from a curated set of DLBCL tissue samples (n= 43) from a rural patient population with defined EBV status and immunodeficiency background. Differential methylation analyses were conducted using linear mixed models to identify significant methylation changes associated with EBV status.Results: Principle component analysis (PCA) and probe-level comparisons revealed a distinct, globally hypermethylated DNA methylome in EBV(+) DLBCL compared to EBV(−) cases, and an overall hypomethylated profile in all DLBCL relative to control tissues. We identified a total of 117,334 differentially methylated probes mapping to 1557 cancer-associated genes in EBV(+) versus EBV(−) DLBCL, and 330,872 probes mapping to 4230 cancer-associated genes in all DLBCL versus controls. Pathway enrichment analysis highlighted distinct biological processes in EBV(+) DLBCL, including P53 feedback loops (hypermethylated genes) and MAPK signaling (hypomethylated genes).Conclusions: These findings demonstrate that EBV(+) DLBCL is epigenetically distinct from EBV(−) disease, with alterations that may contribute to clinical heterogeneity and potentially serve as biomarkers for disease classification and therapeutic targeting.
背景：爱泼斯坦-巴尔病毒（EBV）与多种B细胞淋巴瘤及淋巴增殖性疾病的发病机制相关，包括免疫缺陷状态下发生的弥漫性大B细胞淋巴瘤（DLBCL）。尽管其临床意义重大，但EBV在不同疾病亚型中驱动淋巴瘤发生的机制仍不清楚。全基因组DNA甲基化分析有助于揭示肿瘤异质性及疾病机制。 方法：为深入解析EBV阳性DLBCL的生物学特征，我们对一组EBV阳性/阴性DLBCL样本进行了全基因组甲基化分析。通过Illumina MethylationEPIC芯片平台，对来自农村患者群体、具有明确EBV状态与免疫缺陷背景的DLBCL组织样本（n=43）进行甲基化检测。采用线性混合模型进行差异甲基化分析，以识别与EBV状态相关的显著甲基化改变。 结果：主成分分析与探针水平比较显示，相较于EBV阴性病例，EBV阳性DLBCL呈现出独特的全基因组高甲基化模式；而与对照组织相比，所有DLBCL样本均呈现整体低甲基化特征。在EBV阳性与阴性DLBCL的对比中，共鉴定出117,334个差异甲基化探针，对应1,557个癌症相关基因；在所有DLBCL与对照组织的对比中，发现330,872个差异甲基化探针，对应4,230个癌症相关基因。通路富集分析揭示了EBV阳性DLBCL中独特的生物学过程，包括P53反馈环路（高甲基化基因）和MAPK信号通路（低甲基化基因）。 结论：本研究表明EBV阳性DLBCL在表观遗传学特征上显著区别于EBV阴性病例，这些改变可能解释临床异质性，并有望作为疾病分类和治疗靶向的生物标志物。
The EBV-Positive Tumor Methylome Is Distinct from EBV-Negative in Diffuse Large B-Cell Lymphoma
肿瘤(癌症)患者之家