Integrated copy number and gene expression profiling analysis of epstein–barr virus‐positive diffuse large b‐cell lymphoma

Abstract

Viral oncogenes and host immunosenescence have been suggested as causes of Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV + DLBCL) of the elderly. To investigate the molecular genetic basis of immune evasion and tumor outgrowth, we analyzed copy number alterations (CNAs) and gene expression profiles in EBV + DLBCL samples compared with EBV - DLBCL. There were relatively few genomic alterations in EBV + DLBCL compared with those detected in EBV-negative DLBCL. The most frequent CNAs (>30%) in EBV + DLBCLs were gains at 1q23.2-23.3, 1q23.3, 1q32.1, 5p15.3, 8q22.3, 8q24.1-24.2, and 9p24.1; losses at 6q27, 7q11.2, and 7q36.2-36.3 were also recurrent. A gene expression profile analysis identified the host immune response as a key molecular signature in EBV + DLBCL. Antiviral response genes, proinflammatory cytokines, and chemokines associated with the innate immune response were overexpressed, indicating the presence of a virusinduced inflammatory microenvironment. Genes associated with the B-cell receptor signaling pathway were downregulated. An integrated analysis indicated that SLAMF1 and PDL2 were key targets of the gains detected at 1q23.2-23.3 and 9p24.1. The chromosomal gain at 9p24.1 was associated with poor overall survival. Taken together, our results led to the identification of recurrent copy number alterations and distinct gene expression associated with the host immune response in EBV + DLBCL. We suggest that the upregulation of PDL2 on 9p24.1 promotes immune evasion and is associated with poor prognosis in EBV + DLBCL.

EBV-Positive and EBV-Negative Posttransplant Diffuse Large B Cell Lymphomas Have Distinct Genomic and Transcriptomic Features

“…These findings suggest that the host response to a viral infection in B cells had the most important impact on the transcriptomic signature of EBV þ PT-DLBCL. It is particularly interesting that EBV þ DLBCL of the elderly (EBV þ DLBCL-E), recently investigated by Yoon et al (32), bears GEP characteristics similar to EBV þ DLBCL. In addition, this rare lymphoma developing in individuals aged over 50 years without any known immunodeficiency (33) displayed several other characteristics overlapping with EBV þ PT-DLBCL.…”

LMP1+SLAMF1high cells are associated with drug resistance in Epstein-Barr virus-positive Farage cells

“…Most cases of EBV+ DLBCL, particularly in Asia, have shown an activated B cell (ABC)-like immunophenotype, which is consistent with the substantial NF-κB activation that was revealed by immunohistochemistry and gene expression profiles [4, 8, 10–11]. NF-κB activation is a common feature that occurs through various mechanisms in ABC-DLBCL.…”

“…In our previous gene expression study we observed overexpression of downstream target genes of IL4 in EBV+ DLBCL [4]. CCL22, which is overexpressed in SLAMF1 high and CHOP-treated cells, recruits IL4-secreting Th2 cells [28].…”

“…EBV+ DLBCL exhibits relatively few genetic alterations compared with EBV- DLBCL [4]. However, EBV+ DLBCL is associated with poor prognosis and a median survival of 2 years in Asian populations [1–2, 5–8].…”

“…Histologically, EBV+ tumor cells in EBV+ DLBCL have been detected within a background of extensive infiltrating immune cells, including histocytes, mast cells, and T cell subsets [27]. Previously, we identified the overexpression of several T cell-recruiting chemokines in EBV+ DLBCL [4]. Oyama et al revealed the co-expression of LMP1 and the chemokines CCL17 and CCL22 and found that LMP1+ tumor cells were closely surrounded by CCR4 + Th2 cells and regulatory T cells [28].…”