Genomic variations in EBNA3C of EBV associate with posttransplant lymphoproliferative disorder
Eden M. Maloney, Vincent A. Busque, Sin Ting Hui, Jiaying Toh, Marcelo Fernandez-Vina, Sheri M. Krams, Carlos O. Esquivel, Olivia M. Martinez
Eden M. Maloney, Vincent A. Busque, Sin Ting Hui, Jiaying Toh, Marcelo Fernandez-Vina, Sheri M. Krams, Carlos O. Esquivel, Olivia M. Martinez
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Research Article Transplantation

Genomic variations in EBNA3C of EBV associate with posttransplant lymphoproliferative disorder

Abstract

Epstein-Barr Virus (EBV) is a ubiquitous virus linked to a variety of lymphoid and epithelial malignancies. In solid organ and hematopoietic stem cell transplant recipients, EBV is causally associated with posttransplant lymphoproliferative disorder (PTLD), a group of heterogeneous lymphoid diseases. EBV+ B cell lymphomas that develop in the context of PTLD are generally attributed to the immunosuppression required to promote graft survival, but little is known regarding the role of EBV genome diversity in the development of malignancy. We deep-sequenced the EBV genome from the peripheral blood of 18 solid organ transplant recipients, including 6 PTLD patients. Sequences from 6 EBV+ spontaneous lymphoblastoid B cell lines (SLCL) were similarly analyzed. The EBV genome from PTLD patients had a significantly greater number of variations than EBV from transplant recipients without PTLD. Importantly, there were 15 nonsynonymous variations, including 8 in the latent cycle gene EBNA3C that were associated with the development of PTLD. One of the nonsynonymous variations in EBNA3C is located within a previously defined T cell epitope. These findings suggest that variations in the EBV genome can contribute to the pathogenesis of PTLD.

Authors

Eden M. Maloney, Vincent A. Busque, Sin Ting Hui, Jiaying Toh, Marcelo Fernandez-Vina, Sheri M. Krams, Carlos O. Esquivel, Olivia M. Martinez

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Figure 1

PTLD-derived EBV genomes have significantly more variations in hotspots than EBVlo and EBVhi genomes.

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PTLD-derived EBV genomes have significantly more variations in hotspots ...
(A) The number of variations within a 1000-nt sliding window was determined for each location of the EBV genome from 0–172,000 bp. Variations included insertions, deletions, SNV, and MSV. The bar graph corresponds to the number of variations in each 1000-nt window for SLCL (light blue, n = 6), PTLD (dark blue, n = 6), EBVhi (light green, n = 6), EBVlo (dark green, n = 6), and control (pink, n = 4) groups. Gene locations are shown below: latent genes (red), lytic genes (gray), and noncoding regions (white). Segments (1000 nt) that contain significant differences in number of variations between groups are lettered a–k. (B) Segments (1,000 nt) of the EBV genome that contain significant differences in number of variations between PTLD and EBVhi and/or EBVlo groups. Statistical significance between number of variations from PTLD, EBVhi, and EBVlo groups was determined using 2-way ANOVA with Tukey’s multiple comparisons test. Lines on the bottom indicate significant comparisons: PTLD versus EBVlo, PTLD versus EBVhi, PTLD versus EBVlo, and PTLD versus EBVhi. Region a, includes part of EBNA2 gene, PTLD versus EBVlo, P = 0.0009; region i, within BBLF4 gene, PTLD versus EBVlo, P = 0.001; Region j, includes part of BDLF3 and BDLF2 genes, PTLD versus EBVlo, P = 0.007; Region b, within BPLF1 gene PTLD versus EBVhi, P = 0.02; Region e, within EBNA3C gene, PTLD versus EBVhi, P < 0.0001; Region f, within EBNA3C gene, PTLD versus EBVhi, P < 0.0001; Region g, includes part of EBNA3C, BZLF2, and BZLF1 genes, PTLD versus EBVhi, P = 0.04; Region h, includes part of BZLF1 gene, PTLD versus EBVhi, P = 0.04; Region k, within a noncoding region, PTLD versus EBVhi, P = 0.02; Region c, includes part of EBNA3B and EBNA3C gene, PTLD versus EBVlo, P < 0.0001 and PTLD versus EBVhi, P < 0.0001; Region d, within EBNA3C gene, PTLD versus EBVlo, P < 0.0001, PTLD versus EBVhi, P < 0.0001.