Abstract
Posttransplant lymphoproliferative disorders (PTLDs), 50%‐80% of which are strongly associated with Epstein‐Barr virus (EBV), carry a high morbidity and mortality. Most clinical/epidemiological/tumor characteristics do not consistently associate with worse patient survival, so our aim was to identify if other viral genomic characteristics associated better with survival. We extracted DNA from stored paraffin‐embedded PTLD tissues at our center, identified viral sequences by metagenomic shotgun sequencing (MSS), and analyzed the data in relation to clinical outcomes. Our study population comprised 69 PTLD tissue samples collected between 1991 and 2015 from 60 subjects. Nucleotide sequences from at least one virus were detected by MSS in 86% (59/69) of the tissues (EBV in 61%, anelloviruses 52%, gammapapillomaviruses 14%, CMV 7%, and HSV in 3%). No viruses were present in higher proportion in EBV‐negative PTLD (compared to EBV‐positive PTLD). In univariable analysis, death within 5 years of PTLD diagnosis was associated with anellovirus (P = 0.037) and gammapapillomavirus (P = 0.036) detection by MSS, higher tissue qPCR levels of the predominant human anellovirus species torque teno virus (TTV; P = 0.016), T cell type PTLD, liver, brain or bone marrow location. In multivariable analyses, T cell PTLD (P = 0.006) and TTV PCR level (P = 0.012) remained significant. In EBV‐positive PTLD,EBNA‐LP,EBNA1 and EBNA3C had significantly higher levels of nonsynonymous gene variants compared to the other EBV genes. Multiple viruses are detectable in PTLD tissues by MSS. Anellovirus positivity, not EBV positivity,was associated with worse patient survival in our series. Confirmation and extension of this work in larger multicenter studies is desirable.
Highlights
Posttransplant lymphoproliferative disorders (PTLDs), an abnormal proliferation of lymphoid cells under posttransplant immunosuppression, are a major malignant complication of organ and tissue transplant.[1,2,3,4] PTLDs have a high morbidity and 5‐year mortality that exceeds 50%.3 About 50%‐80% of PTLD cases are strongly related to the oncogenic Epstein‐Barr virus (EBV).[5]
We identified 8 EBV‐negative control tissues and four positive EBV‐positive control tissues that were either Hodgkin lymphoma or diffuse large B cell lymphoma (DLBCL) from immunocompetent patients in a nontransplant setting
We are able to achieve a high degree of coverage of the EBV genome and detected many variants, across all the nine EBV genes tested
Summary
Posttransplant lymphoproliferative disorders (PTLDs), an abnormal proliferation of lymphoid cells under posttransplant immunosuppression, are a major malignant complication of organ and tissue transplant.[1,2,3,4] PTLDs have a high morbidity and 5‐year mortality that exceeds 50%.3 About 50%‐80% of PTLD cases are strongly related to the oncogenic Epstein‐Barr virus (EBV).[5]. About 50%‐80% of PTLD cases are strongly related to the oncogenic Epstein‐Barr virus (EBV).[5] Cytomegalovirus seromismatch has been associated in some studies[6,7] but not consistently. It is not known whether other viruses are associated with PTLD. While recent mortality rates have decreased with general medical advances and newer therapies,[8,9] mortality remains high[10] and graft failure is a significant complication of interventions.[11] Though many prognostic indices have been used to predict survival after PTLD, mortality after PTLD is not fully explained by these indices.[12,13,14] These indices vary considerably in their component prognostic factors; they do not consistently include the same clinical, viral, epidemiologic or tumor characteristics. Host responses to EBV and the degree of overall immunosuppression have been studied as possible contributors to prognosis and outcome, but still do not fully explain the outcomes.[15,16,17]
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