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Review
. 2019 Aug 6:9:713.
doi: 10.3389/fonc.2019.00713. eCollection 2019.

The Global Landscape of EBV-Associated Tumors

Claire Shannon-Lowe  1 , Alan Rickinson  1
Affiliations
Review

The Global Landscape of EBV-Associated Tumors

Claire Shannon-Lowe et al. Front Oncol. .

Abstract

Epstein-Barr virus (EBV), a gamma-1 herpesvirus, is carried as a life-long asymptomatic infection by the great majority of individuals in all human populations. Yet this seemingly innocent virus is aetiologically linked to two pre-malignant lymphoproliferative diseases (LPDs) and up to nine distinct human tumors; collectively these have a huge global impact, being responsible for some 200,000 new cases of cancer arising worldwide each year. EBV replicates in oral epithelium but persists as a latent infection within the B cell system and several of its diseases are indeed of B cell origin; these include B-LPD of the immunocompromised, Hodgkin Lymphoma (HL), Burkitt Lymphoma (BL), Diffuse Large B cell Lymphoma (DLBCL) and two rarer tumors associated with profound immune impairment, plasmablastic lymphoma (PBL) and primary effusion lymphoma (PEL). Surprisingly, the virus is also linked to tumors arising in other cellular niches which, rather than being essential reservoirs of virus persistence in vivo, appear to represent rare cul-de-sacs of latent infection. These non-B cell tumors include LPDs and malignant lymphomas of T or NK cells, nasopharyngeal carcinoma (NPC) and gastric carcinoma of epithelial origin, and leiomyosarcoma, a rare smooth muscle cell tumor of the immunocompromised. Here we describe the main characteristics of these tumors, their distinct epidemiologies, histological features and degrees of EBV association, then consider how their different patterns of EBV latency may reflect the alternative latency programmes through which the virus first colonizes and then persists in immunocompetent host. For each tumor, we discuss current understanding of EBV's role in the oncogenic process, the identity (where known) of host genetic and environmental factors predisposing tumor development, and the recent evidence from cancer genomics identifying somatic changes that either complement or in some cases replace the contribution of the virus. Thereafter we look for possible connections between the pathogenesis of these apparently different malignancies and point to new research areas where insights may be gained.

Keywords: Epstein-Barr virus; carcinoma; latency; lymphoma; lymphoproliferative diseases.

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Figures

Figure 1
Figure 1
Diagrammatic representation of the alternate forms of EBV latency drawn on a linear map of the virus genome. Note that the non-coding EBER RNAs and the BART miRs are expressed in all forms of latency. Latency 0 represents an antigen-negative form of infection. Latency I involves selective expression of EBNA1 from the Bam H1Q promoter (Qp). Latency II involves expression of EBNA1 from Qp, LMP1 from the LMP1 promoter (EDL1p), LMP2A from the LMP2A promoter (Tp1) and LMP2B from the LMP2B promoter (Tp2). Latency I/II includes a number of latency profiles that are intermediate between Latencies I and II with different degrees of LMP1 and/or LMP2A and/or LMP2B expression (represented here by light shading); in some cases LMP2B is expressed from a different promoter (L2TRp) in the terminal repeat region. Latency III involves expression of all six EBNA proteins, BHRF1 and the BHRF1 miRs from the BamH1W (Wp) and/or BamH1C (Cp) promoters, plus LMP1, 2A, and 2B expressed from EDL1p, Tp1, and Tp2, respectively.
Figure 2
Figure 2
A diagram of EBV-B cell and EBV-epithelial cell interactions thought to occur during primary and persistent EBV infection in the immunocompetent host. Orally acquired virus particles infect both resting B cells and oral epithelium. Current evidence suggests that oropharyngeal B cells may be the initial target, leading to local foci of EBV-transformed B cell growth (via a Latency III- type infection) in oropharyngeal lymphoid tissues; mucosal epithelial cells may then acquire infectious virus either by direct transfer from virus bound to the resting B cell surface or from a small fraction of transformed B cells switching into lytic cycle. Some other virus-transformed B cells are able to down-regulate viral antigen expression, stop proliferating and enter the recirculating memory B cell pool. How this occurs is unclear. One possible route is via a physiologic germinal center (GC) reaction, another via a non-GC route; in either case, this transition may involve progressively more restricted forms of Latency (II and/or I) before entry into Latency 0. Occasional reactivation of latently-infected memory B cells into lytic cycle, possibly induced by triggers of plasma cell differentiation, produces virions that through close cell-cell contact can initiate new latent B cell infections or establish new foci of virus replication in epithelial cells. Although not shown on the diagram, the above events are subject to immune controls; for a description of immune responses to latent and lytic infections, see Taylor et al. (23).
Figure 3
Figure 3
Diagrammatic representation of the germinal center (GC) reaction, showing the physiologic events involved in affinity maturation of antibody responses. Initially antigen-stimulated naïve B cells are induced into clonal expansion as centroblasts (CB), undergoing somatic hypermutation of immunoglobulin genes and producing a centrocyte (CC) population encompassing a range of variant sequences. This is an iterative process and may involve cells undergoing several rounds of CC/CB transition. Most centrocytes then die by apoptosis. Only those expressing immunoglobulin with increased affinity for the original antigen are able to escape by capturing antigen from the surface of follicular dendritic cells (FDCs) and attracting antigen-specific T cell help. Following class switch recombination (CSR) to generate different immunoglobulin isotypes, these centrocytes differentiate either into memory B cells or plasmablasts/plasma cells and leave the GC. Note that, although not shown on the diagram, memory cells in the recirculating pool may be recruited back into a germinal center reaction or directly driven to become plasma cells following re-exposure to antigen. EBV-associated B-LPD and B cell lymphomas display genotypic and/or phenotypic markers that indicate their origin from precursors at one or other position on this B cell differentiation pathway; here we show the presumed identity of those precursors for B-LPD, BL, HL, the various DLBCLs, PBL, and PEL.
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