Abstract
Epstein–Barr virus (EBV) is a ubiquitous oncovirus associated with specific epithelial and lymphoid cancers. Among the epithelial cancers, nasopharyngeal carcinoma (NPC), lymphoepithelioma-like carcinoma (LELC), and EBV-associated gastric cancers (EBVaGC) are the most common. The role of EBV in the pathogenesis of NPC and in the modulation of its tumour immune microenvironment (TIME) has been increasingly well described. Much less is known about the pathogenesis and tumour–microenvironment interactions in other EBV-associated epithelial cancers. Despite the expression of EBV-related viral oncoproteins and a generally immune-inflamed cancer subtype, EBV-associated epithelial cancers have limited systemic therapeutic options beyond conventional chemotherapy. Immune checkpoint inhibitors are effective only in a minority of these patients and even less efficacious with molecular targeting drugs. Here, we examine the key similarities and differences of NPC, LELC, and EBVaGC and comprehensively describe the clinical, pathological, and molecular characteristics of these cancers. A deeper comparative understanding of these EBV-driven cancers can potentially uncover targets in the tumour, TIME, and stroma, which may guide future drug development and cast light on resistance to immunotherapy.
Highlights
Epstein–Barr virus (EBV) is a ubiquitous oncovirus affecting more than 90% of adult populations globally and has been classified as a type I carcinogen leading to 1.5% of all cancers [1]
Squamous cell carcinoma and undifferentiated carcinoma Type IIa presents with round vesicular nuclei with prominent nucleoli, indistinct cell margins, with a syncytial appearance Type IIb can be found in irregular and moderately well-defined areas, or in loosely connected cells admixed with the tumour microenvironment Type 2b: EBV-encoded RNA (EBER)-ISH positive nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway activation through Latent Membrane Protein 1 (LMP1), silencing of CDKN2A, CCND1 amplification, JAK/signal transducer and activator of transcription (STAT), NOTCH, phosphatidylinositol 3-kinase (PI3K) pathway, TP53 mutations Immune cell signaling esp
The hypermethylated profiles observed in EBV-associated gastric cancers (EBVaGC) may be a result of DNMT3b overexpression after EBV infection [96], as well as LMP2A-induced STAT3 phosphorylation resulting in increased expression of DNMT1 [84]
Summary
Epstein–Barr virus (EBV) is a ubiquitous oncovirus affecting more than 90% of adult populations globally and has been classified as a type I carcinogen leading to 1.5% of all cancers [1]. Common EBV-associated epithelial cancers include nasopharyngeal carcinoma (NPC), lymphoepithelioma-like carcinoma (LELC) and EBV-associated gastric cancers (EBVaGC). Significantly less is known about LELC owing to the rarity of the disease They may differ in clinical presentations and anatomical site, what these viral-driven cancers have in common is a characteristic immune-suppressed tumour immune microenvironment (TIME) driven primarily by EBV. Elevated serum EBV capsid antigen (VCA) Immunoglobulin A (IgA) or EBV DNA titers are associated with an increased risk of developing NPC, with raised levels associated with advanced disease and observed to precede the clinical onset of NPC [4, 16]. Other risk factors include male gender, an increased intake of salty food, and exposure to wood dust or iron fillings, in comparison to EBV-negative gastric cancer [22]
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