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Volume 40 Issue 5
October 2025
    Citation: Xiaoqing Liu, Guangjie Jiang, Chianru Tan, Kun Chen, Zhewei Sun, Jiaying Du, Bei Wang, Fuqi Ai, Yimin Ma, Yueru Tian, Yong Guo, Ming Guan. The pathogenic role and genomic characteristics of Epstein-Barr virus in vitreoretinal lymphoma .VIROLOGICA SINICA, 2025, 40(5) : 804-811.  http://dx.doi.org/10.1016/j.virs.2025.09.007
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    The pathogenic role and genomic characteristics of Epstein-Barr virus in vitreoretinal lymphoma

    • a. Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China;

    • b. School of Biomedical Engineering, Tsinghua University, Beijing 100084, China

    • Epstein-Barr virus (EBV) infection is well-known for its association with lymphoproliferative disorders and various lymphomas, causing significant global morbidity and mortality. EBV-positive vitreoretinal lymphoma (VRL) is exceedingly rare. As a result, the pathogenic role and genomic characteristics of EBV in VRL remain poorly understood. In this study, we employed droplet digital PCR (ddPCR) combined with EBV-specific immunofluorescence assay to detect EBV in the vitreous fluid of fifty-three VRL patients. We found that approximately 28% (15/53) of the patients were EBV positive. Analysis of clinical data showed that EBV-positive VRL patients had shorter progression-free survival (PFS) compared to EBV-negative patients (P = 0.004). Additionally, through integration of EBV-targeted sequencing and PCR-based deep sequencing, we found that all five VRL-derived EBV genomes formed a distinct cluster within one phylogenetic branch. Meanwhile, several non-synonymous mutations were exclusively detected in the VRL group, including S229T in latent membrane protein 1 (LMP1) and G2248R in the Epstein-Barr virus BamHI-PraL fragment 1 (BPLF1). In conclusion, our findings suggest that EBV as a risk factor associated with poor prognosis in VRL, and we provide a genome-wide view of EBV sequence variations from VRL patients. This may offer insights into the pathogenic role of EBV in VRL and could potentially assist in the diagnosis and treatment of this disease.
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      2. Bonzheim, I., Giese, S., Deuter, C., Susskind, D., Zierhut, M., Waizel, M., Szurman, P., Federmann, B., Schmidt, J., Quintanilla-Martinez, L., Coupland, S.E., Bartz-Schmidt, K.U.,Fend, F., 2015. High frequency of MYD88 mutations in vitreoretinal B-cell lymphoma: a valuable tool to improve diagnostic yield of vitreous aspirates. Blood, 126, 76-79.

      3. Chen, K., Qin, H., Li, X., Zhou, X., Ma, J.,Guan, M., 2024. Diagnostic potential of vitreoretinal lymphoma by detection of gene mutations with NGS in 25 Chinese patients. Clin Chim Acta, 561, 119827.

      4. Gao, S., Zhou, Y., Jin, X., Lin, Z., Zhong, Y.,Shen, X., 2019. Primary vitreoretinal natural killer/T-cell lymphoma with breast involvement: A case report and review of the literature. Surv Ophthalmol, 64, 225-232.

      5. Hernandez-Verdin, I., Kirasic, E., Wienand, K., Mokhtari, K., Eimer, S., Loiseau, H., Rousseau, A., Paillassa, J., Ahle, G., Lerintiu, F., et al., 2023. Molecular and clinical diversity in primary central nervous system lymphoma. Ann Oncol, 34, 186-199.

      6. Hosseini, S.M., Abrishami, M., Barashki, E.,Zamani, G., 2021. Primary Intraocular Lymphoma in a Patient with Bilateral Epstein-Barr Virus Panuveitis. Case Rep Ophthalmol Med, 2021, 9496173.

      7. Lee, J., Kim, B., Lee, H., Park, H., Ho Byeon, S., Choi, J.R., Lee, S.C., Lee, S.T.,Lee, C.S., 2020. Whole exome sequencing identifies mutational signatures of vitreoretinal lymphoma. Haematologica, 105, e458-460.

      8. Liu, M., Wang, X., Zhang, L., Feng, G., Zeng, Y., Wang, R., & Xie, Z., 2022. Epidemiological characteristics and disease burden of infectious mononucleosis in hospitalized children in China: A nationwide retrospective study. Virologica Sinica, 37, 637-645.

      9. Menean, M., Giuffre, C., Cicinelli, M.V., Marchese, A., Modorati, G., Bandello, F.,Miserocchi, E., 2024. A comprehensive overview of diagnosis, imaging and treatment of vitreoretinal lymphoma. Eur J Ophthalmol, 34, 931-940.

      10. Mittra, R.A., Pulido, J.S., Hanson, G.A., Kajdacsy-Balla, A.,Brummitt, C.F., 1999. Primary ocular Epstein-Barr virus-associated non-Hodgkin's lymphoma in a patient with AIDS: a clinicopathologic report. Retina, 19, 45-50.

      11. Moussa, K., Gonzales, J.A., Shantha, J., Acharya, N.R.,Doan, T., 2023. Prevalence of Epstein-Barr Virus in Patients with Intraocular Inflammation. Ocul Immunol Inflamm, 31, 978-980.

      12. Palser, A.L., Grayson, N.E., White, R.E., Corton, C., Correia, S., Ba Abdullah, M.M., Watson, S.J., Cotten, M., Arrand, J.R., Murray, P.G., Allday, M.J., Rickinson, A.B., Young, L.S., Farrell, P.J.,Kellam, P., 2015. Genome diversity of Epstein-Barr virus from multiple tumor types and normal infection. J Virol, 89, 5222-5237.

      13. Sun, C., Muraoka, Y., Ishihara, K., Morooka, S., Akada, M., Hata, M.,Tsujikawa, A., 2025. A CASE OF EPSTEIN-BARR VIRUS-ASSOCIATED PRIMARY VITREORETINAL LYMPHOMA IN AN IMMUNOSUPPRESSED PATIENT. Retin Cases Brief Rep, 19, 23-27.

      14. Wang, M.M., Tan, W.J., Lim, T.S.,Chan, A.S.Y., 2021. PreservCyt Is an Optimal Fixative that Permits Cytologic and Molecular Analyses of Vitreoretinal Lymphoma Biopsies. Ocul Immunol Inflamm, 29, 430-439.

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      16. Xu, M., Yao, Y., Chen, H., Zhang, S., Cao, S.M., Zhang, Z., Luo, B., Liu, Z., Li, Z., Xiang, T., et al., 2019. Genome sequencing analysis identifies Epstein-Barr virus subtypes associated with high risk of nasopharyngeal carcinoma. Nat Genet, 51, 1131-1136.

      17. Yin, Q., Wang, J.,Wang, Z., 2022. Epstein-Barr virus central nervous system involvement in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Ann Hematol, 101, 2471-2476.

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      The pathogenic role and genomic characteristics of Epstein-Barr virus in vitreoretinal lymphoma

        Corresponding author: Yueru Tian, vicky8025@126.com
        Corresponding author: Yong Guo, yongguo@tsinghua.edu.cn
        Corresponding author: Ming Guan, guanming@shmu.edu.cn
      • a. Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China;
      • b. School of Biomedical Engineering, Tsinghua University, Beijing 100084, China
      • Received Date: 22 July 2025
      • Accepted Date: 24 September 2025

      Abstract: Epstein-Barr virus (EBV) infection is well-known for its association with lymphoproliferative disorders and various lymphomas, causing significant global morbidity and mortality. EBV-positive vitreoretinal lymphoma (VRL) is exceedingly rare. As a result, the pathogenic role and genomic characteristics of EBV in VRL remain poorly understood. In this study, we employed droplet digital PCR (ddPCR) combined with EBV-specific immunofluorescence assay to detect EBV in the vitreous fluid of fifty-three VRL patients. We found that approximately 28% (15/53) of the patients were EBV positive. Analysis of clinical data showed that EBV-positive VRL patients had shorter progression-free survival (PFS) compared to EBV-negative patients (P = 0.004). Additionally, through integration of EBV-targeted sequencing and PCR-based deep sequencing, we found that all five VRL-derived EBV genomes formed a distinct cluster within one phylogenetic branch. Meanwhile, several non-synonymous mutations were exclusively detected in the VRL group, including S229T in latent membrane protein 1 (LMP1) and G2248R in the Epstein-Barr virus BamHI-PraL fragment 1 (BPLF1). In conclusion, our findings suggest that EBV as a risk factor associated with poor prognosis in VRL, and we provide a genome-wide view of EBV sequence variations from VRL patients. This may offer insights into the pathogenic role of EBV in VRL and could potentially assist in the diagnosis and treatment of this disease.

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