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

Abstract

The molecular pathogenesis of posttransplant diffuse large B cell lymphoma (PT‐DLBCL) is largely unknown. We have recently shown that Epstein‐Barr virus–positive (EBV+) and –negative (EBV−) PT‐DLBCL have distinct gene expression profiles, and the transcriptomic profile of EBV− PT‐DLBCL is similar to that of DLBCL in immunocompetent individuals (IC‐DLBCL). To validate these observations at the genomic level, we performed array–comparative genome hybridization (aCGH) analysis of 21 EBV+ PT‐DLBCL, 6 EBV− PT‐DLBCL, and 11 control IC‐DLBCL, and subsequently combined genomic and transcriptomic data. The analysis showed that EBV+ and EBV− PT‐DLBCL have distinct aCGH profiles and shared only one recurrent imbalance. EBV− PT‐DLBCL, however, displayed at least 10 aberrations recurrent in IC‐DLBCL, among which characteristic gain of 3/3q and 18q, and loss of 6q23/TNFAIP3 as well as 9p21/CDKN2A. The most prevalent aberration in EBV+ PT‐DLBCL was gain/amplification of 9p24.1 targeting PDCD1LG2/PDL2. Our data indicate that the FOXP1 oncogene and the tumor suppressor CDKNA2 implicated in EBV− DLBCL, do not play a critical role in the pathogenesis of EBV+ PT‐DLBCL. Altogether, genomic profiling of PT‐/IC‐DLBCL confirms that EBV− and EBV+ PT‐DLBCL are distinct entities, while EBV− PT‐DLBCL has features in common with IC‐DLBCL. These findings support the hypothesis that EBV− PT‐DLBCL are de novo lymphomas in transplant recipients.

EBV-Negative Monomorphic B-Cell Posttransplant Lymphoproliferative Disorder with Marked Morphologic Pleomorphism and Pathogenic Mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53

“…It has been postulated that EBV-negative PTLD represents a distinct entity [5, 8]. In support of this hypothesis, gene expression profiling studies have revealed clear differences between EBV-positive and EBV-negative PTLDs [10, 18]. …”

“…The pathogenesis of non-EBV-related PTLD may be similar to non-Hodgkin's lymphomas (NHL) [6]. EBV-negative PTLD has been proposed to be a distinct entity and typically presents as a late complication of transplantation with a median of 50–60 months [5, 7–10]. EBV-negative PTLDs typically display monomorphic morphology [1].…”

Survival outcomes of allogeneic hematopoietic cell transplants with EBV‐positive or EBV‐negative post‐transplant lymphoproliferative disorder, A CIBMTR study

“…Other potential risks for PTLD may include issues related to alternative donors and alternative GVHD prophylaxis and donor/recipient EBV serostatus. For EBV serostatus, there may be a higher risk of developing PTLD in EBV‐positive recipients receiving cells from EBV‐seronegative donors since it is much harder to generate a primary immune response to EBV reactivation post‐alloHCT . For our cohort, EBV‐negative donors were used in 53 EBV‐positive recipients and 43 developed EBV pos PTLD with the remainder developing EBV neg PTLD.…”

The Immune Response to Epstein Barr Virus and Implications for Posttransplant Lymphoproliferative Disorder

“…The regulation of PD-L1 expression has been examined in EBV+ B cells and it may have both viral and genetic components. Green et al, (77) identified an AP-1 responsive element in the PD-L1 gene and showed the EBV protein LMP1 can increase PD-L1 expression via the JAK/STAT pathway while a gain/amplification of chromosomal region 9p24.1, which includes the PD-L1 and PD-L2 genes, was found in 2 of 5 clinical EBV+ B cell PTLD specimens in another study (78). Collectively, these results suggest that inhibitory pathways may play an important role in impaired T cell responses in PTLD.…”