Gene expression profiling reveals clear differences between EBV-positive and EBV-negative posttransplant lymphoproliferative disorders

Am J Transplant. 2013 May;13(5):1305-16. doi: 10.1111/ajt.12196. Epub 2013 Mar 14.

Abstract

Posttransplant patients are at risk of developing a potentially life-threatening posttransplantation lymphoproliferative disorder (PTLD), most often of diffuse large B cell lymphoma (DLBCL) morphology and associated with Epstein-Barr Virus (EBV) infection. The aim of this study was to characterize the clinicopathological and molecular-genetic characteristics of posttransplant DLBCL and to elucidate whether EBV(+) and EBV(-) posttransplant DLBCL are biologically different. We performed gene expression profiling studies on 48 DLBCL of which 33 arose posttransplantation (PT-DLBCL; 72% EBV+) and 15 in immunocompetent hosts (IC-DLBCL; none EBV+). Unsupervised hierarchical analysis showed clustering of samples related to EBV-status rather than immune status. Except for decreased T cell signaling these cases were inseparable from EBV(-) IC-DLBCL. In contrast, a viral response signature clearly segregated EBV(+) PT-DLBCL from EBV(-) PT-DLBCL and IC-DLBCL cases that were intermixed. The broad EBV latency profile (LMP1+/EBNA2+) was expressed in 59% of EBV(+) PT-DLBCL and associated with a more elaborate inflammatory response compared to intermediate latency (LMP1+/EBNA2-). Inference analysis revealed a role for innate and tolerogenic immune responses (including VSIG4 and IDO1) in EBV(+) PT-DLBCL. In conclusion we can state that the EBV signature is the most determining factor in the pathogenesis of EBV(+) PT-DLBCL.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Child
  • Child, Preschool
  • Epstein-Barr Virus Infections / complications*
  • Epstein-Barr Virus Infections / genetics
  • Epstein-Barr Virus Infections / virology
  • Female
  • Follow-Up Studies
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation, Neoplastic*
  • Herpesvirus 4, Human / genetics*
  • Humans
  • In Situ Hybridization
  • Lymphoproliferative Disorders / complications
  • Lymphoproliferative Disorders / genetics*
  • Lymphoproliferative Disorders / metabolism
  • Male
  • Middle Aged
  • Organ Transplantation*
  • Retrospective Studies
  • Viral Proteins / biosynthesis*
  • Viral Proteins / genetics
  • Virus Latency
  • Young Adult

Substances

  • Viral Proteins