Prognostic Epstein-Barr Virus (EBV) miRNA biomarkers for survival outcome in EBV-associated epithelial malignancies: Systematic review and meta-analysis

Abstract

Background The EBV-associated epithelial tumours consist 80% of all EBV-associated cancer, where the nasopharyngeal cancer (NPC) and EBV-associated gastric carcinoma (EBVaGC) are considered as the most frequent EBV-associated epithelial tumours. It has been shown that the BART-encoded miRNAs are abundantly expressed in EBV-associated epithelial tumours, hence, these miRNAs may serve as diagnostic and prognostic biomarkers for EBV-associated epithelial tumours. Therefore, the purpose of this systematic review and meta-analysis is to assess these EBV miRNAs as prognostic biomarkers for NPC and GC. Method This systematic review was developed based on PRISMA guidelines and utilizing PubMed, Web of Science, Scopus, Cochrane, and Google scholar databases. The retrieved articles were thoroughly screened in accordance with the selection criteria. The hazard ratio (HR) and 95% confidence interval (CI) for patient survival outcomes were used to evaluate EBV miRNA expression levels. To assess the risk of bias, funnel plot symmetry and Egger’s bias test were employed. Result Eleven studies met the selection criteria for inclusion, and four were included in the meta-analysis. Most of the articles considered in this study were from China, with one study from South Korea. The overall pooled effect size estimation (HR) for upregulated EBV miRNAs was 3.168 (95% CI: 2.020–4.969), demonstrating that upregulated EBV miRNA expression enhanced the mortality risk in NPC and GC patients by three times. Conclusion To the best of our knowledge, this is the first meta-analysis that investigates the significance of EBV miRNAs as prognostic biomarkers in NPC and GC patients. The pooled effect estimates of HR of the various studies revealed that higher EBV miRNA expression in NPC and GC may result in a worse survival outcome. To assess the clinical significance of EBV miRNAs as prognostic biomarkers, larger-scale prospective studies are needed.

The viral etiology of EBV-associated gastric cancers contributes to their unique pathology, clinical outcomes, treatment responses and immune landscape

“…Further, larger scale studies would be beneficial in understanding the various dimensions of EBVaGCs and their differences compared to EBVnGCs. Additionally, therapeutics targeting EBV-associated miRNAs are relatively unexplored ( 111 ) and given the roles for these virally encoded miRNAs in EBV-positive malignancies ( 100 ), could make for effective targets. An example of such a therapeutic was in a recent study in which researchers employed anti-miRNAs to silence miR-BART7-3p, reducing tumor growth in tested animal models ( 305 ).…”

“…Specifically, miR-BART5-5p and miR-BART19-5p are able to downregulate LMP1, an activator of many cellular immune signalling pathways ( 109 , 110 ). Upregulated expression of EBV miRNA is associated with a 3-times higher mortality risk in NPCs and GCs ( 111 ), with miR-BART20-5p specifically associated with worse recurrence-free survival in EBVaGCs ( 112 ).…”

Virological Markers in Epstein–Barr Virus-Associated Diseases

“…A meta-analysis concluded that miRNA expression increased the mortality risk in NPC and GC patients by threefold (hazard ratio: 3.168; 95% CI: 2.020–4.969), meaning they may be used as prognostic biomarkers. Based on the survival data of 711 NPC and 59 GC patients, the meta-analysis investigated a total of seven EBV miRNAs, which were all upregulated [ 163 ]. A better understanding of EBV-miRNA expression in EBV-associated GC and NPC will open up new avenues for GC and NPC treatment [ 163 , 164 ].…”

“…Based on the survival data of 711 NPC and 59 GC patients, the meta-analysis investigated a total of seven EBV miRNAs, which were all upregulated [ 163 ]. A better understanding of EBV-miRNA expression in EBV-associated GC and NPC will open up new avenues for GC and NPC treatment [ 163 , 164 ]. Circular RNAs are another class of predominantly non-coding RNAs, which may play a role in the viral biology and pathogenicity of EBV-associated malignancies.…”

Tumor Molecular and Microenvironment Characteristics in EBV-Associated Malignancies as Potential Therapeutic Targets: Focus on Gastric Cancer

“…By regulating the immune landscape, miRNAs may directly and indirectly aid the infected host cell in malignant transformation. A recent meta-analysis evaluated the prognostic value of miRNAs in NPC and EBVaGC and found that miRNA expression is directly correlated with poorer prognosis [ 27 ].…”