Tan Ming, Tan Qihua
Department of Oncology, Rigshospitalet Copenhagen, Denmark.
Epidemiology, Biostatistics and Biodemography, Department of Public Health, Faculty of Health Science, University of Southern Denmark Odense M, Denmark.
Int J Mol Epidemiol Genet. 2025 Feb 25;16(1):1-8. doi: 10.62347/RIOX7768. eCollection 2025.
Epstein-Barr virus (EBV) associated gastric cancer (EBVaGC) represents a distinct subtype of gastric carcinoma clinically characterized by low frequency of lymph node metastasis and better prognosis as compared to the EBV-negative gastric cancer (EBVnGC). Differential expression analysis of the transcriptome from tumor tissues revealed frequent involvement of immune genes which emphasizes the exclusive significance of immune response in EBVaGC patients. Considering the reported over-expression of toll-like receptor (TLR) genes in EBV infection and giving the crucial roles of TLRs in the innate immune system, we assumed that the entire TLR signaling pathway could have been differentially regulated in EBVaGC.
We tested our hypothesis by performing a differential expression analysis of the whole TLR signaling pathway using gene set enrichment test.
A self-matched test detected a significant upregulation of the TLR signaling pathway in tumor as compared with non-tumor gastric tissues of EBVaGCs (P = 4×10) but no significant differential regulation of the pathway in EBVnGCs. A comparison of tumor gastric tissue in EBVaGCs versus non-tumor gastric tissue in EBVnGCs showed an even more significant upregulation of the pathway with a high enrichment of overexpressed genes (P = 2.5×10).
Briefly, this study revealed a distinct pattern of activation of the TLR signaling pathway in EBVaGCs which can be seen as a specific feature of molecular pathology in the disease. This feature characterizes the disease as a distinct subtype of gastric cancer in oncogenesis which can be linked to its clinical manifestation and prognosis to motivate improved treatment strategies for both EBVaGC and EBVnGC patients.
爱泼斯坦 - 巴尔病毒（EBV）相关胃癌（EBVaGC）是胃癌的一种独特亚型，其临床特征为与EBV阴性胃癌（EBVnGC）相比，淋巴结转移频率较低且预后较好。对肿瘤组织转录组的差异表达分析显示免疫基因频繁参与，这突出了免疫反应在EBVaGC患者中的独特意义。考虑到报道的Toll样受体（TLR）基因在EBV感染中的过表达以及TLR在先天免疫系统中的关键作用，我们推测整个TLR信号通路在EBVaGC中可能受到差异调节。
我们通过使用基因集富集测试对整个TLR信号通路进行差异表达分析来检验我们的假设。
一项自身匹配测试检测到，与EBVaGC的非肿瘤胃组织相比，肿瘤中TLR信号通路显著上调（P = 4×10），但在EBVnGC中该通路无显著差异调节。EBVaGC的肿瘤胃组织与EBVnGC的非肿瘤胃组织的比较显示，该通路有更显著的上调，且过表达基因高度富集（P = 2.5×10）。
简而言之，本研究揭示了EBVaGC中TLR信号通路的一种独特激活模式，这可被视为该疾病分子病理学的一个特定特征。这一特征将该疾病在肿瘤发生过程中表征为一种独特的胃癌亚型，这可能与其临床表现和预后相关，从而推动针对EBVaGC和EBVnGC患者改进治疗策略。
