title: 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.
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Samsung Biomedical Research Institute, Seoul, Korea.
authors.forename: Heejei
authors.initials: H
authors.lastname: Yoon
authors.forename: Sanghui
authors.initials: S
authors.lastname: Park
authors.forename: Hyunjeong
authors.initials: H
authors.lastname: Ju
authors.forename: Sang Yun
authors.initials: SY
authors.lastname: Ha
authors.forename: InSuk
authors.initials: I
authors.lastname: Sohn
authors.forename: Jisuk
authors.initials: J
authors.lastname: Jo
authors.forename: In-Gu
authors.initials: IG
authors.lastname: Do
authors.forename: Sookee
authors.initials: S
authors.lastname: Min
authors.forename: Seok Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Won Seog
authors.initials: WS
authors.lastname: Kim
authors.forename: Hae Yong
authors.initials: HY
authors.lastname: Yoo
authors.forename: Young Hyeh
authors.initials: YH
authors.lastname: Ko
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002877:Chromosomes, Human; D056915:DNA Copy Number Variations; D005260:Female; D020869:Gene Expression Profiling; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged