Epstein-Barr Virus and Classical Hodgkin’s Lymphoma

VE Gurtsevich

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Vladimir Eduardovich Gurtsevich, DSci, Professor, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-25-64; e-mail: gurvlad532@yahoo.com

For citation: Gurtsevitch VE. Epstein-Barr Virus and Classical Hodgkin’s Lymphoma. Clinical oncohematology. 2016;9(2):101–14 (In Russ).

DOI: 10.21320/2500-2139-2016-9-2-101-114


ABSTRACT

Among other oncogenic human viruses, the Epstein-Barr virus (EBV) drew special attention due to its unique properties. Being widespread among the population of the planet, the virus is also a leader in the number of associated different benign and malignant neoplasms of lymphoid and epithelial origin. The oncogenic potential of EBV is related to its ability to infect and transform human lymphocytes. In cases, when the interaction between reproduction of EBV, its latent state and immune control of the body is impaired, conditions for long-term proliferation of EBV-infected cells and their malignant transformation are formed. According to some investigators, the molecular mechanisms of EBV-associated carcinogenesis are due to the ability of the viral genome to promote the expression of series of products that simulate a number of growth factors and transcription and produce an anti-apoptotic effect. These products impair EBV-encoded signaling pathways that regulate a variety of cellular functions of homeostasis giving a cell the ability to proliferate indefinitely. However, the exact mechanism by which the EBV initiates tumor formation is not clear. The review provides summarized information on the structure and oncogenic potential of EBV, morphological and clinical cases of Hodgkin’s lymphoma (HL), and the role of EBV in the pathogenesis of types of HL associated with the virus. The review also dwells on the latest data on the use of EBV DNA plasma levels of patients with HL as a biomarker reflecting the effectiveness of the treatment performed and the prognosis of the disease.


Keywords: Epstein-Barr virus, EBV, latent membrane protein 1, LMP1, Hodgkin’s lymphoma, copies of EBV DNA.

Received: February 5, 2016

Accepted: February 8, 2016

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REFERENCES

  1. Zur Hausen H, de Villiers EM. Reprint of: cancer “causation” by infections—individual contributions and synergistic networks. Semin Oncol. 2015;42(2):207–22. doi: 10.1053/j.seminoncol.2015.02.019.
  2. Santos-Juanes J, Fernandez-Vega I, Fuentes N, et al. Merkel cell carcinoma and Merkel cell polyomavirus: a systematic review and meta-analysis. Br J Dermatol. 2015;173(1):42–9. doi: 10.1111/bjd.13870.
  3. Rickinson AB, Young LS, Rowe M. Influence of the Epstein-Barr virus nuclear antigen EBNA 2 on the growth phenotype of virus-transformed B cells. J Virol. 1987;61(5):1310–7.
  4. Rickinson AB, Long HM, Palendira U, et al. Cellular immune controls over Epstein-Barr virus infection: new lessons from the clinic and the laboratory. Trends Immunol. 2014;35(4):159–69. doi: 10.1016/j.it.2014.01.003.
  5. Woodman CB, Collins SI, Vavrusova N, et al. Role of sexual behavior in the acquisition of asymptomatic Epstein-Barr virus infection: a longitudinal study. Pediatr Infect Dis J. 2005;24(6):498–502. doi: 10.1097/01.inf.0000164709.40358.b6.
  6. Henle G, Henle W, Diehl V. Relation of Burkitt’s tumor-associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci USA. 1968;59(1):94–101. doi: 10.1073/pnas.59.1.94.
  7. Tanner J, Weis J, Fearon D, et al. Epstein-Barr virus gp350/220 binding to the B lymphocyte C3d receptor mediates adsorption, capping, and endocytosis. Cell. 1987;50(2):203–13. doi:10.1016/0092-8674(87)90216-9.
  8. Connolly SA, Jackson JO, Jardetzky TS, et al. Fusing structure and function: a structural view of the herpesvirus entry machinery. Nat Rev Microbiol. 2011;9(5):369–81. doi: 10.1038/nrmicro2548.
  9. Janz A, Oezel M, Kurzeder C, et al. Infectious Epstein-Barr virus lacking major glycoprotein BLLF1 (gp350/220) demonstrates the existence of additional viral ligands. J Virol. 2000;74(21):10142–52. doi: 10.1128/jvi.74.21.10142-10152.2000.
  10. Ogembo JG, Kannan L, Ghiran I, et al. Human complement receptor type 1/CD35 is an Epstein-Barr Virus receptor. Cell Rep. 2013;3(2):371–85. doi:10.1016/j.celrep.2013.01.023.
  11. Kempkes B, Robertson ES. Epstein-Barr virus latency: current and future perspectives. Curr Opin Virol. 2015;14:138–44. doi: 10.1016/j.coviro.2015.09.007.
  12. Sample J, Kieff E. Transcription of the Epstein-Barr virus genome during latency in growth-transformed lymphocytes. J Virol. 1990;64(4):1667–74.
  13. Babcock GJ, Decker LL, Volk M, et al. EBV persistence in memory B cells in vivo. Immunity. 1998;9(3):395–404. doi: 10.1016/S1074-7613(00)80622-6.
  14. Shannon-Lowe C, Adland E, Bell AI, et al. Features distinguishing Epstein-Barr virus infections of epithelial cells and B cells: viral genome expression, genome maintenance, and genome amplification. J Virol. 2009;83(15):7749–60. doi: 10.1128/JVI.00108-09.
  15. Rickinson A. Epstein-Barr virus. Virus Res. 2002;82(1–2):109–13. doi: 10.1016/s0168-1702(01)00436-1.
  16. Rowe M, Lear AL, Croom-Carter D, et al. Three pathways of Epstein-Barr virus gene activation from EBNA1-positive latency in B lymphocytes. J Virol. 1992;66(1):122–31.
  17. Portis T, Dyck P, Longnecker R. Epstein-Barr Virus (EBV) LMP2A induces alterations in gene transcription similar to those observed in Reed-Sternberg cells of Hodgkin lymphoma. Blood. 2003;102(12):4166–78. doi: 10.1182/blood-2003-04-1018.
  18. Sample J, Young L, Martin B, et al. Epstein-Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J Virol. 1990;64(9):4084–92.
  19. Sixbey JW, Shirley P, Chesney PJ, et al. Detection of a second widespread strain of Epstein-Barr virus. The Lancet. 1989;2(8666):761–5. doi: 10.1016/s0140-6736(89)90829-5.
  20. Gratama JW, Ernberg I. Molecular epidemiology of Epstein-Barr virus infection. Adv Cancer Res. 1995;67:197–255. doi: 10.1016/s0065-230x(08)60714-9.
  21. Young LS, Dawson CW, Eliopoulos AG. The expression and function of Epstein-Barr virus encoded latent genes. Mol Pathol. 2000;53(5):238–47. doi: 10.1136/mp.53.5.238.
  22. Mosialos G, Birkenbach M, Yalamanchili R, et al. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell. 1995;80(3):389–99. doi: 10.1016/0092-8674(95)90489-1.
  23. Nitta T, Chiba A, Yamashita A, et al. NF-kappaB is required for cell death induction by latent membrane protein 1 of Epstein-Barr virus. Cell Signal. 2003;15(4):423–33. doi: 10.1016/S0898-6568(02)00141-9.
  24. Aviel S, Winberg G, Massucci M, Ciechanover A. Degradation of the Epstein-Barr virus latent membrane protein 1 (LMP1) by the ubiquitin-proteasome pathway. Targeting via ubiquitination of the N-terminal residue. J Biol Chem. 2000;275(31):23491–9. doi: 10.1074/jbc.M002052200.
  25. Gires O, Kohlhuber F, Kilger E, et al. Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. EMBO J. 1999;18(11):3064–73. doi: 10.1093/emboj/18.11.3064.
  26. Bentz GL, Whitehurst CB, Pagano JS. Epstein-Barr virus latent membrane protein 1 (LMP1) C-terminal-activating region 3 contributes to LMP1-mediated cellular migration via its interaction with Ubc9. J Virol. 2011;85(19):10144–53. doi: 10.1128/JVI.05035-11.
  27. Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985;43(3):831–40. doi: 10.1016/0092-8674(85)90256-9.
  28. Dawson CW, Port RJ, Young LS. The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin Cancer Biol. 2012;22(2):144–53. doi: 10.1016/j.semcancer.2012.01.004.
  29. Смирнова К.В., Дидук С.В., Сенюта Н.Б., Гурцевич В.Э. Молекулярно-биологические свойства гена LMP1 вируса Эпштейна—Барр: структура, функции и полиморфизм. Вопросы вирусологии. 2015;60(3):5–13.
    [Smirnova KV, Diduk SV, Senyuta NB, Gurtsevich VE. Molecular biological properties of the Epstein-Barr virus LMP1 gene: structure, function, and polymorphism. Voprosy virusologii. 2015;60(3):5–13. (In Russ)]
  30. Vockerodt M, Morgan SL, Kuo M, et al. The Epstein-Barr virus oncoprotein, latent membrane protein-1, reprograms germinal centre B cells towards a Hodgkin’s Reed-Sternberg-like phenotype. J Pathol. 2008;216(1):83–92. doi: 10.1002/path.2384.
  31. Raab-Traub N. Epstein-Barr virus in the pathogenesis of NPC. Semin Cancer Biol. 2002;12:431–41. doi: 10.1016/s1044579x0200086x.
  32. Raab-Traub N. Novel mechanisms of EBV-induced oncogenesis. Curr Opin Virol. 2012;2(4):453–8. doi: 10.1016/j.coviro.2012.07.001.
  33. Soni V, Cahir-McFarland E, Kieff E. LMP1 TRAFficking activates growth and survival pathways. Adv Exp Med Biol. 2007;597:173–87. doi: 10.3390/v5041131.
  34. Man C, Rosa J, Lee LT, et al. Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structures and induces chromosomal aberrations in human epithelial cells. Oncogene. 2007;26(21):3069–80. doi: 10.1038/sj.onc.1210106.
  35. Guo L, Tang M, Yang L, et al. Epstein-Barr virus oncoprotein LMP1 mediates surviving upregulation by p53 contributing to G1/S cell cycle progression in nasopharyngeal carcinoma. Int J Mol Med. 2012;29(4):574–80. doi: 10.3892/ijmm.2012.889.
  36. Horikawa T, Yoshizaki T, Kondo S, et al. Epstein-Barr Virus latent membrane protein 1 induces Snail and epithelial-mesenchymal transition in metastatic nasopharyngeal carcinoma. Br J Cancer. 2011;104(7):1160–7. doi: 10.1038/bjc.2011.38.
  37. Xiao L, Hu ZY, Dong X, et al. Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy. Oncogene. 2014;33(37):4568–78. doi: 10.1038/onc.2014.32.
  38. Sun W, Liu DB, Li WW, et al. Interleukin-6 promotes the migration and invasion of nasopharyngeal carcinoma cell lines and upregulates the expression of MMP-2 and MMP-9. Int J Oncol. 2014;44(5):1551–60. doi: 10.3892/ijo.2014.2323.
  39. Tzellos S, Farrell PJ. Epstein-Barr virus sequence variation-biology and disease. Pathogens. 2012;1(2):156–74. doi: 10.3390/pathogens1020156.
  40. Walling DM, Shebib N, Weaver SC, et al. The molecular epidemiology and evolution of Epstein-Barr virus: sequence variation and genetic recombination in the latent membrane protein-1 gene. J Infect Dis. 1999;179(4):763–74. doi: 10.1086/314672.
  41. Hu LF, Zabarovsky ER, Chen F, et al. Isolation and sequencing of the Epstein-Barr virus BNLF-1 gene (LMP1) from a Chinese nasopharyngeal carcinoma. J Gen Virol. 1991;72(Pt 10):2399–409. doi: 10.1099/0022-1317-72-10-2399.
  42. Nitta T, Chiba A, Yamamoto N, et al. Lack of cytotoxic property in a variant of Epstein-Barr virus latent membrane protein-1 isolated from nasopharyngeal carcinoma. Cell Signal. 2004;16(9):1071–81. doi: 10.1016/s0898-6568(04)00032-4.
  43. da Costa VG, Marques-Silva AC, Moreli ML. The Epstein-Barr virus latent membrane protein-1 (LMP1) 30-bp deletion and XhoI-polymorphism in nasopharyngeal carcinoma: a meta-analysis of observational studies. Syst Rev. 2015;4(1):46. doi: 10.1186/s13643-015-0037-z.
  44. Rowe M, Peng-Pilon M, Huen DS, et al. Upregulation of bcl-2 by the Epstein-Barr virus latent membrane protein LMP1: a B-cell-specific response that is delayed relative to NF-kappaB activation and to induction of cell surface markers. J Virol. 1994;68(9):5602–12.
  45. Trivedi P, Hu LF, Chen F, et al. Epstein-Barr virus (EBV)-encoded membrane protein LMP1 from a nasopharyngeal carcinoma is non-immunogenic in a murine model system, in contrast to a B cell-derived homologue. Eur J Cancer. 1994;30(1):84–8. doi: 10.1016/s0959-8049(05)80024-3.
  46. Knecht H, Bachmann E, Brousset P, et al. Deletions within the LMP1 oncogene of Epstein-Barr virus are clustered in Hodgkin’s disease and identical to those observed in nasopharyngeal carcinoma. Blood. 1993;82(10):2937–42.
  47. Miller WE, Edwards RH, Walling DM, et al. Sequence variation in the Epstein-Barr virus latent membrane protein 1. J Gen Virol. 1994;75(Pt 10):2729–40. doi: 10.1099/0022-1317-75-10-2729.
  48. Weiss LM. Epstein-Barr virus and Hodgkin’s disease. Curr Oncol Rep. 2000;2(2):199–204. doi: 10.1007/s11912-000-0094-9.
  49. Ковригина А.М., Пробатова Н.А. Лимфома Ходжкина и крупноклеточные лимфомы. М.: МИА, 2007.
    [Kovrigina AM, Probatova NA. Limfoma Khodzhkina i krupnokletochnye limfomy. (Hodgkin’s lymphomas and large cell lymphomas.) Moscow: MIA Publ.; 2007. (In Russ)]
  50. Клиническая онкогематология: Руководство для врачей, 2-е изд. Под ред. М.А. Волковой. М.: Медицина, 2007.
    [Volkova MA, ed. Klinicheskaya  onkogematologiya: Rukovodstvo dlya vrachei. (Clinical oncohematology: manual for physicians.) 2nd edition. Moscow: Meditsina Publ.; 2007. (In Russ)]
  51. Dorsett Y, Robbiani DF, Jankovic M, et al. A role for AID in chromosome translocations between c-myc and the IgH variable region. J Exp Med. 2007;204(9):2225–32. doi: 10.1084/jem.20070884.
  52. Stein H. Hodgkin lymphoma – introduction. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008. pp. 321–34.
  53. Diehl V, Stein H, Hummel M, et al. Hodgkin’s lymphoma: biology and treatment strategies for primary, refractory, and relapsed disease. Hematology Am Soc Hematol Educ Program. 2003;1:225–47. doi: 10.1182/asheducation-2003.1.225.
  54. Chapman AL, Rickinson AB. Epstein-Barr virus in Hodgkin’s disease. Ann Oncol. 1998;9(Suppl 5):S5–16. doi: 10.1093/annonc/9.suppl_5.s5.
  55. Deacon EM, Pallesen G, Niedobitek G, et al. Epstein-Barr virus and Hodgkin’s disease: transcriptional analysis of virus latency in the malignant cells. J Exp Med. 1993;177(2):339–49. doi: 10.1084/jem.177.2.339.
  56. Kuppers R, Rajewsky K, Zhao M, et al. Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci USA. 1994;91(23):10962–6. doi: 10.1073/pnas.91.23.10962.
  57. Thomas RK, Re D, Wolf J, et al. Part I: Hodgkin’s lymphoma—molecular biology of Hodgkin and Reed-Sternberg cells. Lancet Oncol. 2004;5(1):11–8. doi: 10.1016/S1470-2045(03)01319-6.
  58. Cartwright RA, Watkins G. Epidemiology of Hodgkin’s disease: a review. Hematol Oncol. 2004;22(1):11–26. doi: 10.1002/hon.723.
  59. Jarrett AF, Armstrong AA, Alexander E. Epidemiology of EBV and Hodgkin’s lymphoma. Ann Oncol. 1996;7(Suppl 4):5–10. doi: 10.1093/annonc/7.suppl_4.s5.
  60. Glaser SL, Lin RJ, Stewart SL, et al. Epstein-Barr virus-associated Hodgkin’s disease: epidemiologic characteristics in international data. Int J Cancer. 1997;70(4):375–82. doi: 10.1002/(sici)1097-0215(19970207)70:4<375::aid-ijc1>3.0.co;2-t.
  61. Cader FZ, Kearns P, Young L, et al. The contribution of the Epstein-Barr virus to the pathogenesis of childhood lymphomas. Cancer Treat Rev. 2010;36(4):348–53. doi: 10.1016/j.ctrv.2010.02.011.
  62. Jarrett RF, Gallagher A, Jones DB, et al. Detection of Epstein-Barr virus genomes in Hodgkin’s disease: relation to age. J Clin Pathol. 1991;44(10):844–8. doi: 10.1136/jcp.44.10.844.
  63. Armstrong AA, Alexander FE, Cartwright R, et al. Epstein-Barr virus and Hodgkin’s disease: further evidence for the three disease hypothesis. Leukemia. 1998;12(8):1272–6. doi: 10.1038/sj.leu.2401097.
  64. Oyama T, Ichimura K, Suzuki R, et al. Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients. Am J Surg Pathol. 2003;27(1):16–26. doi: 10.1097/00000478-200301000-00003.
  65. Oyama T, Yamamoto K, Asano N, et al. Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin Cancer Res. 2007;13(17):5124–32. doi: 10.1158/1078-0432.ccr-06-2823.
  66. Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med. 2004;350(13):1328–37. doi: 10.1056/NEJMra032015.
  67. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer. 2005;5(4):251–62. doi: 10.1038/nrc1589.
  68. Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol. 2008;8(1):22–33. doi: 10.1038/nri2217.
  69. Caldwell RG, Wilson JB, Anderson SJ, et al. Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity. 1998;9(3):405–11. doi: 10.1016/s1074-7613(00)80623-8.
  70. Gires O, Zimber-Strobl U, Gonnella R, et al. Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J. 1997;16(20):6131–40. doi: 10.1093/emboj/18.11.3064.
  71. Laichalk LL, Thorley-Lawson DA. Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J Virol. 2005;79(2):1296–307. doi: 10.1128/JVI.79.2.1296-1307.2005.
  72. Alexander FE, Jarrett RF, Lawrence D, et al. Risk factors for Hodgkin’s disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents. Br J Cancer. 2000;82(5):1117–21. doi: 10.1054/bjoc.1999.1049.
  73. Mueller N, Evans A, Harris NL, et al. Hodgkin’s disease and Epstein-Barr virus. Altered antibody pattern before diagnosis. N Engl J Med. 1989;320(11):689–95. doi: 10.1056/nejm198903163201103.
  74. Weiss LM, Strickler JG, Warnke RA, et al. Epstein-Barr viral DNA in tissues of Hodgkin’s disease. Am J Pathol. 1987;129(1):86–91.
  75. Anagnostopoulos I, Herbst H, Niedobitek G, et al. Demonstration of monoclonal EBV genomes in Hodgkin’s disease and Ki-1-positive anaplastic large cell lymphoma by combined Southern blot and in situ hybridization. Blood. 1989;74(2):810–6.
  76. Re D, Kuppers R, Diehl V. Molecular pathogenesis of Hodgkin’s lymphoma. J Clin Oncol. 2005;23(26):6379–86. doi: 10.1200/JCO.2005.55.013.
  77. Mancao C, Altmann M, Jungnickel B, et al. Rescue of “crippled” germinal center B cells from apoptosis by Epstein-Barr virus. Blood. 2005;106(13):4339–44. doi: 10.1182/blood-2005-06-2341.
  78. Chaganti S, Bell AI, Pastor NB, et al. Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes. Blood. 2005;106(13):4249–52. doi: 10.1182/blood-2005-06-2327.
  79. Kapatai G, Murray P. Contribution of the Epstein Barr virus to the molecular pathogenesis of Hodgkin lymphoma. J Clin Pathol. 2007;60(12):1342–9. doi: 10.1136/jcp.2007.050146.
  80. Kuppers R. B cells under influence: transformation of B cells by Epstein-Barr virus. Nat Rev Immunol. 2003;3(10):801–12. doi: 10.1038/nri1201.
  81. Huen DS, Henderson SA, Croom-Carter D, et al. The Epstein-Barr virus latent membrane protein-1 (LMP1) mediates activation of NF-kappa B and cell surface phenotype via two effector regions in its carboxy-terminal cytoplasmic domain. Oncogene. 1995;10:549–60.
  82. Kieser A, Kilger E, Gires O, et al. Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. EMBO J. 1997;16(21):6478–85. doi: 10.1093/emboj/16.21.6478.
  83. Kube D, Holtick U, Vockerodt M, et al. STAT3 is constitutively activated in Hodgkin cell lines. Blood. 2001;98(3):762–70. doi: 10.1182/blood.V98.3.762.
  84. Dutton A, Reynolds GM, Dawson CW, et al Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin’s lymphoma cells through a mechanism involving Akt kinase and mTOR. J Pathol. 2005;205(4):498–506. doi: 10.1002/path.1725.
  85. Brielmeier M, Mautner J, Laux G, et al. The latent membrane protein 2 gene of Epstein-Barr virus is important for efficient B cell immortalization. J Gen Virol. 1996;77(Pt 11):2807–18. doi: 10.1099/0022-1317-77-11-2807.
  86. Casola S, Otipoby KL, Alimzhanov M, et al. B cell receptor signal strength determines B cell fate. Nat Immunol. 2004;5(3):317–27. doi: 10.1038/ni1036.
  87. Engels N, Yigit G, Emmerich CH, et al. Epstein-Barr virus LMP2A signaling in statu nascendi mimics a B cell antigen receptor-like activation signal. Cell Commun Signal. 2012;10(1):9. doi: 10.1186/1478-811X-10-9.
  88. Portis T, Dyck P, Longnecker R. Epstein-Barr Virus (EBV) LMP2A induces alterations in gene transcription similar to those observed in Reed-Sternberg cells of Hodgkin lymphoma. Blood. 2003;102(12):4166–78. doi: 10.1182/blood-2003-04-1018.
  89. Portis T, Longnecker R. Epstein-Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/Akt pathway. Oncogene. 2004;23(53):8619–28. doi: 10.1038/sj.onc.1207905.
  90. Farrell K, Jarrett RF. The molecular pathogenesis of Hodgkin lymphoma. Histopathology. 2011;58(1):15–25. doi: 10.1111/j.1365-2559.2010.03705.x.
  91. Herbst H, Foss HD, Samol J, et al. Frequent expression of interleukin-10 by Epstein-Barr virus-harboring tumor cells of Hodgkin’s disease. Blood. 1996;87:2918–29.
  92. Hsu SM, Lin J, Xie SS, et al. Abundant expression of transforming growth factor-beta 1 and -beta 2 by Hodgkin’s Reed-Sternberg cells and by reactive T lymphocytes in Hodgkin’s disease. Hum Pathol. 1993;24(3):249–55. doi: 10.1016/0046-8177(93)90034-e.
  93. Kapp U, Yeh WC, Patterson B, et al. Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J Exp Med. 1999;189(12):1939–46. doi: 10.1084/jem.189.12.1939.
  94. Munz C, Moormann A. Immune escape by Epstein-Barr virus associated malignancies. Semin Cancer Biol. 2008;18(6):381–7. doi: 10.1016/j.semcancer.2008.10.002.
  95. Lichtenstein AV, Melkonyan HS, Tomei LD, et al. Circulating nucleic acids and apoptosis. Ann NY Acad Sci. 2001;945(1):239–49. doi: 10.1111/j.1749-6632.2001.tb03892.x.
  96. Sidransky D. Emerging molecular markers of cancer. Nat Rev Cancer. 2002;2(3):210–9. doi: 10.1038/nrc755.
  97. Skvortsova TE, Rykova EY, Tamkovich SN, et al. Cell-free and cell-bound circulating DNA in breast tumours: DNA quantification and analysis of tumour-related gene methylation. Br J Cancer. 2006;94(10):1492–5. doi: 10.1038/sj.bjc.6603117.
  98. Lo YM, Chan LY, Lo KW, et al. Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res. 1999;59(6):1188–91.
  99. Hou X, Zhao C, Guo Y, et al. Different Clinical Significance of Pre- and Post-treatment Plasma Epstein-Barr Virus DNA Load in Nasopharyngeal Carcinoma Treated with Radiotherapy. Clin Oncol. (R Coll Radiol) 2011;23(2):128–33. doi: 10.1016/j.clon.2010.09.001.
  100. Wang WY, Twu CW, Chen HH, et al. Plasma EBV DNA clearance rate as a novel prognostic marker for metastatic/recurrent nasopharyngeal carcinoma. Clin Cancer Res. 2010;16(3):1016–24. doi: 10.1158/1078-0432.ccr-09-2796.
  101. Lo YM, Chan AT, Chan LY, et al. Molecular prognostication of nasopharyngeal carcinoma by quantitative analysis of circulating Epstein-Barr virus DNA. Cancer Res. 2000;60:6878–81.
  102. Lo YM, Chan LY, Chan AT, et al. Quantitative and temporal correlation between circulating cell-free Epstein-Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. Cancer Res. 1999;59:5452–5.
  103. Au WY, Pang A, Choy C, et al. Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients. Blood. 2004;104(1):243–9. doi: 10.1182/blood-2003-12-4197.
  104. Wang ZY, Liu QF, Wang H, et al. Clinical implications of plasma Epstein-Barr virus DNA in early-stage extranodal nasal-type NK/T-cell lymphoma patients receiving primary radiotherapy. Blood. 2012;120(10):2003–10. doi: 10.1182/blood-2012-06-435024.
  105. Kasamon YL, Jacene HA, Gocke CD, et al. Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma. Blood. 2012;119(18):4129–32. doi: 10.1182/blood-2012-01-402792.
  106. Kanakry JA, Li H, Gellert LL, et al. Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American cooperative group trial. Blood. 2013;121(18):3547–53. doi: 10.1182/blood-2012-09-454694.
  107. Hohaus S, Santangelo R, Giachelia M, et al. The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma. Clin Cancer Res. 2011;17(9):2885–92. doi: 10.1158/1078-0432.ccr-10-3327.
  108. Dinand V, Sachdeva A, Datta S, et al. Plasma Epstein Barr Virus (EBV) DNA as a Biomarker for EBV associated Hodgkin lymphoma. Indian Pediatr. 2015;52(8):681–5. doi: 10.1007/s13312-015-0696-9.
  109. Vockerodt М, Yap L-F, Shannon-Lowe C, et al. The Epstein-Barr virus and the pathogenesis of lymphoma. J Pathol. 2015;235(2):312–22. doi: 10.1002/path.4459.
  110. Grywalska E, Markowicz J, Grabarczyk P, et al. Epstein-Barr virus-associated lymphoproliferative disorders. Postepy Hig Med Dosw (Online). 2013;67:481–90. doi 10.5604/17322693.1050999.