Epstein-Barr Virus Causes Lymphomas

EBV has been declared a Class I human carcinogen by the IARC. Epstein Barr Virus and Kaposi's Sarcoma Herpesvirus/Human Herpesvirus 8. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans). IARC Monograph 70. Lyon: International Agency for Research on Cancer; 1997.)

"5.5 Evaluation. There is sufficient evidence for the carcinogenicity of EBV in the causation of Burkitt's lymphoma, sinonasal angiocentric T-cell lymphoma, immunosuppression-related lymphoma, Hodgkin's disease and nasopharyngeal carcinoma."

"EBV is carcinogenic to humans (Group I)."

IARC Monograph 70, Epstein-Barr Virus, summary (1997) / IARC (pdf, 10 pp)

Reviews

Epstein-Barr virus, infectious mononucleosis, Burkitt's lymphoma and nasopharyngeal carcinoma. G Klein. Israel J Med Sci 1977 Jul;13(7):716-724. "The timing and extent of seroconversion are strongly related to socioeconomic status. In low socioeconomic groups, infection occurs during early childhood, as a rule. It is not accompanied by any recognized disease, and the route of transmission is unknown. Only a minority of children become infected in high socioeconomic groups where a later infection, during the teens, predominates."

Klein - Israel J Med Sci 1977 full article / UCSF (pdf, 9 pp)

The spectrum of Epstein-Barr virus-associated lymphoproliferative disease in Korea: incidence of disease entities by age groups. EY Cho, KH Kim, WS Kim, KH Yoo, HH Koo, YH Ko. J Korean Med Sci 2008 Apr;23(2):185-192. "T or NK cell NHLs were the most common forms of EBV-positive NHLs (107/167, 64%); among these, nasal-type NK/T cell lymphomas were the most common (89/107, 83%). According to the age, Burkitt's lymphoma was the most common in early childhood; in teenagers, chronic (active) EBV infection-associated LPD was the most common type. The incidence of NK/T cell lymphoma began to increase from the twenties and formed the major type of EBV-associated tumor throughout life. Diffuse large B cell lymphoma formed the major type in the sixties and seventies."

Cho - J Korean Med Sci 2008 abstract / PubMed

Infectious aetiology of Hodgkin and non-Hodgkin lymphomas: a review of the epidemiological evidence. H Hjalgrim, EA Engels. J Intern Med 2008 Dec;264(6):537-548.

Hjalgrim & Engels - J Intern Med 2008 abstract / PubMed

Innate immune modulation in EBV infection. S Ning. Herpesviridae 2011 Jan 5;2(1):1. "The virus in "true latency" [latency 0] is neither pathogenic nor visible to the host immune system due to the lack of any viral protein production. But before the establishment of the final "true latency", the virus goes through several different "transitional" latency programs, named latency 3, 2 and 1, which selectively express several of the nine viral latent proteins as well as noncoding RNAs (EBERs, BARF0, and miRNAs) and are associated with EBV oncogenesis."

Ning - Herpesviridae 2011 full article / PubMed Central
Ning / Herpesviridae 2011 full article

Strain Differences

Epstein-Barr virus latent gene sequences as geographical markers of viral origin: unique EBNA3 gene signatures identify Japanese viruses as distinct members of the Asian virus family. A Sawada, D Croom-Carter, O Kondo, M Yasui, M Koyama-Sato, M Inoue, K Kawa, AB Rickinson, RJ Tierney. J Gen Virol 2011 May;92(Pt 5):1032-1043. "Thus, while Chinese viruses mainly fall into two families with strongly linked 'Wu' or 'Li' alleles at EBNA2 and EBNA3A/B/C, Japanese viruses all have the consensus Wu EBNA2 allele but fall into two families at EBNA3A/B/C. One family has variant Li-like sequences at EBNA3A and 3B and the consensus Li sequence at EBNA3C; the other family has variant Wu-like sequences at EBNA3A, variants of a low frequency Chinese allele 'Sp' at EBNA3B and a consensus Sp sequence at EBNA3C. Thus, EBNA3A/B/C allelotypes clearly distinguish Japanese from Chinese strains. Interestingly, most Japanese viruses also lack those immune-escape mutations in the HLA-A11 epitope-encoding region of EBNA3B that are so characteristic of viruses from the highly A11-positive Chinese population."

Sawada - J Gen Virol 2011 abstract / PubMed
HLA*1101 frequency map / Pypop

Distinctive EBV variants associated to pediatric benign and malignant pathologies: LMP1 sequence characterization and linkage with other viral gene polymorphisms. MA Lorenzetti, M Gantuz, J Altcheh, E De Matteo, PA Chabay, MV Preciado. J Clin Microbiol 2012 Mar;50(3):609-618. 15 pediatric patients with IM and 20 pediatric EBV-associated lymphomas from Argentina. "Similar sequence polymorphisms were detected in both pathological conditions, IM and lymphoma, but these differ from those previously described in healthy donors from Argentina and Brazil. The results suggest that certain LMP1 polymorphisms, namely the 30bp deletion and high copy number of the 33bp repeats, could be associated to EBV-related pathologies, either benign or malignant instead of just tumor related. Additionally, this is the first study to describe the Alaskan variant in EBV-related lymphomas previously restricted to nasopharyngeal carcinomas from North America."

Lorenzetti - J Clin Microbiol 2012 abstract / PubMed

Whole-genome sequencing of the akata and mutu epstein-barr virus strains. Z Lin, X Wang, MJ Strong, M Concha, M Baddoo, G Xu, C Baribault, C Fewell, W Hulme, D Hedges, CM Taylor, EK Flemington. J Virol 2013 Jan;87(2):1172-1182. "A comparative analysis of Akata with another four completely sequenced EBV strains, B95-8/Raji, AG876, Mutu, and GD1, demonstrated that the Akata strain is most closely related to the GD1 strain and exhibits the greatest divergence from the type II strain, AG876. A global comparison of latent and lytic gene sequences showed that the four latency genes, EBNA2, EBNA3A, EBNA3B, and EBNA3C, are uniquely defining of type I and type II strain differences. Within type I strains, LMP1, the latency gene, is among the most divergent of all EBV genes, with three insertion or deletion loci in its CTAR2 and CTAR3 signaling domains. Analysis of the BHLF1 and LF3 genes showed that the reading frames identified in the B95-8/Raji genome are not conserved in Akata (or Mutu, for BHLF1), suggesting a primarily non-protein-coding function in EBV's life cycle."

Lin - J Virol 2013 abstract / PubMed

Sequence analysis of EBV immediate-early gene BZLF1 and BRLF1 in lymphomas. Y Yang, Y Jia, Y Wang, X Wang, Z Sun, B Luo. J Med Virol 2014 Oct;86(10):1788-1795. BZLF1 in 26 and BRLF1 analyzed in 33 lymphomas. "The variation types BZLF1-B and BR1-C were more frequent in the lymphomas, compared with the throat washing samples from the healthy donors."

Yang - J Med Virol 2014 abstract / PubMed

Sequence analysis of EBV immune evasion gene BNLF2a in EBV associated tumors and healthy individuals from nasopharyngeal carcinoma endemic and non-endemic regions of China. S Liu, X Wang, J Shu, Z Zhao, Z Sun, B Luo. J Med Virol 2015 Nov;87(11):1946-1952. "408 cases of EBV positive tumors (76 lymphomas, 45 gastric carcinomas, and 85 nasopharyngeal carcinomas in northern China and 27 lymphomas, 30 gastric carcinomas, and 57 nasopharyngeal carcinomas in southern China) and throat washings from healthy individuals (39 in northern China and 49 in southern China)... The variation patterns of BNLF2a were significantly different between samples from northern and southern China (P<0.05), and between the tumors and healthy donor samples from the northern China (P<0.0167). Type BNLF2a-B was more frequent in healthy donors of northern China (33.3%), and the proportion of this type was higher in the northern than in the southern NPCs."

Liu - J Med Virol 2015 abstract / PubMed

EBV and Hodgkin's Disease

Viral involvement in Hodgkin's disease: detection of clonal type A Epstein-Barr virus genomes in tumour samples. S Gledhill, A Gallagher, DB Jones, AS Krajewski, FE Alexander, E Klee, DH Wright, C O'Brien, DE Onions, RF Jarrett. Br J Cancer 1991 Aug;64(2):227-232. "EBV genomes were detected in 11/35 cases while none of the cases was positive for HHV-6. Ten of the EBV-positive cases were subsequently analysed using a probe for the terminal region of the virus; the results suggested that the EBV-infected cells were clonally expanded... The age distribution of the EBV-positive cases indicated a statistically significant trend for an increase in positivity with increasing age."

Gledhill - Br J Cancer 1991 full article landing / PubMed Central

Detection of Epstein-Barr virus genomes in Hidgkin's disease: Relation to age. RF Jarrett, A Gallagher, DB Jones, FE Alexander, AS Krajewski, A Kelsey, J Adams, B Angus, S Gledhill, DH Wright, RA Cartwright, DE Onions. J Clin Pathol 1991 Oct;44(10):844-848. 95 patients. "Most samples from children or adults aged 50 years or over contained detectable EBV genomes; samples from young adults were only rarely positive."

Jarrett - J Clin Pathol 1991 full article / PubMed Central

Epstein-Barr virus and Hodgkin's disease. H Herbst, G Niedobitek. Int J Clin Lab Res 1993;23(1):13-16. "Seroepidemiological and molecular biological studies have established an association of Hodgkin's disease with Epstein-Barr virus. Recently, Epstein-Barr virus genomes and gene products have been detected in the neoplastic cells of approximately 50% of cases, most notably the latent membrane protein, which has transforming potential."

Herbst - Int J Clin Lab Res 1993 abstract / PubMed

The impact of EBV, proliferation rate, and Bcl-2 expression in Hodgkin's disease in childhood. A Claviez, M Tiemann, J Peters, H Kreipe, R Schneppenheim, R Parwaresch. Ann Hematol 1994 Feb;68(2):61-66. 21 patients aged 4 to 17. "EBER was detected in eight of 21 patients (38%) in Hodgkin and Reed-Sternberg cells and reactive lymphocytes irrespective of initial clinical stage and histological subtype, whereas LMP-1, positive in ten of 21 patients (48%), was restricted to neoplastic cells. All cases positive for EBER expressed LMP-1 as well. Additionally, oncoprotein Bcl-2 was identified in nine of 21 patients (43%), indicating, besides immortalization of HD cells by EBV, a further growth advantage due to apoptosis prevention by overexpression of this protein."

Claviez - Ann Hematol 1994 abstract / PubMed

Risk factors for Hodgkin's disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents. FE Alexander, RF Jarrett, D Lawrence, AA Armstrong, J Freeland, DA Gokhale, E Kane, GM Taylor, DH Wright, RA Cartwright. Br J Cancer 2000 Mar;82(5):1117-1121. 19/103 tumors were EBV+. History of infectious mononucleosis & Hodgkin's disease, OR= 2.43 (95% CI= 1.10-5.33); history of IM and EBV-positive HD, OR= 9.16 (95% CI= 1.07-78.31).

Alexander - Br J Cancer 2000 abstract / PubMed

The correlation of Epstein-Barr virus expression and lymphocyte subsets with the clinical presentation of nodular sclerosing Hodgkin disease. A Kandil, S Bazarbashi, WA Mourad. Cancer 2001 Jun 1;91(11):1957-1963. EBV expression was seen in 24 (50%) cases.

Kandil - Cancer 2001 abstract / PubMed

South Asian ethnicity and material deprivation increase the risk of Epstein-Barr virus infection in childhood Hodgkin's disease. KJ Flavell, JP Biddulph, JE Powell, SE Parkes, D Redfern, M Weinreb, P Nelson, JR Mann, LS Young, PG Murray. Br J Cancer 2001 Aug;85(3):350-356. "62% of [55] cases were Epstein-Barr virus-positive... The relative risk of Epstein-Barr virus-positivity showed a gradient with increasing Townsend score; the risk being 7-times higher in the most deprived quartile compared with the least deprived group."

Flavell - Br J Cancer 2001 abstract / PubMed

Epstein-Barr virus (EBV) in Chinese pediatric Hodgkin disease: Hodgkin disease in young children is an EBV-related lymphoma. XG Zhou, K Sandvej, PJ Li, XL Ji, QH Yan, XP Zhang, JP Da, SJ Hamilton-Dutoit. Cancer 2001 Sep 15;92(6):1621-1631. In 104 pediatric and 52 adult Chinese HD cases, "EBV was identified in tumor cells in 113 of 156 (72%) HD cases but was more frequent in pediatric cases (93 of 104; 89%) compared with adult cases (20 of 52; 38%) (P < 0.01; chi-square test). EBV was found in 86 out of 91 (95%) cases in children aged 3-10 years and in 7 out of 13 (54%) cases in children aged 11-14 years (P < 0.01; chi-square test)... The authors believe that pediatric HD now should be regarded as a distinctive EBV-related lymphoma."

Zhou - Cancer 2001 abstract / PubMed

A defective, rearranged Epstein-Barr virus genome in EBER-negative and EBER-positive Hodgkin's disease. YJ Gan, BI Razzouk, T Su, JW Sixbey. Am J Pathol 2002 Mar;160(3):781-786. "The Epstein-Barr virus (EBV) has been linked to approximately half the cases of Hodgkin’s disease (HD), with virus localized by EBER in situ hybridization to the malignant Reed-Sternberg cell that characteristically makes up less than 1% of the tumor mass. Recent descriptions of relapsed HD, shown to be EBV-positive at initial diagnosis but EBV-negative on reoccurrence, raise the possibility of viral DNA loss during tumor progression in some individuals." 8/24 EBER-negative HD had PCR evidence of defective EBV DNA. "Detection of defective EBV genomes with the potential to disrupt viral gene regulation suggests one mechanism for pathogenic diversity that may also account for loss of prototypic EBV from individual tumor cells."

Gan - Am J Pathol 2002 abstract / PubMed
Gan - Am J Pathol 2002 Full Article

Epstein-Barr virus in Hodgkin's disease: the example of central Tunisia. S Korbi, M Trimeche, B Sriha, MT Yacoubi, S Hmissa, M Mokni, P Delvenne, J Boniver, S Rammeh. Ann Pathol 2002 Apr;22(2):96-101. EBV early RNA transcripts (EBER) was detected in 70% of 77 cases.

Korbi - Ann Pathol 2002 abstract / PubMed

Hematopoietic and lymphatic cancers in relatives of patients with infectious mononucleosis. H Hjalgrim, K Rostgaard, J Askling, M Madsen, HH Storm, CS Rabkin, M Melbye. J Natl Cancer Inst 2002 May 1;94(9):678-681. "The unremarkable risk for Hodgkin's lymphoma in family members of patients with EBV-related infectious mononucleosis indicates that socioeconomic confounding is an unlikely explanation for the association between EBV-related infectious mononucleosis and Hodgkin's lymphoma."

Hjalgrim - JNCI 2002 abstract / PubMed
Hjalgrim - JNCI 2002 Full Article

Epstein-barr virus-associated non-Hodgkin's lymphoma of B-cell origin, Hodgkin's disease, acute leukemia, and systemic lupus erythematosus: a serologic and molecular analysis. W Mitarnun, J Pradutkanchana, S Takao, V Saechan, S Suwiwat, T Ishida. J Med Assoc Thai. 2002 May;85(5):552-9. In 58 patients, "EBV internal repeat-1 region (IR-1) in peripheral blood CD3+ cells was detected in 10 of 14 patients (71.5%) with NHL-B, 3 of 8 patients (37.5%) with Hodgkin's disease, 1 of 6 patients (16.7%) with acute leukemia, 4 of 9 patients (44.5%) with SLE, and was not detected in any of the 21 patients with other diseases."

Mitarnun 2002 abstract / PubMed

Hodgkin disease in adult and juvenile groups from two different geographic regions in Brazil: characterization of clinicopathologic aspects and relationship with Epstein-Barr virus infection. E De Oliveira, MM Bacchi, ES Abreu, L Niero-Melo, CE Bacchi. Am J Clin Pathol 2002 Jul;118(1):25-30. "HD in Brazilian patients is highly associated with EBV infection."

de Oliveira - Am J Clin Pathol 2002 abstract / PubMed

Longer failure-free survival interval of Epstein-Barr virus-associated classical Hodgkin's lymphoma: a single-institution study. J Krugmann, A Tzankov, A Gschwendtner, M Fischhofer, R Greil, F Fend, S Dirnhofer. Mod Pathol 2003 Jun;16(6):566-573. "Latent membrane protein1 was detected in 31/119 (26%) classical Hodgkin's lymphoma, and Epstein-Barr virus subtyping was successful in 19 of the 31 virus-infected classical Hodgkin's lymphoma cases, as well as in 28 of 54 reactive tonsils. Subtype A was observed in all classical Hodgkin's lymphoma patients and in 26/28 (93%) tonsils. The 30-base pair latent membrane protein1 gene deletion was found in only 4/31 (13%) Epstein-Barr virus-associated classical Hodgkin's lymphoma as well as in 20/54 (37%) reactive tonsils."

Krugmann - Mod Pathol 2003 abstract / PubMed

Hodgkin's lymphoma: immunohistochemical features and its association with EBV LMP-1. Experience from a South Indian hospital. S Karnik, B Srinivasan, S Nair. Pathology 2003 Jun;35(3):207-211. "EBV LMP-1 was positive in 82 (82%) cases, most often in the nodular sclerosis subtype, 43 (86%) cases."

Karnik - Pathology 2003 abstract / PubMed

Epstein-Barr virus in biopsies from patients with Hodgkin and non-Hodgkin lymphoma at the University of Puerto Rico immunohistochemistry laboratory. FJ Córdova Pérez, CI González-Keelan, R Vélez. P R Health Sci J 2003 Jun;22(2):125-129. "We found an LMP-1 positive rate of 50% for 22 cases of HL and 35% for 63 cases of NHL. Among HL, 5 were children and 16 were adults, with LMP-1 positive rates of 60% and 50% respectively. Among NHL, 3 were children and 59 were adults, with equal LMP-1 positive rates of 33%."

Córdova Pérez - P R Health Sci J 2003 abstract / PubMed

Apoptosis and cell cycle-related genes and proteins in classical Hodgkin lymphoma: application of tissue microarray technique. J Wang, CR Taylor. Appl Immunohistochem Mol Morphol 2003 Sep;11(3):206-213. "The H-RS cells of 62 classic Hodgkin lymphomas were... positive for both EBV latent membrane protein-1 and EBER in 37 (59.68%); there was complete concordance of results for EBV by both procedures."

Wang & Taylor - Appl Immunohistochem Mol Morphol 2003 abstract / PubMed

Epstein-Barr virus expression in Hodgkin's lymphoma in Kuwait. RR Makar, T Saji, TA Junaid. Pathol Oncol Res 2003;9(3):159-165. 60/107 cases (56.1 %) were positive for EBER by ISH and 56 (52.3%) were positive for EBV-LMP I by IHC. "None of the cases that were positive by IHC were negative by ISH, whereas 4 cases that were positive by ISH were negative by IHC."

Makar / Pathol Oncol Res 2003 full article (pdf, 7 pp)

Imbalances of chemokines, chemokine receptors and cytokines in Hodgkin lymphoma: classical Hodgkin lymphoma vs. Hodgkin-like ATLL. K Ohshima, K Karube, M Hamasaki, H Suefuji, T Tutiya, T Yamaguchi, J Suzumiya, M Kikuchi. Int J Cancer 2003 Sep 20;106(5):706-712. "EBV-infected H&RS cells were detected in 9 of 10 cases of HL MC, 5 of 9 of HL-like ATLL and 2 of 10 HL NS... 2 of 5 cases of HL-like ATLL with EBV infection and 2 of 2 HL NS with EBV had IP10/MIG-positive H&RS cells. The chemokine expressions in H&RS cells seemed to be associated with EBV infection rather than histologic subtypes."

Ohshima - Int J Cancer 2003 abstract / PubMed

Comparison of Epstein-Barr virus presence in Hodgkin lymphoma in pediatric versus adult Argentine patients. E De Matteo, AV Barón, P Chabay, J Porta, M Dragosky, MV Preciado. Arch Pathol Lab Med 2003 Oct;127(10):1325-1329. 92 pediatric and 42 adult Hodgkin lymphoma cases from a public center, and 39 adult cases from a private center. "55% of the pediatric cases and 31% of the adult cases were positive [for Epstein-Barr encoded RNAs]. Among adult EBV+ cases, 38% were from the public hospital, and 23% were from the private center. EBV was present in 77% of the pediatric mixed cellularity Hodgkin lymphoma cases when compared with the other histologic subtypes of Hodgkin lymphoma. EBV was mainly detected in mixed cellularity cases (39% in the adult group)."

De Matteo - Arch Pathol Lab Med 2003 abstract / PubMed

The Scotland and Newcastle epidemiological study of Hodgkin's disease: impact of histopathological review and EBV status on incidence estimates. RF Jarrett, AS Krajewski, B Angus, J Freeland, PR Taylor, GM Taylor, FE Alexander. J Clin Pathol 2003 Nov;56(11):811-816. 622 HL patients. "EBV status was determined for 537 cases, including 461 cases with a review diagnosis of CHL; in 154 (33%) of these last cases all of the HRS cells were EBER positive... LMP1 staining identified no EBV+ HL cases that were not picked up using the EBER assay."

Jarrett - J Clin Pathol 2003 full article / PubMed Central

[Epstein-Barr virus presence in Colombian Hodgkin lymphoma cases and its relation to treatment response]. S Quijano, C Saavedra, S Fiorentino, O Orozco, MM Bravo. Biomedica 2004 Jun;24(2):163-173. Lymph nodes from 67 HL patients. "EBERs transcripts were found in 67% of the cases and LMP-1 in the Reed-Sternberg tumor cells at a 56.7% rate. The prevalence, as determined by histological subtype, was 69.81% for nodular sclerosing, 85.71% for mixed cellularity and 40% for lymphocyte-rich. Epstein-Barr virus presence was more frequent in children (84.2%) in comparison with adults (60.4%)."

Quijano - Biomedica 2004 abstract / PubMed

Epstein-Barr virus expression in Hodgkin's disease in Jordan. NM Almasri, HS Khalidi. Saudi Med J 2004 Jun;25(6):770-775. "Epstein Barr virus was seen in 47% of our cases: 22 (65%) of the 34 mixed cellularity and 8 (29%) of 28 nodular sclerosis HD. None of our 2 lymphocyte predominant HD cases showed evidence of EBV. Epstein-Barr virus was seen in 73% of HD cases in children below 15 years of age as opposed to 34% of the young adult group."

Almasri - Saudi Med J 2004 abstract / PubMed

Heterogeneity of risk factors and antibody profiles in epstein-barr virus genome-positive and -negative hodgkin lymphoma. ET Chang, T Zheng, ET Lennette, EG Weir, M Borowitz, RB Mann, D Spiegelman, NE Mueller. J Infect Dis 2004 Jun 15;189(12):2271-2281. "EBV-positive patients were less educated and more likely to have smoked cigarettes and had more prevalent and higher EBV antibody titers, compared with EBV-negative patients."

Chang - J Infect Dis 2004 abstract / PubMed

Hodgkin's disease and association with Epstein-Barr virus in children in Southeast Turkey. F Yilmaz, AK Uzunlar, N Sogutcu, M Ozaydin. Saudi Med J 2005 Apr;26(4):571-575. "Epstein-Barr virus-LMP1 were positive in 31 cases (61.5%) of a total of 52 cases and the most were MC [mixed cellularity] (91.3%)."

Yilmaz - Saudi Med J 2005 abstract / PubMed

Phenotype and frequency of Epstein-Barr virus-infected cells in pretreatment blood samples from patients with Hodgkin lymphoma. G Khan, A Lake, L Shield, J Freeland, L Andrew, FE Alexander, R Jackson, PR Taylor, EA McCruden, RF Jarrett. Br J Haematol 2005 May;129(4):511-519. "[T]he frequency of circulating EBV-infected cells was significantly higher (P < 0.001) in pretreatment blood samples from EBV-associated cases when compared with non-EBV-associated cases."

Khan - Br J Haematol 2005 abstract / PubMed

Association of the Epstein-Barr viruses with Hodgkin lymphoma: an analysis of pediatric cases in Thailand. V Hemsrichart, J Pintong. J Med Assoc Thai 2005 Jun;88(6):782-787. "EBV encoded RNA by in situ hybridization was demonstrated in 92.8% of classic HL: 3 of 4 (75%) with nodular sclerosis; 9 of the 9 with mixed cellularity (100%) and 1 of 1 (100%) with lymphocyte depletion. Case of nodular lymphocyte predominance was negative for EBV..."

Hemsrichart & Pintong - J Med Assoc Thai 2005 abstract / PubMed

Impact of latent Epstein-Barr virus infection on outcome in children and adolescents with Hodgkin's lymphoma. A Claviez, M Tiemann, H Lüders, M Krams, R Parwaresch, G Schellong, W Dörffel. J Clin Oncol 2005 Jun 20;23(18):4048-4056. Eight hundred forty-two children and adolescents (median age, 13.7 years). "Two hundred sixty-three patients (31%) were LMP positive [by immunostaining]. EBV infection correlated with sex (39% male v 23% female; P < .001), histologic subtype (69% mixed cellularity v 22% nodular sclerosis v 6% lymphocyte predominance; P < .001) and young age."

Claviez - J Clin Oncol 2005 abstract / PubMed

Epstein-Barr virus is associated with all histological subtypes of Hodgkin lymphoma in Vietnamese children with special emphasis on the entity of lymphocyte predominance subtype. KC Chang, NT Khen, D Jones, IJ Su. Hum Pathol 2005 Jul;36(7):747-755. "[I]n situ hybridization for EBV-encoded RNA revealed that the tumor cells were positive in 93.2% (41/44) of cases, including all 3 cases of nodular lymphocyte predominance HL."

Chang - Hum Pathol 2005 abstract / PubMed

[Association of Hodgkin lymphoma with Epstein-Barr virus in Hungary]. K Keresztes, B Bessenyei, Z Szöllosi, Z Beck, Z Miltényi, Z Nemes, E Oláh, A Illés. Orv Hetil 2005 Jul 24;146(30):1575-1582. "Out of 109 cases, 61 patients (56%) showed virus positivity by PCR while latent membrane protein 1 positivity was found in 47 cases (43%). As regards to gender ratio, 53% female and 58% male patients were virus positive by PCR. Epstein-Barr virus association did not show any alteration in children (1-14 years) when compared to that of adults (out of the 10 children 6 were positive by PCR). As regards to the lifestyle of Epstein-Barr virus positive patients, the incidence of smoking and the ratio of poor social conditions were significantly higher. Mixed cell type was the most frequent (65%) in these patients and Epstein-Barr PCR virus positivity was highest in this type (60%), primarily in age groups 11-20 and over 51 years. Epstein-Barr virus PCR positivity was 52% in nodular sclerosis (negative cases cumulated in the age group 15-30 years), other histologic subtypes could not be evaluated due to the small number of cases."

Keresztes - Orv Hetil 2005 abstract / PubMed

Epstein-Barr virus infection is not the sole cause of high prevalence for Hodgkin's lymphoma in Saudi Arabia. K Al-Kuraya, R Narayanappa, F Al-Dayel, H El-Solh, A Ezzat, H Ismail, A Belgaumi, P Bavi, V Atizado, G Sauter, R Simon. Leuk Lymphoma 2006 Apr;47(4):707-713. 169 HLs from Saudi Arabia and 30 HLs from Europe. 42/147 (28.6%) and 9/30 (30%) respectively were positive for EBV by ISH.

Al-Kuraya - Leuk Lymphoma 2006 abstract / PubMed

[Prevalence of lymphoma subtypes in Shanxi according to latest WHO classification]. JF Wang, YZ Wang, ZW Chen, RC Taylor. Zhonghua Bing Li Xue Za Zhi 2006 Apr;35(4):218-223. 62/447 lymphoma cases (13.9%) were classic Hodgkin lymphoma; 37 (59.7%) were positive for EBV. "In classic HL, there was complete concordance of results by both EBER in-situ hybridization and LMP-1 immunohistochemistry."

Wang - Zhonghua Bing Li Xue Za Zhi 2006 abstract / PubMed

The effect of Epstein-Barr virus status on clinical outcome in Hodgkin's lymphoma. JM Kwon, YH Park, JH Kang, K Kim, YH Ko, BY Ryoo, SS Lee, SI Lee, HH Koo, WS Kim. Ann Hematol 2006 Jul;85(7):463-468. Results differed by method: In 56 HL patients, "EBV infection was identified in 41.1% of cases by EBER ISH, 26.8% by LMP1 expression, and 26.8% by LMP1 and EBER ISH. EBER-positive HL were significantly more frequent in mixed cellularity (MC) subtype (P=0.014) and advanced stage (P=0.034)."

Kwon - Ann Hematol 2006 abstract / PubMed

The high frequency of EBV infection in pediatric Hodgkin lymphoma is related to the classical type in Bahia, Brazil. I Araujo, AL Bittencourt, HS Barbosa, EM Netto, N Mendonça, HD Foss, M Hummel, H Stein. Virchows Arch 2006 Sep;449(3):315-319. 90 pediatric HL cases. "EBV-positive tumor cells were found exclusively in cHL. The infection occurred with high frequency in all cHL subtypes, but it predominated in the mixed cellularity and lymphocyte depletion subtypes. These results reinforce the hypothesis that EBV plays a major role in the etiology of pediatric cHL in developing areas. Curiously, the frequency of EBV infection in HL was identical to the previously described for Burkitt's lymphoma in the same pediatric population. As both lymphomas have a postulated precursor cell in the germinal center (GC), the pattern of latently EBV-infected GC cells previously described in Bahia may be related to the development of these lymphomas."

Araujo - Virchows Arch 2006 abstract / PubMed

Epstein-barr virus and hodgkin lymphoma. RF Ambinder. Hematology Am Soc Hematol Educ Program 2007;2007:204-209. Review. "The association of infectious mononucleosis and HL is strongest in young adults, but virus in tumor cells is least frequently detected in tumors in young adults. This paradox led to concern that there were uncontrolled confounding factors in cohort studies that had been missed, or that the childhood environment characteristics associated with risk of HL in young adults might also be associated with an increased risk of infectious mononucleosis. Alternatively, EBV might be an etiologically innocent passenger, or the virus might be lost from the neoplastic cells during progression (a phenomenon that is readily demonstrated in EBV BL cell lines in vitro but that is largely hypothetical in vivo)."

Ambinder / Hematology 2007 full article

Association of Hodgkin's lymphoma with Epstein Barr virus infection. E Cickusić, J Mustedanagić-Mujanović, E Iljazović, Z Karasalihović, I Skaljić. Bosn J Basic Med Sci 2007 Feb;7(1):58-65. 81 cases of Hodgkin's lymphoma. Results differed by method: "In neoplastic cells, using an immunohistochemical method, latent membrane protein 1 (LMP1) was found in 33,3% of cases, while in situ hybridization results demonstrated the presence of EBER RNA in 48,1% of the cases. EBER RNA was found in non-neoplastic lymphocytes in 38,3% of cases."

Cickusić - Bosn J Basic Med Sci 2007 abstract / PubMed

Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma. H Hjalgrim, KE Smedby, K Rostgaard, D Molin, S Hamilton-Dutoit, ET Chang, E Ralfkiaer, C Sundström, HO Adami, B Glimelius, M Melbye. Cancer Res 2007 Mar 1;67(5):2382-2388. 586 patients with classic HL and 3,187 controls in Denmark and Sweden. "IM was associated with an increased risk of EBV-positive [OR, 3.23; 95% confidence interval (95% CI) 1.89–5.55] but not EBV-negative HL (OR, 1.35; 95% CI, 0.86–2.14). Risk of EBV-positive HL varied with time since IM and was particularly pronounced in younger adults (OR, 3.96; 95% CI, 2.19–7.18). IM-associated lymphomas occurred with a median of 2.9 years (1.8–4.9 years) after infection. The EBV specificity of the IM association was corroborated by a case-case comparison of IM history between younger adult EBV-positive and EBV-negative HL patients (ORIM EBV+ HL versus EBV– HL, 2.68; 95% CI, 1.40–5.12)."

Hjalgrim / Cancer Res 2007 full article

HLA-A*02 is associated with a reduced risk and HLA-A*01 with an increased risk of developing EBV+ Hodgkin lymphoma. M Niens, RF Jarrett, B Hepkema, IM Nolte, A Diepstra, M Platteel, N Kouprie, CP Delury, A Gallagher, L Visser, S Poppema, GJ te Meerman, A van den Berg. Blood 2007 Nov 1;110(9):3310-3315. 70 patients with EBV+ HL, 31 patients with EBV- HL, and 59 control participants. "HLA-A*01 was significantly overrepresented and HLA-A*02 was significantly underrepresented in patients with EBV+ HL versus controls and patients with EBV- HL. In addition, HLA-A*02 status was determined by immunohistochemistry or HLA-A*02-specific polymerase chain reaction (PCR) on 152 patients with EBV+ HL and 322 patients with EBV- HL. The percentage of HLA-A*02+ patients in the EBV+ HL group (35.5%) was significantly lower than in 6107 general control participants (53.0%) and the EBV- HL group (50.9%)."

Niens - Blood 2007 abstract / PubMed

Changing patterns in the frequency of Hodgkin lymphoma subtypes and Epstein-Barr virus association in Taiwan. KC Chang, PC Chen, D Jones, IJ Su. Cancer Sci 2008 Feb;99(2):345-349. 99 cases of HL diagnosed between 1996 and 2007, and 74 cases between 1982 and 1995. "The overall EBV positivity rate was 50% (86/173 cases). Comparing the distribution of HL cases diagnosed at two different time periods, we found an increased frequency of the nodular sclerosis (NS) subtype (53 vs 68%, P = 0.045), a decreased frequency of the mixed cellularity subtype (35 vs 13%, P < 0.001), a reduced male-to-female ratio (2.9:1 compared to 1.4:1) and mean age (42.4 vs 36.6 years) in the NS subtype, and a significant decrease in EBV positivity rates among the NS and lymphocyte-depletion subtypes (61 vs 39%, P = 0.03). These data indicate shifts in the frequency of histological subtype and EBV association for HL in Taiwan over the last decade, with a trend closer to that seen in Western countries and Japan."

Chang - Cancer Sci 2008 abstract / PubMed

Analysis of Epstein-Barr virus strains and variants in classical Hodgkin's lymphoma by laser microdissection. M García-Cosío, A Santón, P Martín, ME Reguero, E Cristóbal, C Bellas. Histol Histopathol 2008 Feb;23(2):209-217. In 10 HIV-positive and 16 sporadic cHL cases, EBV EBERs were present in all but 2 sporadic cHL cases.

García-Cosío - Histol Histopathol 2008 abstract / PubMed

Pediatric Hodgkin lymphoma in 2 South American series: a distinctive epidemiologic pattern and lack of association of Epstein-Barr virus with clinical outcome. PA Chabay, MH Barros, R Hassan, E De Matteo, G Rey, MK Carrico, IZ Renault, MV Preciado. J Pediatr Hematol Oncol 2008 Apr;30(4):285-291. EBV expression was detected in 52% of cases (54% in Argentina and 48% in Brazil). "In Arg HL, EBV positivity was significantly higher in patients<or=10 years (P=0.0011)."

Chabay - J Pediatr Hematol Oncol 2008 abstract / PubMed

[Correlation of Epstein-Barr virus infection and childhood lymphoma] ZD Xie, L Wang, D Lu, CJ Zhou, KL Shen. Zhonghua Zhong Liu Za Zhi 2008 May;30(5):365-367. IHC and ISH detection of EBV-EBERs in paraffin-embedded specimens of lymphoma collected between 1996 and 2005, including 36 Hodgkin lymphomas (HL) and 51 non-Hodgkin lymphomas (NHL). "EBV was detected in 72.2% (26/36) of the Hodgkin lymphomas, 15.7% (8/51) of the non-Hodgkin lymphomas and 33.3% (15/45) of the reactive hyperplasia of lymph nodes."

Xie - Zhonghua Zhong Liu Za Zhi 2008 abstract / PubMed

Expression of Epstein-Barr virus in Hodgkin lymphoma in a population of United Arab Emirates nationals. S Al-Salam, A John, S Daoud, SM Chong, A Castella. Leuk Lymphoma 2008 Sep;49(9):1769-77. "Nodular sclerosis (NS) subtype was the most common type of HL among UAE nationals followed by mixed cellularity (MC), lymphocytic predominant (LP), unclassified, lymphocytic depletion (LD) and lymphocyte rich (LR) subtypes, respectively. EBV was seen in 17 of 45 (38%) cases of HL and was predominately seen in the MC subtype followed by NS, LD and LR subtypes, respectively. EBV was more frequently expressed in HL in the pediatric age group than the adult age group."

Al-Salam - Leuk Lymphoma 2008 abstract / PubMed

Racial/ethnic variation in EBV-positive classical Hodgkin lymphoma in California populations. SL Glaser, ML Gulley, CA Clarke, TH Keegan, ET Chang, SJ Shema, FE Craig, JA Digiuseppe, RF Dorfman, RB Mann, H Anton-Culver, RF Ambinder. Int J Cancer 2008 Oct 1;123(7):1499-1507. 1,032 incident classical Hodgkin lymphoma cases. "Tumor EBV-positivity was associated with Hispanic and Asian/Pacific Islander (API) but not black race/ethnicity, irrespective of demographic and clinical factors." No details in abstract.

Glaser - Int J Cancer 2008 abstract / PubMed

Latent Epstein-Barr Virus Infection of Tumor Cells in Classical Hodgkin's Lymphoma Predicts Adverse Outcome in Older Adult Patients. A Diepstra, GW van Imhoff, M Schaapveld, H Karim-Kos, A van den Berg, E Vellenga, S Poppema. J Clin Oncol 2009 Aug 10;27(23):3815-21. 34% of 412 patients were positive for EBV in tumor cells.

Diepstra - J Clin Oncol 2009 abstract / PubMed

Plasma EBV-DNA monitoring in Epstein-Barr virus-positive Hodgkin lymphoma patients. M Spacek, P Hubacek, J Markova, M Zajac, Z Vernerova, K Kamaradova, J Stuchly, T Kozak. APMIS 2011 Jan;119(1):10-16. 29 of 150 patients were EBV-positive by ISH for EBER, or by IHC for LMP1. "EBV-positive HL was significantly associated with EBV-DNA positivity both in the plasma and whole blood in pretreatment samples, increasing age and MC subtype. Serial analysis of plasma EBV-DNA showed that response to therapy was associated with decline in viral load. Moreover, significantly increased plasma EBV-DNA level recurred before disease relapse in one patient."

Spacek - APMIS 2011 abstract / PubMed

Disease patterns in pediatric classical Hodgkin lymphoma: a report from a developing area in Brazil. MH Barros, R Hassan, G Niedobitek. Hematol Oncol 2011 Dec;29(4):190-195. 100 consecutive cases. "EBV was identified in 44.8% of cases, without preferential association with age groups (≤10 years vs. >10 years). [Mixed cellularity] cases were independently associated with EBV infection of tumour cells (p = 0.045) and with a CD4/CD20 ratio <1 in the microenvironment (p = 0.014)."

Barros - Hematol Oncol 2011 abstract / PubMed

Aberrant Cytoplasmic Expression of Cyclin B1 Protein and its Correlation with EBV-LMP1, P53 and P16(INK4A) in Classical Hodgkin Lymphoma in China. P Zhao, Y Lu, L Liu, M Zhong. Pathol Oncol Res 2011 Jun;17(2):369-373. EBV-LMP1 was overexpressed in 85% of Hodgkin lymphomas. "Cyclin B1 was positively correlated with EBV-LMP1(P < 0.001) and P53(P < 0.001), but was inversely related to P16(INK4A) (P < 0.05)."

Zhao - Pathol Oncol Res 2010 abstract / PubMed

Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups. KY Urayama, RF Jarrett, H Hjalgrim, A Diepstra, Y Kamatani, A Chabrier, V Gaborieau, A Boland, A Nieters, et al; Genetics Section, International Agency for Research on Cancer, Lyon, France. J Natl Cancer Inst 2012 Feb 8;104(3):240-253. "Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 × 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 10(-10)..."

Urayama - J Natl Cancer Inst 2012 abstract / PubMed

Antibody titers against EBNA1 and EBNA2 in relation to Hodgkin lymphoma and history of infectious mononucleosis. NE Mueller, ET Lennette, K Dupnik, BM Birmann. Int J Cancer 2012 Jun 15;130(12):2886-2891. 55 EBV+ with history of IM, 173 EBV+ with no history of IM. "In multivariate logistic regression models, an anti-EBNA1:2 ratio ≤ 1.0 was significantly more prevalent in HL cases than siblings (odds ratio, 95% confidence interval = 2.43, 1.05-5.65); similar associations were apparent within the IM+ and IM- groups. EBNA antibodies were not significantly associated with IM history in HL cases or siblings. These associations suggest that chronic or more severe EBV infection is a risk factor for HL, independent of IM history."

Mueller - Int J Cancer 2012 abstract / PubMed

On the aetiology of Hodgkin lymphoma. H Hjalgrim. Dan Med J 2012 Jul;59(7):B4485. "Analyses stratified by Hodgkin lymphoma EBV status indicated that the increased risk after infectious mononucleosis was confined to the subset of Hodgkin lymphomas that harbour the virus in the malignant cells. The genetic analyses pointed to increased and decreased risk of EBV-positive Hodgkin lymphoma associated with HLA-A*01 and HLA-A*02 alleles, respectively. The increased risk of EBV-positive Hodgkin lymphoma after infectious mononucleosis was not explained by the two HLA class I alleles, but HLA-A*02 abrogated its effect."

Hjalgrim / Dan Med J 2012 full article (landing)

Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma. LI Levin, ET Chang, RF Ambinder, ET Lennette, MV Rubertone, RB Mann, M Borowitz, EG Weir, SL Abbondanzo, NE Mueller. Blood 2012 Nov 1;120(18):3750-3755. 128 incident Hodgkin lymphoma cases and 368 matched controls from active-duty US military personnel. "Among 40 EBV(+) Hodgkin lymphoma cases and matched controls, statistically significant increased risks were associated with elevated anti-EBV VCA IgG antibody titers (relative risk = 3.1; 95% confidence interval [CI], 1.1-8.7), and an anti-EBNA-1/anti-EBNA-2 antibody ratio ≤ 1.0 versus > 1.0 (relative risk = 4.7; 95% CI, 1.6-13.8)... EBV(+) disease was significantly associated with a low anti-EBNA-1/anti-EBNA-2 antibody ratio."

Levin - Blood 2012 abstract / PubMed

Comparison of three methods for the detection of Epstein-Barr virus in Hodgkin's lymphoma in paraffin-embedded tissues. ZL Qi, XQ Han, J Hu, GH Wang, JW Gao, X Wang, DY Liang. Mol Med Report 2013 Jan;7(1):89-92. 59 cases. "Our results revealed that the PCR method presented the highest (44/59, 74.6%) detection rate among the three methods. The other two methods identified 66.1% (39/59, LMP1) and 67.8% (40/59, EBER1 ISH) EBV-positive results, respectively. Three samples were positive for LMP1 but negative when using EBER1 ISH, while another four samples were EBER1-positive but LMP1-negative. Of the four major histopathological subtypes of HL, the lymphocyte predominant (LR) subtype is the one most frequently associated with EBV, followed by the mixed cellularity (MC), nodular sclerosis (NS) and lymphocyte depletion (LD) subtypes. Our results also indicated the seldomly reported fact that EBV-positive cases in children were more numerous than those of adults with HL."

Qi - Mol Med Report 2013 abstract / PubMed

[Epstein-Barr virus infection and expression of latent membrane protein 2A in Hodgkin's lymphoma of Uygur patients]. X Li, SE Yang, YQ Guo, SH Zang, L Guo, W Gulikezi, B Zhao, W Liu, JP Bai. Zhonghua Bing Li Xue Za Zhi 2013 Apr;42(4):239-242. "EBV was detected in 26/40 (65.0%) of HL and 5/20 of lymphoid reactive hyperplasia (P < 0.05). The expression level of EBER showed significant difference among various histological subtypes of HL (P < 0.05) and between patients with and without B symptom (P = 0.02)... The expression of LMP2A in the mixed cellularity and nodular sclerosis classical HL associated with EBV infection was 57.7% (15/26)."

Li - Zhonghua Bing Li Xue Za Zhi 2013 abstract / PubMed

Detection of Epstein-Barr Virus and Genotyping Based on EBNA2 Protein in Mexican Patients With Hodgkin Lymphoma: A Comparative Study in Children and Adults. I Palma, AE Sánchez, E Jiménez-Hernández, F Alvarez-Rodríguez, M Nava-Frias, P Valencia-Mayoral, C Salinas-Lara, N Velazquez-Guadarrama, J Portilla-Aguilar, RY Pena, P Ramos-Salazar, A Contreras, A Alfaro, AM Espinosa, N Nájera, G Gutierrez, JM Mejia-Arangure, J Arellano-Galindo. Clin Lymphoma Myeloma Leuk 2013 Jun;13(3):266-272. "Thirty-two of the 42 samples (76.1%) were positive for EBV in children and 16 of 24 (66.6%) samples were positive in adults (P = .41). In both children and adults, EBV was found more frequently in male patients. Thirty-four of 48 cases could be typed (70.8%). EBNA2A was found in 7/21 (33.3%) children and in 4/13 (30.8%) adults (P = 1.0), and EBNA2B was found in 10/21 (47.6%) children and in 9/13 (69.2%) adults (P = .22). A mix of subtypes was found in 4/21 (19%) children."

Palma - Clin Lymphoma Myeloma Leuk 2013 abstract / PubMed

Epstein-Barr virus infection correlates with the expression of COX-2, p16(INK4A) and p53 in classic Hodgkin lymphoma. S Al-Salam, A Awwad, M Sudhadevi, S Daoud, NJ Nagelkerke, A Castella, S Chong, M Alashari. Int J Clin Exp Pathol 2013 Nov 15;6(12):2765-2777. "EBV, COX-2, p16(INK4A) and p53 were detected in 55% (52/95), 64% (61/95), 62% (59/95), and 65% (62/95) of the cases respectively. EBV was detected in 62% (38/61), 70% (41/59), and 69% (43/62) of COX2, p16 and p53 positive cases respectively. On the other hand, EBV-non-infected cases of cHL are associated with 59% (20/34), 69% (25/36), and 73% (24/33) of COX2, p16 and p53 negative cases respectively. In conclusion, EBV infection is associated with the expression of COX-2, p16(INK4A) and p53. EBV might be the dominant factor in determining the expression of these three proteins."

Al-Salam - Int J Clin Exp Pathol 2013 full article / PubMed Central

Changing trend of Epstein-Barr virus association in Hodgkin lymphoma in the Republic of Korea. YW Koh, HJ Kang, DH Yoon, C Suh, JE Kim, CW Kim, J Huh. Ann Hematol 2013 Dec;92(12):1653-1660. Data from 1980-1995 and 1996-2011 were compared. Age distribution showed a marked decrease in children (age < 15 years) (21.0 % to 8.6 %, p = 0.004) and sharp increase in young adults (ages 15-29 years) and ages 30-59 years. Male predominance decreased from 3.04 to 1.57... EBV-positive HL decreased from 66.7 % to 38.2 %. However, in young adult females, EBV positive cases increased, contributing to the peak in this age group. Epidemiology of HL in Korea is rapidly changing into a Western pattern concurrent with the socioeconomic changes. Analysis of the cases stratified by EBV status and sex identified a smaller hidden peak in the young adult age, which confirms the four disease hypothesis proposed by Jarrett. We propose EBV testing as an essential component in epidemiologic study of Hodgkin lymphoma."

Koh - Ann Hematol 2013 abstract / PubMed

Epstein-Barr virus (EBV) positive classical Hodgkin lymphoma of Iraqi children: An immunophenotypic and molecular characterization of Hodgkin/Reed-Sternberg cells. A Di Napoli, MF Al-Jadiri, C Talerico, E Duranti, E Pilozzi, P Trivedi, E Anastasiadou, AR Alsaadawi, AF Al-Darraji, SA Al-Hadad, AM Testi, S Uccini, L Ruco. Pediatr Blood Cancer 2013 Dec;60(12):2068-2072. 57 Iraqi cases under 14 years of age. EBV was found in 44 of 51 (86%) of classical Hodgkin lymphomas.

Di Napoli - Pediatr Blood Cancer 2013 abstract / PubMed

Epstein-Barr virus and Hodgkin lymphoma in Jordan. MA Sughayer, HA Haddad, RM Al-Yousef, M El-Khateeb, H Abu-Rass. Hematol Oncol Stem Cell Ther 2014 Jun;7(2):85-89. 100 consecutive cases. "[T]he most common subtype was nodular sclerosis (NS), representing 70% of the cases, and 45.7% of cHL (43% of all HL) cases were positive for EBV LMP-1. The positive cases were significantly related to age: ≤15 years and >51years (p: 0.009 and 0.014 respectively), male gender (p: 0.03) and mixed cellularity (MC) subtype (p: <0.0001)."

Sughayer - Hematol Oncol Stem Cell Ther 2014 abstract / PubMed

Prevalence and Prognostic Significance of Epstein-Barr Virus Infection in Classical Hodgkin's Lymphoma: A Meta-analysis. JH Lee, Y Kim, JW Choi, YS Kim. Arch Med Res 2014 Jul;45(5):417-431. 119 published studies including 13,045 cases. "The pooled prevalence of EBV infection in cHL was 47.9%, which was significantly higher in Africa and Central and South America than other regions. EBV-positive cHL showed higher incidence in children than in adults (69.7 vs. 41.1%). EBV-positive cHL was significantly related to male (OR = 1.8, 95% CI: 1.510-2.038; p <0.001), mixed cellularity subtype (OR = 3.8, 95% CI: 3.243-4.451; p <0.001), and advanced clinical stages (OR = 1.2, 95% CI: 1.072-1.369; p = 0.002)."

Lee - Arch Med Res 2014 abstract / PubMed

Epstein-Barr virus infection is inversely correlated with the expression of retinoblastoma protein in Reed-Sternberg cells in classic Hodgkin lymphoma. S Al-Salam, A Awwad, M Alashari. Int J Clin Exp Pathol 2014 Oct 15;7(11):7508-7517. 46 (55%) of 82 cases were positive for LMP-1 by IHC.

Al-Salam - Int J Clin Exp Pathol 2014 full article / PubMed Central

[Clinicopathologic features and association with Epstein-Barr virus infection in 235 cases of Hodgkin lymphoma from northern China]. Y Shi, X Li. Zhonghua Bing Li Xue Za Zhi 2015 Feb;44(2):84-89. 72 / 235 (30.6%) cases were positive for LMP1 by IHC, and 40 / 101 (39.6%) were positive for EBER by ISH.

Shi - Zhonghua Bing Li Xue Za Zhi 2015 abstract / PubMed

Pediatric Hodgkin Lymphoma in a South Indian Regional Cancer Center: Its Immunomorphology, Tumor-Associated Macrophages, and Association with Epstein-Barr Virus. MA Zameer, CS Premalata, B Arunakumari, L Appaji, C Rama Rao. Pediatr Hematol Oncol 2015 May;32(4):229-238."Fifty-two of seventy-four (70.3%) cases were of late germinal center/early post-germinal center phenotype (CD10-/bcl6-/MUM1+/CD138-). Epstein-Barr virus (EBV) association using Epstein-Barr virus encoded RNA (EBER) RISH and EBV-LMP1 immunohistochemistry (IHC) revealed an EBV association of 93%."

Zameer - Pediatr Hematol Oncol 2015 abstract / PubMed

[Infection status and prognostic significance analysis of Epstein-Barr virus in 207 cases with newly diagnosed Hodgkin's lymphoma]. S Kang, Y Qin, X He, S Zhou, X Han, P Liu, M Dong, L Zhou, J Yang, S Yang, C Zhang, L Gui, Y Shi. Zhonghua Yi Xue Za Zhi 2015 Aug 25;95(32):2594-2598. 66 / 207 (31.9%) cases were positive for EBER or LMP-1. "The EBV positive rate had two peaks in age, respectively, in the age of 0-15 yeaR-old and >60 yeaR-old."

Kang - Zhonghua Yi Xue Za Zhi 2015 abstract / PubMed

The impact of HLA-class I and EBV-latency-II antigen-specific CD8+ T-cells on the pathogenesis of EBV+ Hodgkin Lymphoma. K Jones, L Wockner, RM Brennan, C Keane, PK Chattopadhyay, M Roederer, DA Price, DK Cole, B Hassan, K Beck, D Gottlieb, DS Ritchie, JF Seymour, F Vari, P Crooks, SR Burrows, MK Gandhi. Clin Exp Immunol 2016 Feb;183(2):206-220. "In newly diagnosed EBV+ cHL, the magnitude of ex vivo LMP1/2A-specific CD8+ T-cell responses was elevated in HLA-A*02+ patients. Furthermore, in a controlled in vitro assay, LMP2A-specific CD8+ T-cells from healthy HLA-A*02 heterozygotes expanded to a greater extent with HLA-A*02-restricted compared to non-HLA-A*02-restricted cell lines. In an extensive analysis of HLA-class I-restricted immunity, immuno-dominant EBNA3A/3B/3C-specific CD8+ T-cell responses were stimulated by numerous HLA-class I molecules, whereas the sub-dominant LMP1/2A-specific responses were largely confined to HLA-A*02. Our results demonstrate that HLA-A*02 mediates a modest, but nonetheless stronger, EBV-specific CD8+ T-cell response than non-HLA-A*02 alleles, an effect confined to EBV-latency-II antigens. Thus, the protective effect of HLA-A*02 against EBV+ cHL is not a surrogate association, but reflects the impact of HLA-class I on EBV-latency-II antigen-specific CD8+ T-cell hierarchies."

Jones - Clin Exp Immunol 2016 abstract / PubMed

Classical Hodgkin Lymphoma with Positive Epstein-Barr Virus Status is Associated with More FOXP3 Regulatory T Cells. A Pavlovic, M Glavina Durdov, V Capkun, J Jakelic Pitesa, M Bozic Sakic. Med Sci Monit 2016 Jul 5;22:2340-2346. 30 / 102 cases were EBV positive, "mainly in patients older than 54 years and in mixed cellularity subtype. In EBV-positive cHL, higher numbers of CD8+ cells were found. In cHL with positive EBV status, more FOXP3+ Treg were found, as well as higher numbers of FOXP3+CD4+ Treg compared with EBV-negative cHL."

Pavlovic - Med Sci Monit 2016 abstract / PubMed

Changing patterns in the Epstein-Barr virus (EBV)and Hodgkin lymphoma association in Tunisia. MB Dhiab, S Ziadi, H Saad, T Louhichi, M Trimeche. Ann Hematol 2016 Sep;95(9):1537-1543. EBER by ISH "showed a significant decrease in the prevalence of EBV-positive HL from 69.3 % for the period 1991-2001 to 40.1 % for the 2002-2012 period (p = 0.00001). EBV positivity has decreased in all age groups but was more pronounced among young patients."

Dhiab - Ann Hematol 2016 abstract / PubMed

Example: Anti-smoking junk

Cigarette smoking and risk of Hodgkin's Disease: A population-based case-control study. NC Briggs, HI Hall, EA Brann, CJ Moriarty, RS Levine. Am J Epidemiol 2002;156(11):1011-1020. "Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals adjusted for age, registry, race/ethnicity, Jewish upbringing, education, and childhood domicile. Compared with never smokers, current smokers had a significantly increased risk of Hodgkin’s disease (odds ratio (OR) = 1.8, 95% confidence interval (CI): 1.3, 2.9)." They simply ignored EBV infection! This is an example of deliberate anti-smoker scientific fraud, under the auspices of the Centers for Disease Control, and published by the coruupt Johns Hopkins Bloomberg School of Public Health. In the year 2002, when no one can legitimately pretend ignorance, they purposely ignore the role of EBV infection, in order to falsely blame by confounding.

Briggs / Am J Epidemiol 2002 abstract

Cigarette smoking and risk of Hodgkin lymphoma: a population-based case-control study. H Hjalgrim, K Ekström-Smedby, K Rostgaard, RM Amini, D Molin, S Hamilton-Dutoit, C Schöllkopf, ET Chang, E Ralfkiaer, HO Adami, B Glimelius, M Melbye. Cancer Epidemiol Biomarkers Prev 2007 Aug;16(8):1561-1566. 586 classic HL cases and 3,187 population controls in a Danish-Swedish case-control study. "Odds ratios (OR) for an association with cigarette smoking were calculated by logistic regression for HL overall and stratified by age, sex, major histology subtypes, and tumor EBV status, adjusting for known confounders. RESULTS: Compared with never smokers, current cigarette smokers were at an increased overall HL risk [adjusted OR, 1.57; 95% confidence interval (95% CI), 1.22-2.03]. The association was strongest for EBV-positive HL (adjusted OR, 2.36; 95% CI, 1.51-3.71), but also applied to EBV-negative HL (adjusted OR, 1.43; 95% CI, 1.05-1.97; P(homogeneity EBV-pos) versus P(homogeneity EBV-neg) = 0.04). The association did not vary appreciably by age, sex, or histologic subtype, the apparent EBV-related difference present in all strata. There was no evidence of a dose-response pattern, whether by age at smoking initiation, daily cigarette consumption, number of years smoking, or cumulative number of cigarettes smoked." [The known confounder they ignored is that EBV infection occurs earlier as well as more frequently in the lower socioeconomic classes, of which smokers are more likely to belong.]

Hjalgrim - Cancer Epidemiol Biomarkers Prev 2007 abstract / PubMed

See the National Cancer Institute fudge about EBV and HD!

The National Cancer Institute claims that "At this time, the cause or causes of Hodgkin's disease are not known," and insists on calling EBV merely a "risk factor:" "Viruses -- Epstein-Barr virus is an infectious agent that may be associated with an increased chance of getting Hodgkin's disease." They refuse to admit that EBV is CAUSAL, and not merely associated with an increased chance of getting Hodgkin disease. (Risk Factors Associated with Hodgkin's Disease. National Cancer Institute. Posted 06/25/1999, Updated 09/16/2002; viewed 11-30-02, 06-18-05, 10-02-05, and 07-01-06.)

Risk Factors Associated with Hodgkin's Disease / National Cancer Institute

See the American Cancer Society drag its feet about EBV and HD!

The American Cancer Society mirrors the attitude of the NCI in its evasion of the causal role of EBV. "There seems to be a slightly increased rate for Hodgkin's disease in people who have had infectious mononucleosis (sometimes called "mono" for short), an infection caused by the Epstein-Barr virus. However, half of patients with Hodgkin's disease show no evidence of a previous Epstein-Barr virus infection." And they insist that "Even if someone has one or more risk factors for Hodgkin's disease, it is impossible to know for sure how much that risk factor could contribute to causing the cancer. In general, we can say that no major risk factors for Hodgkin's disease have been discovered yet." (What Are the Risk Factors for Hodgkin's Disease? American Cancer Society, as of 10-02-05 and 07-01-06.)

What Are the Risk Factors for Hodgkin's Disease? / American Cancer Society

EBV and Burkitt lymphoma

Precipitating antibody in human serum to an antigen present in cultured Burkitt's lymphoma cells. LJ Old, EA Boyse, HF Oettgen, ED Harven, G Geering, B Williamson, P Clifford. Proc Natl Acad Sci U S A 1966 Dec;56(6):1699-1704. 19 of 20 (95%) sera of patients with carcinoma of the postnasal space were positive to an antigen prepared from cultured Burkitt's lymphoma cells.

Old - PNAS 1966 full article / PubMed

A Burkitt lymphoma cell line with integrated Epstein-Barr virus at a stable chromosome modification site. NC Popescu, MC Chen, S Simpson, S Solinas, JA DiPaolo. Virology 1993 Jul;195(1):248-251. "Virus insertion into chromosomal DNA caused a stable modification site expressed as a distinctive achromatic region adjacent to the band 2p13. The chromatid lesion at the site of EBV integration involving a recombinogenic and fragile site may have contributed to the development of the NAB-2 BL."

Popescu - Virology 1993 abstract / PubMed

The role of Epstein-Barr virus-encoded small RNAs (EBERs) in oncogenesis. A Nanbo, K Takada. Rev Med Virol 2002 Sep-Oct;12(5):321-326. "EBERs play a key role in the maintenance of malignant phenotypes of Burkitt's lymphoma (BL) cells... Furthermore, we demonstrated that EBERs confer resistance to interferon (IFN)-alpha-induced apoptosis by inhibition of double-stranded (ds) RNA-activated protein kinase (PKR), which is the key mediator of the antiviral effect of IFN-alpha. These studies provide a new notion that RNA molecules contribute to oncogenesis."

Nanbo - Rev Med Virol 2002 abstract / PubMed

Frequent presence of subtype A virus in Epstein-Barr virus-associated malignancies. SC Peh, LH Kim, S Poppema. Pathology 2002 Oct;34(5):446-450. In 17 Hodgkin's, 14 Burkitt's, 4 T-cell and 3 B-cell non-Hodgkin's lymphomas, "All cases showed presence of type A virus, consistently detected with nested PCR protocol but not with single step PCR. There was no type B virus or mix infections detected."

Peh - Pathology 2002 abstract / PubMed

Burkitt lymphoma: revisiting the pathogenesis of a virus-associated malignancy. GL Kelly, AB Rickinson. Hematology Am Soc Hematol Educ Program 2007;2007:277-284. Review.

Kelly / Hematology Am Soc Hematol Educ Program 2007 full article

Epstein-Barr virus and Burkitt lymphoma. G Brady, GJ MacArthur, PJ Farrell. J Clin Pathol 2007 Dec;60(12):1397-1402. Review.

Brady / J Clin Pathol 2007 full article

Sporadic paediatric and adult Burkitt lymphomas share similar phenotypic and genotypic features. SS Chuang, WT Huang, PP Hsieh, YC Jung, H Ye, MQ Du, CL Lu, CY Cho, SC Hsiao, YH Hsu, KJ Lin. Histopathology 2008 Mar;52(4):427-435. In 17 paediatric and 14 adult BLs, 24% versus 21% were positive for EBER.

Chuang - Histopathology 2008 abstract / PubMed

Detection of Epstein-Barr virus in children and adolescents with Burkitt's lymphoma by in situ hybridization using tissue microarrays. M Pizza, P Bruniera, SM Luporini, HR Marcelino da Silva, ML Borsato, HC de Castro, FA Soares, RA Paes. Hematology 2008 Apr;13(2):114-118. "The presence of EBV using in situ hybridization was found in 33/50 (66%) and there was no association between the presence of the virus in the tumor cells or patient age, as well as the survival rate."

Pizza - Hematology 2008 abstract / PubMed

Viral Studies in Burkitt Lymphoma: Association With Epstein-Barr Virus but Not HHV-8. EM Queiroga, G Gualco, L Chioato, WJ Harrington, I Araujo, LM Weiss, CE Bacchi. Am J Clin Pathol 2008 Aug;130(2):186-192. "EBV was present in 45.0% of all BL cases with higher incidence in the pediatric group; most cases were EBV type A. We found no association of BL with HHV-8 in EBV + BL or in EBV-cases, including the HIV + BL group." Number of cases is not given in the abstract.

Queiroga - Am J Clin Pathol 2008 abstract / PubMed

Burkitt lymphoma in Brazil is characterized by geographically distinct clinicopathologic features. EM Queiroga, G Gualco, LM Weiss, DP Dittmer, I Araujo, CE Klumb, WJ Harrington Jr, CE Bacchi. Am J Clin Pathol 2008 Dec;130(6):946-956. "234 patients from 5 geographic regions that are widely disparate socioeconomically, including pediatric (61.1%) and adult (37.6%) populations. EBV was present in 52.6% of all BL cases, varying from 29% (12/42) in the South to 76% (13/17) in the North. Most of the cases were EBV type A. The frequency was higher in the pediatric group, and EBV association within this age range predominated in all regions except the South."

Queiroga - Am J Clin Pathol 2008 abstract / PubMed

Children with endemic Burkitt lymphoma are deficient in EBNA1-specific IFN-gamma T cell responses. AM Moormann, KN Heller, K Chelimo, P Embury, R Ploutz-Snyder, JA Otieno, M Oduor, C Münz, R Rochford. Int J Cancer 2009 Apr 1;124(7):1721-1726. "Significantly fewer children with eBL, 16% (7/44) had EBNA1-specific IFN-gamma responses in contrast to healthy children living in a malaria holoendemic area or in an area with sporadic malaria transmission, 67% (40/60) and 72% (43/60) responders, respectively (p < 0.003). Children with eBL maintained IgG(1) dominated antibody responses to EBNA1 similar to healthy children suggesting a selective loss of IFN-gamma secreting EBNA1-specific T cells in the presence of intact humoral immunity. CD8(+) T cell responses to EBV lytic and latent antigens not expressed in the tumors were similarly robust in eBL patients compared to healthy children. In addition, CD4(+) T cell responses to a malaria protein, merozoite surface protein 1, were present in lymphoma patients."

Moormann - Int J Cancer 2009 abstract / PubMed

Sporadic Burkitt lymphoma in southern China: 12 years' experience in a single institution in Guangzhou. Z Ye, Y Xiao, H Shi, Z Ke, Y Liu, Y Liang, A Han. J Clin Pathol 2011 Dec;64(12):1132-1135. in southern China, 5 / 17 (29.4%) cases of sporadic Burkitt lymphoma were positive for EBER.

Ye - J Clin Pathol 2011 abstract / PubMed

Early Age at Time of Primary Epstein-Barr Virus Infection Results in Poorly Controlled Viral Infection in Infants From Western Kenya: Clues to the Etiology of Endemic Burkitt Lymphoma. E Piriou, AS Asito, PO Sumba, N Fiore, JM Middeldorp, AM Moormann, R Ploutz-Snyder, R Rochford. J Infect Dis 2012 Mar 15;205(6):906-913. "We observed a significantly younger age at time of primary EBV infection in children from Kisumu compared with children from Nandi (mean age, 7.28 months [±0.33 SEM] in Kisumu vs 8.39 months [±0.26 SEM] in Nandi), with 35.3% of children in Kisumu infected before 6 months of age... Children from a region at high risk for eBL were infected very early in life with EBV, resulting in higher viral loads throughout infancy."

Piriou - J Infect Dis 2012 abstract / PubMed

Carcinogenicity of malaria and of some polyomaviruses. V Bouvard, RA Baan, Y Grosse, B Lauby-Secretan, F El Ghissassi, L Benbrahim-Tallaa, N Guha, K Straif; WHO International Agency for Research on Cancer Monograph Working Group. Lancet Oncol 2012 Apr;13(4):339-340. "Different mechanisms would explain the joint contribution of EBV and chronic P falciparum infection to eBL. In vivo, infection with P falciparum expands a subset of immature transitional B cells, and leads to activation of the activation-induced deaminase (AID), which generates mutations involved in immunoglobulin class-switching. In vitro, malarial antigens (eg, PfEMP1) directly cause polyclonal B-cell activation and proliferation, and alter different cellular pathways that inhibit apoptosis. B-cell proliferation may increase the EBV-infected compartment while B-cell activation can reactivate latent EBV, which was shown to directly increase AID activity and prevent apoptosis. These mechanisms lead to increased survival of B cells that harbour the specific chromosomal c-MYC translocation that characterises eBL. Thus, P falciparum can disturb the immature immune system in young children by expanding the B-cell pool in which eBL arises, and reactivate latent EBV. Despite limited epidemiological evidence in humans, this strong mechanistic evidence led the Working Group to conclude that malaria caused by infection with P falciparum in holoendemic areas is 'probably carcinogenic to humans' (Group 2A)."

Bouvard / Lancet Oncol 2012 full article

Relationship of epstein-barr virus and interleukin 10 promoter polymorphisms with the risk and clinical outcome of childhood burkitt lymphoma. C Minnicelli, MH Barros, CE Klumb, SO Romano, IR Zalcberg, R Hassan. PLoS One 2012;7(9):e46005. 62 pediatric patients and 216 healthy donors. "EBV was detected in tumor samples by EBER-ISH in 54.1% of cases."

Minnicelli - PLoS One 2012 full article / PubMed Central
Minnicelli / PLoS One 2012 full article

Epstein-Barr nuclear antigen 1 induces expression of the cellular microRNA hsa-miR-127 and impairing B-cell differentiation in EBV-infected memory B cells. New insights into the pathogenesis of Burkitt lymphoma. A Onnis, M Navari, G Antonicelli, F Morettini, S Mannucci, G De Falco, E Vigorito, L Leoncini. Blood Cancer J 2012 Aug 31;2:e84. "In particular, it has been shown that B-cell differentiation in EBV-positive BL is impaired at the post-transcriptional level by altered expression of hsa-miR-127. Here, we show that the overexpression of hsa-miR-127 is due to the presence of the EBV-encoded nuclear antigen 1 (EBNA1) and give evidence of a novel mechanism of direct regulation of the human miRNA by this viral product. Finally, we show that the combinatorial expression of EBNA1 and hsa-miR-127 affects the expression of master B-cell regulators in human memory B cells, confirming the scenario previously observed in EBV-positive BL primary tumors and cell lines."

Onnis - Blood Cancer J 2012 full article / PubMed Central

Relationship between Non-Hodgkin's lymphoma and blood levels of Epstein-Barr Virus in children in north-western Tanzania: a case control study. R Kabyemera, N Masalu, P Rambau, E Kamugisha, B Kidenya, A De Rossi, MR Petrara, D Mwizamuholya. BMC Pediatr 2013 Jan 7;13(1):4. 32 BL, 2 DLBL, 1 NHL-not otherwise specified, 70 controls. 21/35 (60%) cases and 21/70 (30%) controls "had detectable EBV in peripheral blood (OR = 4.77, 95% CI 1.71 -- 13.33, p = 0.003). In addition, levels of EBV in blood were significantly higher in NHL cases than in controls (p = 0.024)."

Kabyemera / BMC Pediatr 2013 to full article

Identification of a novel variant of LMP-1 of EBV in patients with endemic Burkitt lymphoma in western Kenya. EM Wohlford, AS Asito, K Chelimo, PO Sumba, PC Baresel, RA Oot, AM Moormann, R Rochford. Infect Agent Cancer 2013 Sep 9;8(1):34. 38 endemic Burkitt lymphoma patients and 22 healthy controls. "The frequency of a 30 base pair deletion of LMP-1 previously linked to NPC was not associated with eBL compared to healthy controls. However a novel LMP-1 variant was identified, called K for Kenya and for the G318K mutation that characterizes it. The K variant LMP-1 was found in 40.5% of eBL sequences and 25.0% of healthy controls. All K variant sequences contained mutations in both of the previously described minimal T cell epitopes in the C terminal end of LMP-1. These mutations occurred in the anchor residue at the C-terminal binding groove of both epitopes, a pocket necessary for MHC loading."

Wohlford / Infect Agent Cancer 2013 full article

Epstein-Barr virus patterns in US Burkitt lymphoma tumors from the SEER residual tissue repository during 1979-2009. SM Mbulaiteye, ST Pullarkat, BN Nathwani, LM Weiss, Nagesh Rao, B Emmanuel, CF Lynch, B Hernandez, V Neppalli, D Hawes, MG Cockburn, A Kim, M Williams, S Altekruse, K Bhatia, MT Goodman, W Cozen. APMIS 2014 Jan;122(1):5-15. "MYC rearrangement was found in 89% and EBER positivity in 29% of 82 cases with results. EBER positivity varied with age (from 13% in age group 0-19 to 55% in age group 20-34, and fell to 25% in age group 60+ years, p = 0.08); with race (56% in Blacks/Hispanics vs 21% in Whites/Asians/Pacific Islanders, p = 0.006); and by HIV status (64% in HIV positive vs 22% in HIV negative cases, p = 0.03)."

Mbulaiteye - APMIS 2014 abstract / PubMed

Burkitt's lymphoma of the jaws in the Amazon region of Brazil. HA Rebelo-Pontes, MC de Abreu, DM Guimarăes, FP Fonseca, BA de Andrade, OP de Almeida, DS Júnior, FS Corręa-Pontes. Med Oral Patol Oral Cir Bucal 2014 Jan 1;19(1):e32-38. All 7 BLs were positive for EBV.

Rebelo-Pontes / Med Oral Patol Oral Cir Bucal 2014 full article

Study of Epstein-Barr virus expression in Burkitt's lymphoma by polymerase chain reaction and in situ hybridization: A study in Iran. P Deyhimi, M Kalantari. Dent Res J (Isfahan) 2014 May;11(3):380-385. 18 cases. "EBV RNA was detected in 50% of the BL specimens. Type 1 and 2 accounted for 70 and 30% of the cases, respectively."

Deyhimi - Dent Res J (Isfahan) 2014 full article / PubMed Central

Epstein-Barr Virus Nuclear Antigen 3A Promotes Cellular Proliferation by Repression of the Cyclin-Dependent Kinase Inhibitor p21WAF1/CIP1. ML Tursiella, ER Bowman, KC Wanzeck, RE Throm, J Liao, J Zhu, CE Sample. PLoS Pathog 2014 Oct 2;10(10):e1004415. In the endemic form of Burkitt lymphoma, infected cells are typically limited to EBNA-1 (Latency I). "Interestingly, a subset of eBLs maintain a variant program of EBV latency - Wp-restricted latency (Wp-R) - that includes expression of the EBNA-3 proteins (3A, 3B and 3C), in addition to EBNA-1. In xenograft assays, Wp-R BL cell lines were notably more tumorigenic than their counterparts that maintain Latency I, suggesting that the additional latency-associated proteins expressed in Wp-R influence cell proliferation and/or survival... Consistent with the enhanced tumorigenic potential of Wp-R BLs, knockdown of EBNA-3A expression resulted in abrupt cell-cycle arrest in G0/G1 that was concomitant with conversion of retinoblastoma protein (Rb) to its hypophosphorylated state, followed by a loss of Rb protein... In agreement with the known ability of EBNA-3A and EBNA-3C to cooperatively repress p14ARF and p16INK4a expression, knockdown of EBNA-3A in LCLs resulted in rapid elevation of p14ARF and p16INK4a." And, "p21WAF1/CIP1, a potent inducer of G1 arrest, was upregulated following knockdown of EBNA-3A."

Tursiella - PLoS Pathog 2014 full article / PubMed Central
Tursiella / PLoS Pathog 2014 full article

The role of EBV in the pathogenesis of Burkitt's Lymphoma: an Italian hospital based survey. G Pannone, R Zamparese, M Pace, MC Pedicillo, S Cagiano, P Somma, ME Errico, V Donofrio, R Franco, A De Chiara, G Aquino, P Bucci, E Bucci, A Santoro, P Bufo. Infect Agent Cancer 2014 Oct 15;9(1):34. 40 childhood and 8 adult Burkitt's lymphomas. "Only 38 cases out of 48 were analyzed for LMP-1 showing various percentage of stained cells in 47.4% of the patients. Considering ISH for EBER detection results: 1 out 2 (50%) adult analyzed cases was positive, with 50% of stained tumor cells (this patient was a 22 years old female, coming from Napoli);15 out 24 (62.5%) children analyzed Burkitt's lymphomas resulted as positive for EBER;the overall positivity has been observed in 16/26 Burkitt's lymphomas (61.53%)."

Pannone - Infect Agent Cancer 2014 abstract / PubMed

AID expression in peripheral blood of children living in a malaria holoendemic region is associated with changes in B cell subsets and Epstein-Barr virus. JR Wilmore, AS Asito, C Wei, E Piriou, PO Sumba, I Sanz, R Rochford. Int J Cancer 2015 Mar 15;136(6):1371-1380. "High frequency of malaria exposure led to increased expression of AID, which coincided with decreases in the IgM+ memory B cells. In the children from the malaria endemic region, the presence of a detectible EBV viral load was associated with higher AID expression compared to children with undetectable EBV, but this effect was not seen in children with sporadic exposure to malaria. This study demonstrates that intensity of malaria transmission correlates with AID expression levels in the presence of EBV suggesting that malaria and EBV infection have a synergistic effect on the development of c-myc translocations and BL."

Wilmore - Int J Cancer 2015 abstract / PubMed

The impact of malaria co-infections on longitudinal Epstein-Barr virus kinetics in Kenyan children. A Reynaldi, TE Schlub, K Chelimo, PO Sumba, E Piriou, S Ogolla, AM Moormann, R Rochford, MP Davenport. J Infect Dis 2016 Mar 15;213(6):985-991. "Residence in an area of high malaria transmission was associated with a higher rate of EBV expansion during primary EBV infection of infants and during subsequent episodes of EBV DNA detection, as well as longer episodes of EBV DNA detection and shorter intervals between subsequent episodes of EBV DNA detection. In addition, we found that concurrent P. falciparum parasitemia also increases the likelihood of the first and subsequent peaks of EBV in peripheral blood. This suggests that malaria infection is associated with increased EBV growth and contributes to eBL pathogenesis."

Reynaldi - J Infect Dis 2016 abstract / PubMed

Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells. JS Kalchschmidt, R Bashford-Rogers, K Paschos, AC Gillman, CT Styles, P Kellam, MJ Allday. J Exp Med 2016 May 30;213(6):921-928. "[I]t was shown that transactivation of the AID gene (AICDA) is associated with EBNA3C binding to highly conserved regulatory elements located proximal to and upstream of the AICDA transcription start site. EBNA3C binding initiated epigenetic changes to chromatin at specific sites across the AICDA locus."

Kalchschmidt - J Exp Med 2016 abstract / PubMed

Modeling of EBV infection and antibody responses in Kenyan infants with different levels of malaria exposure shows maternal antibody decay is a major determinant of early EBV infection. A Reynaldi, TE Schlub, E Piriou, S Ogolla, OP Sumba, AM Moormann, R Rochford, MP Davenport. J Infect Dis 2016 Aug 28 [Epub ahead of print]. [Number of subjects not given in abstract.] "We found that high malaria exposure was associated with a faster decline of maternally-derived IgG antibody to both the EBV viral capsid antigen (VCA) and Epstein-Barr virus nuclear antigen (EBNA1), followed by a more rapid rise in antibody response to EBV antigens in children from the high malaria region."

Reynaldi - J Infect Dis 2016 abstract / PubMed

EBV & Other Lymphomas

[Detection of Epstein-Barr virus nucleic acid sequences in non-Hodgkin's lymphoma]. A Sauerbrei, P Wutzler, I Farber, K Wutke, B Brichacek, I Hirsch. Arch Geschwulstforsch 1987;57(6):445-452. EBV nucleic acid and EBNA were found in 5/25 NHLs.

Sauerbrei - Arch Geschwulstforsch 1987 abstract / PubMed

Epstein-Barr virus-associated peripheral T-cell lymphoma of activated CD8 phenotype. IJ Su, KH Lin, CJ Chen, HF Tien, HC Hsieh, DT Lin, JY Chen. Cancer 1990 Dec 15;66(12):2557-2562. Two childhood cases.

Su - Cancer 1990 abstract / PubMed

Frequent latent Epstein-Barr virus infection of neoplastic T cells and bystander B cells in human immunodeficiency virus-negative European peripheral pleomorphic T-cell lymphomas. P Korbjuhn, I Anagnostopoulos, M Hummel, M Tiemann, F Dallenbach, MR Parwaresch, H Stein. Blood 1993 Jul 1;82(1):217-223. 38 of 81 cases (47%) of PMTCL were positive for EBER by ISH. "By EBER-ISH, the virus was located in the tumor cells in 30 of the 38 EBV-positive cases, with the proportion of the infected cells ranging from 1% to 100%. In 18 of these cases and in the 8 cases without EBV-infected tumor cells, the virus was, respectively, either additionally or exclusively detectable in occasional nonmalignant lymphoid bystander cells."

Korbjuhn - Blood 1993 full article (pdf, 7pp)

Sinonasal T-cell lymphoma in the differential diagnosis of lethal midline granuloma using in situ hybridization for Epstein-Barr virus RNA. M Dictor, A Cervin, O Kalm, E Rambech. Mod Pathol 1996 Jan;9(1):7-14. 12 cases of primary sinonasal T-cell lymphoma, 23 cases of nonspecific rhinitis and 10 cases of Wegener's granulomatosis. "All hybridizable lymphoma sections, regardless of phase of development, gave a strong ISH signal easily detected at low magnification in 50 to 100% of tumor cells. Scattered positive cells were usually present even in necrotic areas. In contrast, no case of Wegener's granulomatosis or nonspecific rhinitis produced a true hybridization signal."

Dictor - Mod Pathol 1996 abstract / PubMed

[Two cases of lethal midline granuloma thought to be of natural killer cell origin]. S Tamura, N Yamanaka, T Saito, I Takano, M Hotomi, M Yokoyama. Nippon Jibiinkoka Gakkai Kaiho 1996 Jan;99(1):46-53.

Tamura - Nippon Jibiinkoka Gakkai Kaiho 1996 abstract / PubMed

Epstein-Barr virus in T and natural killer (NK) cell non-Hodgkin's lymphomas. P Kanavaros, J Briere, JF Emile, P Gaulard. Leukemia 1996 Jun;10 Suppl 2:s84-s87. Review.

Kanavaros - Leukemia 1996 abstract / PubMed

[Epstein-Barr virus infection in midline malignant reticulosis]. W Liu, J van Gorp, G Li. Zhonghua Zhong, Liu, Za Zhi 1997 Jan;19(1):49-52. "ALCs [atypical lymphoid cells] were positive for EBER 1/2 in 31/37 (83.8%) cases; EBV-DNA was detected in 12/15 (77.8%) cases; LMP was expressed in some ALCs in 5/19 (26.3%) cases."

Liu - Zhonghua Zhong Liu Za Zhi 1997 abstract / PubMed

[Clinical characteristics of Epstein-Barr virus-associated natural killer cell lymphoma/leukemia]. K Kawa. Nippon Rinsho 1997 Feb;55(2):424-428. Review.

Kawa - Nippon Rinsho 1997 abstract / PubMed

Natural killer cell lymphoma/leukemia: pathology and treatment. YL Kwong, AC Chan, RH Liang. Hematol Oncol 1997 May;15(2):71-79. Review. "A consistent association with monoclonal Epstein-Barr virus infection in the tumour cell has been observed... Clinically, most cases occur in the nasal area and upper aerodigestive tract. However, occurrence in non-nasal sites such as the skin, gastrointestinal tract and testis is also observed."

Kwong - Hematol Oncol 1997 abstract / PubMed

Nonnasal lymphoma expressing the natural killer cell marker CD56: A clinicopathologic study of 49 cases of an uncommon agressive neoplasm. KC John, VC Sin, KF Wong, CS Ng, WYW Tsang, CH Chan, MMC Cheung, WH Lau. Blood 1997 Jun 15;89(12):4501-4513. 32/34 (94%) of nasal-type NK/T cell lymphomas were EBV-positive. 5/5 (100%) of NK cell leukemia/lymphomas were EBV-positive. One case each of hepatosplenic T-cell lymphoma and S100 protein+ T-cell lymphoproliferative disease and two cases each of T-chronic lymphocytic/prolymphocytic leukemia, lymphoblastic lymphoma, and true histiocytic lymphoma were EBV-negative.

John / Blood 1997 full article

Angiocentric T-cell lymphoma presenting as lethal midline granuloma. PY Lee, NJ Freeman, J Khorsand, MA Weinstock. Int J Dermatol 1997 Jun;36(6):419-427. Case report.

Lee - Int J Dermatol 1997 abstract / PubMed

[Detection of Epstein-Barr virus DNA in malignant lymphomas]. N Kuljic-Kapulica. Vojnosanit Pregl 1997 Sep;54(5):465-468. EBV DNA was found in in 38.78% of 49 patients with Hodgkin's disease, and 21.74% of 46 patients with non-Hodgkin's lymphomas.

Kuljik-Kapulica - Vojnosanit Pregl 1997 abstract / PubMed

Integrated and episomal forms of Epstein-Barr virus (EBV) in EBV associated disease. K Oshima, J Suzumiya, M Kanda, M Kikuchi. Cancer Lett 1998 Jan 9;122(1-2):43-50. "Integrated EBV was demonstrated in 11 of 104 cases; five of 14 cases with B cell lymphoma (36%), one of 12 cases with nasopharyngeal carcinomas (8%), four of 31 cases with natural killer (NK) leukemia/lymphoma (13%) and one of 11 cases with chronic EBV infection (9%). However, none of the 24 T cell lymphoma, seven Hodgkin's disease, or five acute EBV infection cases showed integrated EBV. In addition, seven of the 11 cases with EBV integration (five B cell lymphoma and two NK leukemia/lymphoma) showed only an integration form, however, the other four (two NK leukemia/lymphoma, one nasopharyngeal carcinoma and one chronic EBV infection) showed both integrated and episomal forms. The integrated form was frequently found in B cell lymphoma and especially in high grade B cell lymphoma."

Ohshima - Cancer Lett 1998 abstract / PubMed

[Epstein-Barr virus infection and expression of T-cell intracellular antigen-1 (TIA-1) in intestinal T-cell lymphoma.] X Ren, W Liu, G Li, F Li, S Zhang. Zhonghua Bing Li Xue Za Zhi 1999 Oct;28(5):348-351. "Intestinal T-cell lymphoma may be an EBV-associated extranodal NK/T cell lymphoma."

Ren - Zhonghua Bing Li Xue Za Zhi 1999 abstract / PubMed

Sinonasal lymphoma: a clinicopathologic analysis of 58 cases from the Massachusetts General Hospital. I Cuadra-Garcia, GM Prouix, CL Wu, CC Wang, BZ Pilch, NL Harris, JA Ferry. Am J Surg Pathol 1999 Nov;23(11):1356-1369. Of 33 diffuse large B-cell lymphomas, "Only 2 of 11 cases tested (one in an HIV-positive patient and one of lymphomatoid granulomatosis type) were Epstein-Barr virus (EBV)-positive." 13/14 nasal-type natural killer (NK)/T-cell lymphomas were EBV-positive.

Cuadra-Garcia - Am J Surg Pathol 1999 abstract / PubMed

Epstein-Barr virus (EBV)-infected cells were frequently but dispersely detected in T-cell lymphomas of various types by in situ hybridization with an RNA probe specific to EBV-specific nuclear antigen 1. T Yamamoto, Y Nakamura, K Kishimoto, H Takeuchi, M Shirakata, T Mitsuya, K Hirai. Virus Res 1999 Dec 1;65(1):43-55. "Using ISH with improved antisense RNA probe specific to EBNA-1 mRNA, the virus was detected in 19 (59%) of 32 cases, whereas the EBER1 transcript was found in only 15 (47%) of 32 cases by conventional EBER-ISH, resulting in 21 EBV-positive cases (66%) by combining the two methods."

Yamamoto - Virus Res 1999 abstract / PubMed

Skin is the frequent site for involvement of peripheral T-cell and natural killer cell lymphomas in Korea. KH Cho, WW Choi, CS Youn, CW Kim, DS Heo. J Dermatol 2000 Aug;27(8):500-507.

Cho - J Dermatol 2000 abstract / PubMed

Epstein-Barr virus-infected natural killer cell leukemia. K Akashi, S Mizuno. Leuk Lymphoma 2000 Dec;40(1-2):57-66. Review; discussion of hemophagocytic lymphohistiocytosis.

Akashi - Leuk Lymphoma 2000 abstract / PubMed

[Angiocentric T/NK cell lymphoma: a special clinical-pathological entity of lethal midline granuloma. A case report]. M Koch, GJ Blatterspiel, G Niedobitek, J Constantinidis. Laryngorhinootologie 2001 Jul;80(7):410-415. Case & review.

Koch - Laryngorhinootologie 2001 abstract / PubMed

Diagnostic and prognostic implications of circulating cell-free Epstein-Barr virus DNA in natural killer/T cell lymphoma. KI Lei, LY Chan, WY Chan, PJ Johnson, YM Lo. Clin Cancer Res 2002 Jan;8(1):29-34. "Plasma EBV DNA, as measured by real-time quantitative PCR, is a useful tumor marker for diagnosis, disease monitoring, and prediction of outcome in patients with NK/T cell lymphoma."

Lei - Clin Cancer Res 2002 abstract / PubMed
Lei - Clin Cancer Res 2002 Full Article

Epstein-barr virus-associated non-Hodgkin's lymphoma of B-cell origin, Hodgkin's disease, acute leukemia, and systemic lupus erythematosus: a serologic and molecular analysis. W Mitarnun, J Pradutkanchana, S Takao, V Saechan, S Suwiwat, T Ishida. J Med Assoc Thai 2002 May;85(5):552-9. In 58 patients, "EBV internal repeat-1 region (IR-1) in peripheral blood CD3+ cells was detected in 10 of 14 patients (71.5%) with NHL-B, 3 of 8 patients (37.5%) with Hodgkin's disease, 1 of 6 patients (16.7%) with acute leukemia, 4 of 9 patients (44.5%) with SLE, and was not detected in any of the 21 patients with other diseases."

Mitarnun 2002 J Med Assoc Thai abstract / PubMed

Primary nasopharyngeal non-Hodgkin lymphoma and its relationship with Epstein-Barr virus infection. B Zhang, Y Zong, J He, B Zhong, S Lin. Chin Med J (Engl) 2003 Jun;116(6):913-917. "The percentages of EBV infection differed among the 3 major immunophenotypes (B cell: 11.36%, 5/44; peripheral T cell: 81.82%, 18/22; NK/T cell: 100%, 7/7)."

Zhang / Chin Med J (Engl) 2003 full article

Epstein-Barr virus in biopsies from patients with Hodgkin and non-Hodgkin lymphoma at the University of Puerto Rico immunohistochemistry laboratory. FJ Córdova Pérez, CI González-Keelan, R Vélez. P R Health Sci J 2003 Jun;22(2):125-129. "We found an LMP-1 positive rate of 50% for 22 cases of HL and 35% for 63 cases of NHL. Among HL, 5 were children and 16 were adults, with LMP-1 positive rates of 60% and 50% respectively. Among NHL, 3 were children and 59 were adults, with equal LMP-1 positive rates of 33%."

Córdova Pérez - P R Health Sci J 2003 abstract / PubMed

Prevalence and characterization of anaplastic large cell lymphoma and its association with Epstein-Barr virus in Pakistani patients. S Noorali, S Pervez, N Yaqoob, T Moatter, MI Nasir, S Haroon, E Hodges, JL Smith. Pathol Res Pract 2004;200(10):669-679. "Association of Epstein-Barr virus (EBV) was noted in seven out of 28 cases (25%) of ALCL by PCR, whereas ISH for EBV-encoded nuclear RNA-1 (EBER-1) detected the presence of EBV in two (16.7%) out of 12 cases, where one was T-cell ALCL and the other null-cell ALCL. Immunostaining for LMP-1 could not be performed, because tissue material was not available."

Noorali - Pathol Res Pract 2004 abstract / PubMed

Nasal NK/T cell lymphoma in Taiwan: a clinicopathologic study of 22 cases, with analysis of histologic subtypes, Epstein-Barr virus LMP-1 gene association, and treatment modalities. TT Kuo, LY Shih, NM Tsang. Int J Surg Pathol 2004 Oct;12(4):375-387. "All 22 cases were positive for EBV by polymerase chain reaction and Epstein-Barr virus early RNA (EBER) in-situ hybridization."

Kuo - Int J Surg Pathol 2004 abstract / PubMed

Features of intestinal T-cell lymphomas in Chinese population without evidence of celiac disease and their close association with Epstein-Barr virus infection. WY Zhang, GD Li, WP Liu, Q Ouyang, XC Ren, FY Li, H Xu. Chin Med J (Engl) 2005 Sep 20;118(18):1542-1548. "EBER1/2 was detected in 41 (97.6%) of the 42 patients. The expression frequency of LMP-1 was 38.1% (16/42)."

Zhang - Chin Med J (Engl) 2005 abstract / PubMed

Epstein-Barr viral infection in extranodal lymphoma of the head and neck: correlation with prognosis and response to treatment. AA Bahnassy, AR Zekri, N Asaad, S El-Houssini, HM Khalid, LM Sedky, NM Mokhtar. Histopathology 2006 Apr;48(5):516-528. "The study included 50 PELHN (11 cases in the nose and paranasal sinuses, 11 in the nasopharynx, 13 in the tonsils, seven in the oropharynx and eight in the oral cavity), five reactive lymph nodes, 15 normal nasopharyngeal tissue and 25 throat washes of healthy subjects from Egypt... EBV was detected in 90% and 70% of the cases using EBER in situ hybridization and PCR, respectively. All cases of nasal type lymphoma were positive for EBV."

Bahnassy - Histopathology 2006 abstract / PubMed

[Prevalence of lymphoma subtypes in Shanxi according to latest WHO classification]. JF Wang, YZ Wang, ZW Chen, RC Taylor. Zhonghua Bing Li Xue Za Zhi 2006 Apr;35(4):218-223. 385/447 (86.1%) lymphoma cases were non-Hodgkin lymphoma (NHL). "Of the NHL cases, 68.3% were of B-cell lineage and 30.6% were of T and/or NK-cell lineage. Histiocytic neoplasm accounted for only 0.8% (3 cases). As for the subtyping of NHL, diffuse large B-cell lymphoma was commonest (35.1%), followed by peripheral T-cell lymphoma, NOS (12.0%), extranodal marginal zone B-cell lymphoma (MALT lymphoma) (11.7%), follicular lymphoma (8.6%), T-lymphoblastic lymphoma (7.0%), anaplastic large cell lymphoma (4.2%), B-small lymphocytic lymphoma (3.6%) and mantle cell lymphoma (2.6%)... Regarding markers for EB virus infection, 14 cases of the B-cell lymphoma gave positive findings with both EBER in-situ hybridization and LMP-1 immunohistochemistry, while 6 of the T/NK-cell lymphoma expressed LMP-1 and 19 showed positive signals for EBER. In NHL, there was discordance in EBER in-situ hybridization and LMP-1 immunohistochemical results."

Wang - Zhonghua Bing Li Xue Za Zhi 2006 abstract / PubMed

Tissue markers of Epstein-Bar virus (EBV) infection in B-cell non-Hodgkin's lymphomas. A Kasprzak, R Spachacz, A Hałoń, M Jeleń, K Stefańska, J Wachowiak, E Trejster, M Zabel. Med Wieku Rozwoj 2006 Jul-Sep;10(3 Pt 1):639-648. Archive tissue material from 26 children and from 27 adults with B-cell NHLs, using immunocytochemical techniques, in situ hybridisation, and PCR. "The detectability and expression of EBV infection were significantly higher in children with B-cell NHLs as compared to adult patients. Expression of EBNA2 and LMP1 and that of EBERs in B-cell NHLs involved mainly cells of CD20(+) phenotype. Positive correlation was confirmed between expression of EBNA2 and LMP1 as well as between expression of the two proteins and EBERs in children with B-cell NHLs. Also in children with B-cell NHLs, type III latency form dominated. In adults the latency forms were more variable. We have demonstrated a novel form of EVB latency with no EBERs expression, noted in children as well as in adults with B-cell NHLs."

Kasprzak - Med Wieku Rozwoj 2006 abstract / PubMed

[Expression of ZEBRA protein of Epstein-Barr virus in Hungarian patients with Hodgkin lymphoma: latent or lytic cycle?] Z Beck, A Illés, K Keresztes, B Bessenyei, Z Szöllosi, A Kis, E Oláh. Orv Hetil 2006 Aug 20;147(33):1539-1544. 47/109 [43.1%] HL and 18/59 [30.5%] NHL samples were positive for LMP1.

Beck - Orv Hetil 2006 abstract / PubMed

[Nasal and pharyngeal non-Hodgkin lymphomas and their relationship with Epstein-Barr virus: a report of 158 cases]. YJ He, XS Jia, K Hasui, EH Wang, AG He. Zhonghua Bing Li Xue Za Zhi 2007 Feb;36(2):94-97. "Among 99 cases studied by EBER-1 in situ hybridization, a positive detection was seen in 70/71 cases (98.6%) of extranodal NK/T cell lymphoma (nasal type), 8/12 cases (66.7%) of T cell lymphoma, and 7/16 cases (43.8%) of B cell lymphoma."

He - Zhonghua Bing Li Xue Za Zhi 2007 abstract / PubMed

Nasal natural killer/T-cell lymphoma and its association with type "i"/XhoI loss strain Epstein-Barr virus in Chile. ME Cabrera, Y Eizuru, T Itoh, C Koriyama, Y Tashiro, S Ding, S Rey, S Akiba, A Corvalan. J Clin Pathol 2007 Jun;60(6):656-660. 7 out of 9 (78%) of WHO-criteria nasal NK/T-cell lymphomas were positive for EBV.

Cabrera - J Clin Pathol 2007 abstract / PubMed

Expression of the Epstein-Barr virus in lymphoproliferative diseases of the lung. M Shimakage, H Sakamoto, S Harada, T Sasagawa, K Kodama. Oncol Rep 2007 Jun;17(6):1347-1352. "Two non-Hodgkin's lymphomas (NHL) originating in the lung, 5 mucosal-associated lymphoid tissue lymphomas (MALT lymphoma) of the lung, 1 lymphoid hyperplasia of the lung and 1 lymphoid interstitial pneumonia (LIP), were subjected to mRNA in situ hybridization, indirect immunofluorescence staining and PCR. mRNA in situ hybridization using BamHIW, BamHIY1Y2, the Epstein-Barr virus nuclear antigen (EBNA) and the EBV encoded small non-polyadenylated RNA (EBER1) probe revealed signals in all the examined samples, although some samples showed weak signals by using the EBER1 probe. Indirect immunofluorescence staining using the anti-leader protein, anti-EBNA2, the anti-latent member protein-1 and anti-BamHIZ coding leftward reading frame-1 antibodies showed definitive fluorescence. PCR also revealed EBV DNA in these specimens. EBV infected all the lymphoproliferative diseases of the lung irrespective of the histological or clinical stages. Furthermore, EBV infected not only the atypical lymphocytes but also the macrophages in the tissues of these diseases."

Shimakage - Oncol Rep 2007 abstract / PubMed
Shimakage / Oncol Rep 2007 full article (pdf, 6 pp)

EBV viral load in tumor tissue is an important prognostic indicator for nasal NK/T-cell lymphoma. PP Hsieh, CL Tung, AB Chan, JB Liao, JS Wang, HH Tseng, HH Su, KC Chang, CC Chang. Am J Clin Pathol 2007 Oct;128(4):579-584. 19 cases. "Patients with a low EBV viral load (<1 copy per cell) more frequently survived for more than 2 years compared with patients with a high EBV viral load (>/=1 copies/cell) (7/7 vs 3/9; P = .014; Fisher exact test). Furthermore, the patients with low EBV viral loads had a better overall survival than patients with high viral loads (50% accumulative survival: not reached vs 4-5 months; Kaplan-Meier survival analysis; P = .049). In contrast, the overall survival of the patients did not correlate with the extent of lesion, age, stage, necrosis, histologic subtypes, CD56 expression, or angiocentric or angiodestructive growth pattern."

Hsieh - Am J Clin Pathol 2007 abstract / PubMed

Epstein-Barr virus infection and risk of lymphoma: immunoblot analysis of antibody responses against EBV-related proteins in a large series of lymphoma subjects and matched controls. S de Sanjosé, R Bosch, T Schouten, S Verkuijlen, A Nieters, L Foretova, M Maynadié, PL Cocco, A Staines, N Becker, P Brennan, Y Benavente, P Boffetta, CJ Meijer, JM Middeldorp. Int J Cancer 2007 Oct 15;121(8):1806-1812. 1,085 incident lymphoma cases from Spain, France, Germany, Czech Republic, Italy and 1,153 age, sex and country matched controls. An abnormal reactive pattern to EBV was observed in 20.9% of 2,238 included subjects with an increased proportion of cases presenting ab_EBV as compared to the control population (23.9% vs. 18.0% p = 0.001). Ab_EBV positivity was a risk factor for all lymphomas combined (odds ratio [OR] = 1.42, 95% confidence interval [CI]=1.15-1.74), and specifically for chronic lymphocytic leukaemia (OR = 2.96, 95%CI = 2.22-3.95).

de Sanjosé - Int J Cancer 2007 abstract / PubMed

Correlation of immunophenotype of sinonasal non-Hodgkin's lymphoma to Epstein-Barr virus infection. YF Feng, QL Wu, YS Zong. Ai Zheng 2007 Nov;26(11):1170-1176. "Seventy-one sinonasal NHLs were found in all 1 412 NHLs (71/1 412, 5.03%). Only 57 out of the 71 NHL biopsy tissues were suitable for this study. The median age of the patients was 50 years (ranged from 3 to 75 years). There were 38 males and 19 females. Forty-four sinonasal NHLs (44/57, 77.19%) were NK/T-cell lymphoma, nasal type, all of which were infected with EBV."

Feng - Ai Zheng 2007 abstract / PubMed

Quantitative analysis of cell-free Epstein-Barr virus DNA in the plasma of patients with peripheral T-cell and NK-cell lymphomas and peripheral T-cell proliferative diseases. S Suwiwat, J Pradutkanchana, T Ishida, W Mitarnun. J Clin Virol 2007 Dec;40(4):277-283. Cell-free EBV DNA was detected in 32/38 (84%) of peripheral T-cell and NK-cell lymphoma patients and 5/7 (71%) of peripheral T-cell proliferative disease patients, but not in the 45 controls.

Suwiwat - J Clin Virol 2007 abstract / PubMed

Epstein-Barr virus-positivity in tumor has no correlation with the clinical outcomes of patients with angioimmunoblastic T-cell lymphoma. Y Lee, KW Lee, JH Kim, SM Bang, JS Lee, BB Park, WS Kim, C Suh, JH Kang, BY Ryoo, JH Lee, DB Shin. Korean J Intern Med 2008 Mar;23(1):30-36. "Among the 27 tumor specimens, ten (37%) were EBV-positive."

Lee - Korean J Intern Med 2008 abstract / PubMed

[Correlation of Epstein-Barr virus infection and childhood lymphoma] ZD Xie, L Wang, D Lu, CJ Zhou, KL Shen. Zhonghua Zhong Liu Za Zhi 2008 May;30(5):365-367. IHC and ISH detection of EBV-EBERs in paraffin-embedded specimens of lymphoma collected between 1996 and 2005, including 36 Hodgkin lymphomas (HL) and 51 non-Hodgkin lymphomas (NHL). "EBV was detected in 72.2% (26/36) of the Hodgkin lymphomas, 15.7% (8/51) of the non-Hodgkin lymphomas and 33.3% (15/45) of the reactive hyperplasia of lymph nodes."

Xie - Zhonghua Zhong Liu Za Zhi 2008 abstract / PubMed

Intravascular large T-cell or NK-cell lymphoma: a rare variant of intravascular large cell lymphoma with frequent cytotoxic phenotype and association with Epstein-Barr virus infection. L Cerroni, C Massone, H Kutzner, T Mentzel, P Umbert, H Kerl. Am J Surg Pathol 2008 Jun;32(6):891-898. 2/4 cases were positive for EBV by ISH, one was negative.

Cerroni - Am J Surg Pathol 2008 abstract / PubMed

Age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorders: special references to lymphomas surrounding this newly recognized clinicopathologic disease. Y Shimoyama, K Yamamoto, N Asano, T Oyama, T Kinoshita, S Nakamura. Cancer Sci 2008 Jun;99(6):1085-1091. "This new disease entity is characterized pathologically by centroblasts, immunoblasts, and Hodgkin and Reed-Sternberg-like giant cells with a varying degree of reactive components, often posing therapeutic and diagnostic problems for hematologists and pathologists, respectively. The aim of the present review is to briefly summarize the overall clinicopathological profile of this newly recognized age-related (also called 'senile') EBV(+) B-LPD and EBV(+) Hodgkin lymphoma for a practical diagnostic approach."

Shimoyama - Cancer Sci 2008 abstract / PubMed

Histological characteristics of 21 Papua New Guinean children with high-grade B-cell lymphoma, which is frequently associated with EBV infection. Y Nomura, EK Lavu, K Muta, D Niino, M Takeshita, S Hirose, S Nakamura, T Yoshino, M Kikuchi, K Ohshima. Pathol Int 2008 Nov;58(11):695-700. "10 of 12 patients (83%) with BL/BLL, one of four (25%) with DLBCL, and three of five (60%) with B-LBL were positive for EBV-ISH. The findings of EBV-positive B-LBL were surprising because it is commonly considered that lymphoblastic lymphoma is not associated with EBV. EBV positivity was not detected in the 12 Japanese patients who were available for the EBV-ISH evaluation. It is concluded that it is possible that a proportion of DLBCL and B-LBL besides BL/BLL are associated with EBV in endemic region."

Nomura - Pathol Int 2008 abstract / PubMed

Lymphocyte-depleted classic Hodgkin lymphoma-a neglected entity? D Benharroch, A Levy, J Gopas, M Sacks. Virchows Arch 2008 Dec;453(6):611-616. "Changes in the definition of lymphocyte-depleted classic Hodgkin lymphoma (LDcHL) have recently led to reclassification of many cases as other pleomorphic lymphomas... Twelve of 201 cHL patients (5.9%) were diagnosed as showing LDcHL histology, a higher percentage of LDcHL than in most recent series. The LD cases were most often positive for Epstein-Barr virus and for sialyl-CD15."

Benharroch - Virchows Arch 2008 abstract / PubMed

Low frequency of Epstein Barr virus association and high frequency of p53 overexpression in an Argentinean pediatric T-cell lymphoma series. PA Chabay, E De Matteo, M Lorenzetti, A Vijnovich Barón, P Valva, MV Preciado. Pediatr Dev Pathol 2009 Jan-Feb;12(1):28-34. EBV expression was found in 8.0 % of 17 cases.

Chabay - Pediatr Dev Pathol 2008 abstract / PubMed

A prospective study of mitochondrial DNA copy number and risk of non-Hodgkin lymphoma. Q Lan, U Lim, CS Liu, SJ Weinstein, S Chanock, MR Bonner, J Virtamo, D Albanes, N Rothman. Blood 2008 Nov 15;112(10):4247-4249. "Mitochondrial DNA (mtDNA) copy number is increased in patients with chronic lymphocytic leukemia (CLL), in Burkitt lymphoma and Epstein-Barr virus-transformed lymphoblastoid cell lines, and in T cells activated via the T-cell receptor... There was a dose-response relationship between tertiles of mtDNA copy number and risk of NHL..." All subjects were recruited as smokers. "The mtDNA copy number was significantly higher in cases compared with controls (Table 1, P = .013), and the risk for developing NHL increased significantly with increasing mtDNA copy number (Table 2, Ptrend = .046). The association was most pronounced for CLL/SLL [small lymphocytic lymphoma], the most common histologic subtype in this case series (33%), with OR equal to 14.1 (95% CI, 1.9-103.2) for subjects in the highest tertile of mtDNA copy number compared with the lowest tertile."

Lan - Blood 2008 full article / PubMed Central

Frequency and distribution of Epstein-Barr virus infection and its association with P53 expression in a series of primary nodal non-Hodgkin lymphoma patients from South India. PS Sasikala, K Nirmala, S Sundersingh, U Mahji, T Rajkumar. Int J Lab Hematol 2010 Feb;32(1 Pt 2):56-64. "EBV, predominantly type A strain, was detected in 27/87 (31%) nodal lymphoid malignancies, 11/46 diffuse large B-cell lymphomas, 6/17 follicular lymphoma, 4/6 anaplastic large cell lymphomas (ALCL), 5/11 peripheral T-cell lymphomas (PTCL) and 1/7 lymphoblastic lymphomas."

Sasikala - Int J Lab Hematol 2008 abstract / PubMed

The prevalence of Epstein-Barr virus infection in different types and sites of lymphomas. Y Zhang, J Peng, Y Tang, J He, J Peng, Q Zhao, R He, X Xie, X Peng, R Gan. Jpn J Infect Dis 2010 Mar;63(2):132-135. By ISH, "Forty-six out of 108 non-Hodgkin lymphoma (NHL) cases were positive for EBER (42.6%). The EBER-positivity rate of NHL in the nasal cavity and nasopharynx (35/60 cases, 58.3%) was higher than that of NHL in stomach (9/30 cases, 30%) and in the superficial lymph nodes (2/18 cases, 11.1%) (P<0.05). The EBER-positivity rate of Hodgkin lymphoma in the superficial lymph nodes was 26.3% (5/19 cases)."

Zhang / Jpn J Infect Dis 2010 full article (pdf, 4 pp)

Diffuse large B-cell lymphoma involving the central nervous system. G Gualco, LM Weiss, GN Barber, CE Bacchi. Int J Surg Pathol 2011 Feb;19(1):44-50. 2 of 36 cases were positive for EBV.

Gualco - Int J Surg Pathol 2011 abstract / PubMed

Nasopharyngeal extranodal NK/T-cell lymphoma, nasal type: retrospective study of 18 consecutive cases in Guangzhou, China. YH Huang, QL Wu, YS Zong, YF Feng, JH Hou. Int J Surg Pathol 2011 Feb;19(1):51-61. "NKTCLs accounted for 69.2% (18/26) of nasopharyngeal T- and NK-cell lineage non-Hodgkin lymphomas. In all, 10 out of 18 patients (55.56%) had cervical lymph node(s) involvement. The serum anti-EBV antibody level was elevated (VCA-IgA titer ≥1:40) in 6 of 12 available patients. Two major immunophenotypic subtypes, namely, TIA-1+/EBERs+/CD56+ (10 cases) and TIA-1+/EBERs+/CD56- (8 cases) could be recognized. Genotyping analysis revealed that 10 out of 13 cases (76.9%) of NKTCL were harbored with del-LMP1 [del-LMP1 (Gly335) variant 7 cases, del-LMP1 (Asp335) variant 3 cases]. XhoI-loss was shown in 8/11 cases (72.73%). BamHI "f" variant of Bam F fragment was shown only in 4/14 cases (28.57%).The most common combination was del-LMP1 (Gly335)/ XhoI-loss/F (6/9, 66.7%)."

Huang - Int J Surg Pathol 2011 abstract / PubMed

Epstein-barr virus in diffuse large B-Cell lymphoma in immunocompetent patients in Japan is as low as in Western Countries. N Wada, J Ikeda, Y Hori, S Fujita, H Ogawa, T Soma, H Sugiyama, S Fukuhara, A Kanamaru, M Hino, Y Kanakura, E Morii, K Aozasa. J Med Virol 2011 Feb;83(2):317-321. "ISH with EBV-encoded small RNAs (EBER) probes revealed positive signals in the nuclei of tumor cells: the frequency of positively stained cells among all tumor cells was almost none in 458 cases, 5-10% in 5, 10-20% in 5, 20-50% in 11, and >50% in 5. When the frequency was >20% or >50%, the EBV-positive rate in the present series (3.3% or 1.0%) was rather similar to that reported in Western cases."

Wada - J Med Virol 2011 abstract / PubMed

The presence of Epstein-Barr virus (EBV) in diffuse large B-cell lymphomas (DLBCLs) in Turkey: special emphasis on 'EBV-positive DLBCL of the elderly'. A Uner, N Akyurek, A Saglam, S Abdullazade, N Uzum, S Onder, I Barista, M Benekli. APMIS 2011 Apr;119(4-5):309-316. 18 of 340 cases (5.3%) showed Epstein-Barr virus expression.

Uner - APMIS 2011 abstract / PubMed

Epstein-Barr virus (EBV)-associated primary central nervous system lymphoma: is incidence of EBV expression associated with median survival time? S Utsuki, H Oka, Y Miyajima, C Kijima, Y Yasui, K Fujii. Brain Tumor Pathol 2011 Apr;28(2):145-149. 33 cases. "Specimens were scored as having one of three possible results: negative (no EBV-positive cells), slightly positive (<50% EBV-positive cells), and strongly positive (>50% EBV-positive cells). Fifteen cases were negative for EBV expression. Sixteen cases were slightly positive, and two cases (68 and 79 years of age) were strongly positive. The incidence of strongly positive EBV expression in PCNSL was 6.1%."

Utsuki - Brain Tumor Pathol 2011 abstract / PubMed

Primary intestinal T-cell and NK-cell lymphomas: a clinicopathological and molecular study from China focused on type II enteropathy-associated T-cell lymphoma and primary intestinal NK-cell lymphoma. J Sun, Z Lu, D Yang, J Chen. Mod Pathol 2011 Jul;24(7):983-992. 38 cases, 6 NK-cell and 32 R-cell. "All tumors of the NK-cell group were positive for Epstein-Barr virus encoded mRNA in the majority of tumor cells and were polyclonal according to the results of commercial BIOMED-2 T-cell receptor gene rearrangement assays."

Sun - Mod Pathol 2011 abstract / PubMed

EBV-positive diffuse large B-cell lymphoma of the elderly: A case series from Peru. BE Beltran, JJ Castillo, D Morales, FH de Mendoza, P Quinones, RN Miranda, A Gallo, M Lopez-Ilasaca, JN Butera, EM Sotomayor. Am J Hematol 2011 Aug;86(8):663-667. 28 out of 199 cases of DLBCL of the elderly were EBV-positive.

Beltran - Am J Hematol 2011 abstract / PubMed

Clinicopathologic and Molecular Features of 122 Brazilian Cases of Nodal and Extranodal NK/T-Cell Lymphoma, Nasal Type, With EBV Subtyping Analysis. G Gualco, P Domeny-Duarte, L Chioato, G Barber, Y Natkunam, CE Bacchi. Am J Surg Pathol 2011 Aug;35(8):1195-1203. 97 cases of nasal/nasopharyngeal region and 23 cases in extranasal sites including 6 nodal cases. All were positive for EBV. "The global distribution of EBV subtypes showed predominance of strain subtype A, 89%, and subtype B, 11%. No dual infections were detected... Striking differences among geographic regions were seen with the vast majority of EBV subtype B (86%) occurring in the south and southeast regions."

Gualco - Am J Surg Pathol 2011 abstract / PubMed

Geographic variation in the prevalence of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly: a comparative analysis of a Mexican and a German population. A Hofscheier, A Ponciano, I Bonzheim, P Adam, C Lome-Maldonado, T Vela, E Cortes, C Ortiz-Hidalgo, F Fend, L Quintanilla-Martinez. Mod Pathol 2011 Aug;24(8):1046-1054. 305 diffuse large B-cell lymphomas. 7% (9 of 136) from Mexico, and 2% (4 of 169) from Germany were positive. "Only cases with EBER+ in the majority of tumor cells were regarded as EBV+ diffuse large B-cell lymphoma." Of EBV+ cases, "Twelve cases (92%) were LMP1 positive and two (15%) expressed EBNA2. An interesting finding was the high frequency of EBV type B with the LMP1 30 bp deletion found in the Mexican cases (50%)."

Hofscheier - Mod Pathol 2011 abstract / PubMed

Epstein Barr virus in relation to apoptosis markers and patients' outcome in pediatric B-cell non-Hodgkin lymphoma. P Chabay, J Lara, M Lorenzetti, P Cambra, G Acosta Haab, L Aversa, E De Matteo, MV Preciado. Cancer Lett 2011 Aug 28;307(2):221-226. 40 patients. "Forty percent showed EBV expression, significantly higher among patients ⩽10years (P=0.027), and associated with immunosuppression (P=0.020), but not associated apoptosis markers. However, EBV was associated with a worse event-free survival (P=0.016), particularly under immunosuppression."

Chabay - Cancer Lett 2011 abstract / PubMed

Tumor-specific but not nonspecific cell-free circulating DNA can be used to monitor disease response in lymphoma. K Jones, JP Nourse, C Keane, P Crooks, D Gottlieb, DS RitchieS, D Gill, MK Gandhi. Am J Hematol 2012 Mar;87(3):258-265. 63 lymphoma patients. "Within EBV-associated lymphomas at presentation, there was a strong correlation between specific and nonspecific circulating c-f DNA (r = 0.9, P < 0.0001). However, only c-f EBV-DNA correlated with clinical/radiological response. In addition, c-f EBV-DNA, and not nonspecific c-f DNA, provided an early marker of relapsed and refractory disease."

Jones - Am J Hematol 2012 abstract / PubMed

Comparison Between Presence of Epstein Barr Virus in Nodal and Extra Nodal Diffuse Large B Cell Lymphoma of Head and Neck, an Iranian Experience. MJ Ashraf, A Makarempour, A Monabati, N Azarpira, B Khademi, A Hakimzadeh, E Abedi, B Valibeigi. Iran Red Crescent Med J 2012 Dec;14(12):764-770. 15 patients with DLBL of neck lymph node and 15 patients with extra nodal DLBL of head and neck mainly in palatine tonsil. "All 30 cases were negative for EBV in IHC method. But in PCR method, 10% of patients were positive for LMP gene. There were 2 positive cases in nodal lymphoma and 1 positive case in extra nodal lymphoma group... Compare with PCR method, it seems that IHC is not a sensitive method for detection of EBV. Overall, the finding of EBV in NHL depends on site, type of lymphoma and the detection method."

Ashraf - Iran Red Crescent Med J 2012 abstract / PubMed

Extranodal NK/T-cell Lymphoma, Nasal Type: A Report of 73 Cases at MD Anderson Cancer Center. S Li, X Feng, T Li, S Zhang, Z Zuo, P Lin, S Konoplev, CE Bueso-Ramos, F Vega, LJ Medeiros, CC Yin. Am J Surg Pathol 2013 Jan;37(1):14-23. "In situ hybridization for Epstein-Barr virus-encoded small RNA was positive in every case."

Li - Am J Surg Pathol 2013 abstract / PubMed

Low incidence of epstein-barr virus-positive diffuse large b-cell lymphoma of the elderly in Tianjin, northern China. Y Pan, B Meng, H Zhang, W Cao, H Wang, C Bi, F Liu, B Sun, X Hao, W Zai, K Fu. Leuk Lymphoma 2013 Feb;54(2):298-303. 3.8% (8 of 212) diffuse large B-cell lymphomas were EBV-positive.

Pan - Leuk Lymphoma 2013 abstract / PubMed

Clinicopathology, immunophenotype, T cell receptor gene rearrangement, Epstein-Barr virus status and p53 gene mutation of cutaneous extranodal NK/T-cell lymphoma, nasal-type. TT Wang, C Xu, SL Liu, B Kan, YP Ran, WP Liu, GD Li, L Wang. Chin Med J (Engl) 2013 Apr;126(7):1281-1287. 100% of 18 cases were positive for EBER1/2.

Wang - Chin Med J 2013 abstract / PubMed

Epstein-Barr virus presence in pediatric diffuse large B-cell lymphoma reveals a particular association and latency patterns: Analysis of viral role in tumor microenvironment. M Cohen, E De Matteo, M Narbaitz, FA Carreńo, MV Preciado, PA Chabay. Int J Cancer 2013 Apr 1;132(7):1572-1580. 25 DLBCL patients. "Forty percent of cases showed EBV expression, with a significantly higher incidence among patients <10 years (p = 0.018), and with immunosuppressed (p = 0.023). T-cell subsets were not altered by EBV presence. Full EBV latency antigen expression (latency type III) was the most frequently pattern observed, together with BZLF1 lytic gene expression. One patient showed II-like pattern (LMP1 without LMP2A expression). Based exclusively on IHC, some patients showed latency II/III (EBERs and LMP1 expression) or I (EBERs only)."

Cohen - Int J Cancer 2013 abstract / PubMed (link to full article)

Immunomorphologic profile and EBV Status of a cohort of 35 Cases of Extranodal NK/T-cell Lymphoma, Nasal Type of Upper Aerodigestive Tract from a Tertiary Care Centre in South India. A Bugalia, MT Manipadam, S Nair. Leuk Lymphoma 2013 Jun;54(6):1201-1207. "EBER-ISH was positive in all 35 cases whereas EBVLMP1 was positive in only 19/35 (54.3%) of cases."

Bugalia - Leuk Lymphoma 2013 abstract / PubMed

Determination of Frequency of Epstein-Barr Virus in Non- Hodgkin Lymphomas Using EBV Latent Membrane Protein 1 (EBV-LMP1) Immunohistochemical Staining. S Ishtiaq, U Hassan, S Mushtaq, N Akhtar. Asian Pac J Cancer Prev 2013;14(6):3963-3967. 2 (22.2%) follicular lymphoma cases, 1 (11.1%) case of T-cell lymphoblastic lymphoma, 4 (44.4%) cases of diffuse large B cell lymphomas, 1 (11.1%) mantle cell lymphoma and 1 (11.1%) angioimmunoblastic T cell lymphoma case were positive for EBV-LMP-1 immunostaining.

Ishtiaq - Asian Pac J Cancer Prev 2013 abstract / PubMed

The prevalence of Epstein-Barr virus infection in head and neck non-Hodgkin's lymphomas in Khorasan, northeast of Iran. RZ Abadi, NS Sistani, N Mohtasham, KK Hesari, T Vaezi, M Pazouki, MT Shakeri. J Pak Med Assoc 2013 Jul;63(7):882-887. 34 cases of head and neck non-Hodgkin's lymphoma (17 low-grade B-cell lymphoma, 14 diffuse large B-cell lymphoma, and 3 peripheral T cell lymphoma) cases and 10 normal lymph node controls. "EBV-DNA was detected in 26.5% of NHL samples. Among NHLs, Epstein-Barr virus was found to be positive in 50% cases with diffuse large B-cell lymphoma and 11.8% of low grade B-cell lymphomas. Epstein-Barr virus was not detected in any cases of peripheral T-cell lymphoma."

Abadi - J Pak Med Assoc 2013 abstract / PubMed

Aggressive mature natural killer cell neoplasms: from epidemiology to diagnosis. M Lima. Orphanet J Rare Dis 2013 Jul 1;8:95. Review.

Lima / Orphanet J Rare Dis 2013 full article

Genetic and Immunohistochemical Characterization of Epstein-Barr Virus-Associated Diffuse Large B-Cell Lymphoma. S Al-Humood, A Alqallaf, S Al-Shemmari, L Al-Faris, B Al-Ayadhy. Acta Haematol 2013 Sep 4;131(1):1-10. In Kuwait. "EBV was detected in 6.9, 18.2 and 25% of the studied cases using IHC, ISH and nPCR, respectively, indicating that nPCR is more sensitive in detecting EBV than IHC and ISH."

Al-Humood - Acta Haematol 2013 abstract / PubMed

Epstein-Barr virus is rarely associated with diffuse large B cell lymphoma in Taiwan and carries a trend for a shorter median survival time. ST Chang, YH Lu, CL Lu, SF Weng, SH Lin, SY Kuo, YT Chuang, K Takeuchi, K Ohshima, SS Chuang. J Clin Pathol 2014 Apr;67(4):326-332. 332 of 424 consecutive DLBCL cases. "15 (4.5%) were EBV-positive and 13 (3.9%) fulfil WHO criteria of EBV-positive DLBCL of the elderly with a median age of 75." (By IHC and ISH.)

Chang - J Clin Pathol 2014 abstract / PubMed

Prevalence and Clinical Implications of Epstein-Barr Virus Infection in de novo Diffuse Large B-Cell Lymphoma in Western Countries. CY Ok, L Li, Z Xu-Monette, C Visco, A Tzankov, G Manyam, S Montes-Moreno, K Dybkćr, A Chiu, A Orazi, Y Zu, G Bhagat, J Chen, KL Richards, ED Hsi, W Choi, J Van Krieken, J Huh, WZ Ai, M Ponzoni, AJ Ferreri, JP Farnen, MB Mřller, C Bueso-Ramos, R Miranda, JN Winter, MA Piris, LJ Medeiros, KH Young. Clin Cancer Res 2014 May 1;20(9):2338-2349. 28 out of 732 DLBCLs were positive for EBV.

Ok - Clin Cancer Res 2014 abstract / PubMed

[A clinicopathologic and prognosis study of Epstein-Barr virus positive diffuse large B-cell lymphoma in west-southern China]. YX Ye, WY Zhang, GD Li, WP Liu, YM Liu, L Lin, DY Liao, J Guo, CY Xie, WJ Jiang, L Liu, SF Zhang. Sichuan Da Xue Xue Bao Yi Xue Ban 2014 Jul;45(4):652-657. 42 of 586 cases of DLBCL were EBV+.

Ye - Sichuan Da Xue Xue Bao Yi Xue Ban 2014 abstract / PubMed

Primary central nervous system Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly: a clinicopathologic study of five cases. SE Jamal, S Li, R Bajaj, Z Wang, L Kenyon, J Glass, CS Pang, S Bhagavathi, SC Peiper, JZ Gong. Brain Tumor Pathol 2014 Oct;31(4):265-273. 5 cases (4%) of 134 DLBCLs were positive for EBV.

Jamal - Brain Tumor Pathol 2014 abstract / PubMed

EBV-positive diffuse large B-cell lymphoma association is not only restricted to elderly patients. M Cohen, M Narbaitz, F Metrebian, E De Matteo, MV Preciado, PA Chabay. Int J Cancer 2014 Dec 15;135(12):2816-2824. 75 DLBCL patients. "Nine percent of cases showed EBV expression, with similar frequency among patients <50 years and ≥50 years (13% and 8%, respectively). T-cell subsets were not altered by EBV presence. Latency type II was the most frequently observed, together with lytic gene expression in EBV+ DLBCL, with ≥20% of EBERs+ cells. These findings suggest that EBV+ DLBCL in our series was similar to the previously described in Asia and Latin-America, displaying latency II or III expression profile and no age-specific characteristics."

Cohen - Int J Cancer 2014 abstract / PubMed

Epstein-barr virus and risk of non-Hodgkin lymphoma in the Cancer Prevention Study-II and a meta-analysis of serologic studies. LR Teras, DE Rollison, M Pawlita, A Michel, J Brozy, S de Sanjose, JL Blase, SM Gapstur. Int J Cancer 2015 Jan 1;136(1):108-116. 225 NHL cases and 2:1 matched controls. "No associations were observed between EBV serostatus or antibody levels and risk of NHL overall. However, when including only the three most common types of NHL (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma), high compared to low early antigen-diffuse (EA-D) and BZLF1-encoded replication activator (ZEBRA) antibodies were associated with approximately 60% higher risk of NHL. Odds ratios (OR) for EBV nuclear antigen-1 and viral capsid antigen (VCA)-p18 were elevated but not statistically significant. In the meta-analysis, both EA (summary OR=1.52, 95% confidence interval (CI): 1.16-2.00) and VCA (summary OR=1.20, 95% CI: 1.00-1.44) were positively associated with NHL risk."

Teras - Int J Cancer 2015 abstract / PubMed

Extranodal natural killer/T-cell lymphoma, nasal type in Taiwan: a relatively higher frequency of T-cell lineage and poor survival for extranasal tumors. J Jhuang, S Chang, S Weng, S Pan, P Chu, P Hsieh, C Wei, S Chou, C Koo, C Chen, J Hsu, S Chuang. Hum Pathol 2015 Feb;46(2):313-321. 100% of 73 cases were positive for EBV.

Jhuang - Hum Pathol 2015 abstract / PubMed

EBV-Positive Diffuse Large B-cell Lymphoma in Young Adults: Is This a Distinct Disease Entity? JY Hong, DH Yoon, C Suh, J Huh, IG Do, I Sohn, J Jo, SH Jung, ME Hong, H Yoon, YH Ko, SJ Kim, WS Kim. Ann Oncol 2015 Mar;26(3):548-555. 571 cases. "The prevalence of EBV positivity was 6.7% (13/195) and 9.3% (35/376) in the young group (≤ 50) and in the elderly group (>50), respectively... EBV positivity of DLBCL in young adults was not associated with unfavorable clinical characteristics or worse outcomes. We suggest that EBV-positive DLBCL should not be confined only in the elderly and "EBV-positive DLBCL in young adults" needs to be considered as a clinically distinct disease entity."

Hong - Ann Oncol 2015 abstract / PubMed

Evaluation of the role of Epstein-Barr virus in cases of nodal or extranodal T- and NK-cell lymphoma using eber in situ hybridization. S Karaarslan, M Hekimgil, S Soydan, Y Ertan, B Doğanavşargil. Pol J Pathol 2015 Jun;66(2):161-169. 62 peripheral T-cell lymphomas. "Using a cut-off value of > 25% of EBER-positive neoplastic lymphoid cells, EBV was positive in 22.6% of all cases. According to subtype, the neoplastic cells of 31.3% of PTCL, NOS and 100% of extranodal NKTCL, nasal type were EBER positive, whereas some cases of ALCL, AITCL, and ETTCL presented EBER-positive non‑neoplastic cells, and all cells of HSTCL and SPTCL were EBV negative."

Karaarslan - Pol J Pathol 2015 abstract / PubMed

Development of EBV-encoded small RNA targeted PCR to classify EBV positive diffuse large B-cell lymphoma (DLBCL) of the elderly. J Lee, M Park, MH Lee, HJ Woo, HW Kim, JY Yang, YB Eom, SH Kim, C Yoo, JB Kim. Int J Clin Exp Pathol 2015 Jul 1;8(7):7859-7868. 91 DLBCL patients. "EBV encoded small RNA1 in situ hybridization (EBER1-ISH) known as a standard method for the diagnosis of DLBCL. In this study, nested PCR of DNA polymerase gene and EBER PCR were conducted to detect EBV. Presence of EBV was indicated in 3 samples (3.30%) by EBER-ISH, 26 samples (28.57%) by nPCR, and 3 samples (3.30%) by EBER PCR. The concordant results were obtained from EBER1-ISH and EBER PCR." "Nested-PCR generally shows higher sensitivity than conventional PCR method, and almost all people are latently infected with EBV. Therefore, we consider the higher positivity in nPCR result is due to the false-positive."

Lee - Int J Clin Exp Pathol 2015 full article / PubMed Central

Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma in the Elderly: A Matched Case-Control Analysis. CG Song, JJ Huang, YJ Li, Y Xia, Y Wang, XW Bi, WQ Jiang, HQ Huang, TY Lin, ZM Li. PLoS One 2015 Jul 29;10(7):e0133973. 16 of 230 (7.0%) consecutive tumors were EBV-positive.

Song - PLoS One 2015 full article / PubMed Central
Song / PLoS One 2015 full article

In Europe expression of EBNA2 is associated with poor survival in EBV-positive diffuse large B-cell lymphoma of the elderly. C Stuhlmann-Laeisz, A Borchert, L Quintanilla-Martinez, S Hoeller, A Tzankov, I Oschlies, M Kreuz, R Trappe, W Klapper. Leuk Lymphoma 2016 Jan;57(1):39-44. 15 out of 598 (2.5%) DLBCLs were positive for EBV.

Stuhlmann-Laeisz - Leuk Lymphoma 2016 abstract / PubMed

Epstein-Barr Virus-Positive Diffuse Large B cell Lymphoma in the Experience of a Tertiary Medical Center in Poland. M Ziarkiewicz, D Wołosz, T Dzieciątkowski, E Wilczek, J Dwilewicz-Trojaczek, WW Jędrzejczak, B Gierej, B Ziarkiewicz-Wróblewska. Arch Immunol Ther Exp (Warsz) 2016 Apr;64(2):159-169. 74 DLBCL patients. "EBER staining revealed 12.2 % of EBV-positive cases, whereas 9.5 % were diagnosed as EBV-positive DLBCL of the elderly. Serologic EBV markers did not correlate with the presence of EBV in tissue samples (P > 0.10)."

Ziarkiewicz - Arch Immunol Ther Exp (Warsz) 2016 abstract / PubMed

Primary Intestinal Diffuse Large B-cell Lymphoma in Taiwan Showed a Relative Higher Rate of Perforation and EBV Association. YH Lu, ST Chang, SF Yang, SF Weng, WT Huang, PP Hsieh, JD Hsu, MH Tsou, SS Chuang. Appl Immunohistochem Mol Morphol 2016 Sep;24(8):541-549. "Seven (12%) of 59 cases were positive for Epstein-Barr virus (EBV) by in situ hybridization."

Lu - Appl Immunohistochem Mol Morphol 2015 abstract / PubMed

Primary Intestinal Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Comprehensive Clinicopathological Analysis of 55 Cases. BH Yu, RH Shui, WQ Sheng, CF Wang, HF Lu, XY Zhou, XZ Zhu, XQ Li. PLoS One 2016 Aug 26;11(8):e0161831. 100% were positive for EBV by ISH.

Yu - PLoS One 2016 full article / PubMed Central
Yu / PLoS One 2016 full article

Mechanisms

Epstein-Barr Virus and methylation of the p16 gene

Arginine butyrate-induced susceptibility to ganciclovir in an Epstein-Barr induced lymphoma. SJ Mentzer, J Fingeroth, JJ Reilly, SP Perrine, DV Faller, Blood Cells Mol Dis 1998 Jun;24(2):114-123. "[A]ntiviral therapy with synthetic nucleosides such as ganciclovir are ineffective because the genes that render the virus susceptible to therapy are not expressed in EBV+ lymphomas... Arginine butyrate was not only effective in inducing EBV thymidine kinase transcription, but also acted synergistically with the antiviral agent ganciclovir to inhibit cell proliferation and decrease cell viability."

Mentzer - Blood Cells Mol Dis 1998 abstract / PubMed

Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. N Khan, A Hislop, N Gudgeon, M Cobbold, R Khanna, L Nayak, AB Rickinson, PA Moss. J Immunol 2004;173(12):7481-7489. "Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status. The functional activity of the herpesvirus-specific immune response decreases in elderly donors, although the characteristic phenotypes of CMV- and EBV-specific memory populations are retained. This demonstrates that aging is associated with a marked accumulation of CMV-specific CD8 T cells together with a decrease in immediate effector function. Moreover, infection with CMV can reduce prevailing levels of immunity to EBV, another persistent virus. These results suggest that carriage of CMV may be detrimental to the immunocompetent host by suppressing heterologous virus-specific immunity during aging."

Khan / J Immunol 2004 full article
CMV Impairs Immunity

Interferon Regulatory Factor 7 Is Associated with Epstein-Barr Virus-Transformed Central Nervous System Lymphoma and Has Oncogenic Properties. L Zhang, J Zhang, Q Lambert, CJ Der, L Del Valle, J Miklossy, K Khalili, Y Zhou, JS Pagano. J Virol 2004 Dec;78(23):12987-12995. "The expression of IRF-7 is increased in EBV-immortalized B lymphocytes compared with that in primary B cells. IRF-7 was phosphorylated and predominantly localized in the nucleus in the immortalized cells. The expression of IRF-7 was detected in 19 of 27 specimens of primary lymphomas of the human central nervous system by immunohistochemical analysis. The association between LMP-1 and IRF-7 was statistically highly significant for these specimens. An appreciable amount of the IRF-7 expressed in lymphoma cells was localized in the nucleus. Furthermore, IRF-7 promoted the anchorage-independent growth of NIH 3T3 cells. LMP-1 and IRF-7 showed additive effects on the growth transformation of NIH 3T3 cells. IRF-7-expressing NIH 3T3 cells formed tumors in athymic mice. Thus, IRF-7 has oncogenic properties and, along with LMP-1, may mediate or potentiate the EBV transformation process in the pathogenesis of EBV-associated lymphomas."

Zhang / J Virology 2004 Full Article

LMP1 strain variants: biological and molecular properties. BA Mainou, N Raab-Traub. J Virol 2006 Jul;80(13):6458-6468. "LMP1 can activate a wide array of signaling pathways, including phosphatidylinositol 3-kinase (PI3K)-Akt and NF-kappaB. Six sequence variants of LMP1, termed Alaskan, China 1, China 2, Med+, Med-, and NC, have been identified, and individuals can be infected with multiple variants. The frequencies of detection of these variants differ for various EBV-associated malignancies from different geographic regions... While all the variants activated the PI3K-Akt signaling pathway to similar extents, the Alaskan, China 1, and Med+ variants had limited binding to the E3 ubiquitin ligase component homologue of Slimb and had slightly enhanced NF-kappaB signaling."

Mainou / J Virol 2006 full article
Mainou - J Virol 2006 full article / PubMed Central

Epstein-barr virus-induced resistance to drugs that activate the mitotic spindle assembly checkpoint in Burkitt's lymphoma cells. M Leao, E Anderton, M Wade, K Meekings, MJ Allday. J Virol. 2007 Jan;81(1):248-260. "[L]atent EBV can compromise the mitotic spindle assembly checkpoint and rescue Burkitt's lymphoma (BL)-derived cells from caspase-dependent cell death initiated in aberrant mitosis. This leads to unscheduled mitotic progression, resulting in polyploidy and multi- and/or micronucleation... These data suggest that a subset of latent EBV gene products may increase the likelihood of damaged DNA being inherited because of the impaired checkpoint and enhanced survival capacity. This could lead to greater genetic diversity in progeny cells and contribute to tumorigenesis. Furthermore, since it appears that this restricted latent EBV expression interferes with the responses of Burkitt's lymphoma-derived cells to cytotoxic drugs, the results of this study may have important therapeutic implications in the treatment of some BL."

Leao / J Virol. 2007 full article
Leao - J Virol. 2007 full article / PubMed Central

A molecular link between malaria and Epstein-Barr virus reactivation. A Chęne, D Donati, AO Guerreiro-Cacais, V Levitsky, Q Chen, KI Falk, J Orem, F Kironde, M Wahlgren, MT Bejarano. PLoS Pathog 2007 Jun;3(6):e80. "We show that CIDR1alpha binds to the EBV-positive B cell line Akata and increases the number of cells switching to the viral lytic cycle as measured by green fluorescent protein (GFP) expression driven by a lytic promoter. The virus production in CIDR1alpha-exposed cultures was directly proportional to the number of GFP-positive Akata cells (lytic EBV) and to the increased expression of the EBV lytic promoter BZLF1. Furthermore, CIDR1alpha stimulated the production of EBV in peripheral blood mononuclear cells derived from healthy donors and children with BL. Our results suggest that P. falciparum antigens such as CIDR1alpha can directly induce EBV reactivation during malaria infection that may increase the risk of BL development for children living in malaria-endemic areas. To our knowledge, this is the first report to show that a microbial protein can drive a latently infected B cell into EBV replication."

Chęne / PLoS Pathog 2007 full article
Chęne - PLoS Pathog 2007 full article / PubMed Central

Epstein-Barr Virus Infection of Langerhans Cell Precursors as a Mechanism of Oral Epithelial Entry, Persistence, and Reactivation. DM Walling, AJ Ray, JE Nichols, CM Flaitz, CM Nichols. J Virol 2007 Jul;81(13):7249-7268. "In this study, we present the first evidence demonstrating that EBV latently infects a unique subset of blood-borne mononuclear cells that are direct precursors to Langerhans cells and that EBV both latently and productively infects oral epithelium-resident cells that are likely Langerhans cells. These data form the basis of a proposed new model of EBV transition from blood to oral epithelium in which EBV-infected Langerhans cell precursors serve to transport EBV to the oral epithelium as they migrate and differentiate into oral Langerhans cells. This new model contributes fresh insight into the natural history of EBV infection and the pathogenesis of EBV-associated epithelial disease."

Walling / J Virol 2007 abstract

Latent membrane protein 1 of Epstein-Barr virus activates the hTERT promoter and enhances telomerase activity in B lymphocytes. L Terrin, J Dal Col, E Rampazzo, P Zancai, M Pedrotti, G Ammirabile, S Bergamin, S Rizzo, R Dolcetti, A De Rossi. J Virol 2008 Oct;82(20):10175-10187. "In the present study, we provide evidence indicating that, in B lymphocytes, LMP1 directly promotes the activation of telomerase by acting at the transcriptional level on the hTERT promoter. These effects are mediated by engagement of the NF-κB, MAPK, and ERK1/2 pathways." LMP1 transactivates the hTERT promoter in both epithelial and B cells.

Terrin - J Virol 2008 full article / PubMed Central

Nucleoside diphosphate kinase/Nm23 and Epstein-Barr virus. M Murakami, R Kaul, P Kumar, ES Robertson. Mol Cell Biochem 2009 Sep;329(1-2):131-139. "Nm23-H1 was discovered as the first metastasis suppressor gene about 20 years ago... EBNA3C and EBNA1, required for EBV-mediated lymphoproliferation and for maintenance EBV genome extrachromosomally in dividing mammalian cells, respectively, target and disrupt the physiological role of Nm23-H1 in the context of cell proliferation and cell migration."

Murakami - Mol Cell Biochem 2009 abstract / PubMed

Three Epstein-Barr virus latency proteins independently promote genomic instability by inducing DNA damage, inhibiting DNA repair and inactivating cell cycle checkpoints. B Gruhne, R Sompallae, MG Masucci. Oncogene 2009 Nov 12;28(45):3997-4008. "EBV nuclear antigens, EBNA-1 and EBNA-3C, and the latent membrane protein 1, LMP-1, independently promote genomic instability, as detected by nonclonal chromosomal aberrations, DNA breaks and phosphorylation of histone H2AX. EBNA-1 promotes the generation of DNA damage by inducing reactive oxygen species (ROS), whereas DNA repair is inhibited in LMP-1-expressing cells through downregulation of the DNA damage-sensing kinase, ataxia telangiectasia mutated (ATM), reduction of phosphorylation of its downstream targets Chk2 and inactivation of the G(2) checkpoint. EBNA-3C enhances the propagation of damaged DNA through inactivation of the mitotic spindle checkpoint and transcriptional downregulation of BubR1."

Gruhne - Oncogene 2009 abstract / PubMed

Epigenetic Repression of p16INK4A by Latent Epstein-Barr Virus Requires the Interaction of EBNA3A and EBNA3C with CtBP. L Skalska, RE White, M Franz, M Ruhmann, MJ Allday. PLoS Pathog 2010;6(6): e1000951. "[C]hromatin remodelling and epigenetic repression of p16INK4A requires the interaction of both EBNA3A and EBNA3C with CtBP. The repression of p16INK4A by latent EBV will not only overcome senescence in infected B cells, but may also pave the way for p16INK4A DNA methylation during B cell lymphomagenesis."

Skalska / PLoS Pathog 2010 full article

Micro RNAs of Epstein-Barr Virus Promote Cell Cycle Progression and Prevent Apoptosis of Primary Human B Cells. E Seto, A Moosmann, S Grömminger, N Walz, A Grundhoff, W Hammerschmidt. PLoS Pathog 2010;6(8):e1001063. "To assess the roles of EBV's miRNAs in this model, we generated EBV mutants that lack the capacity to encode viral miRNAs. Phenotypic analysis of human primary B cells infected with these mutant viruses revealed that miRNAs encoded in EBV's BHRF1 locus strongly promote B cell proliferation, regulate cell cycle functions, and prevent apoptosis early after infection."

Seto / PLoS Pathog 2010 full article

A new model of Epstein-Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas. SD Ma, S Hegde, KH Young, R Sullivan, D Rajesh, Y Zhou, E Jankowska-Gan, WJ Burlingham, X Sun, ML Gulley, W Tang, JE Gumperz, SC Kenney. J Virol 2011 Jan;85(1):165-177. In humanized mice, a lytic replication-defective BZLF1-deleted (Z-KO) virus and lytically active BZLF1(+) control virus established long-term latency. "The infection appeared well controlled in some animals, but others eventually developed CD20(+) diffuse large B cell lymphomas (DLBCL). Animals infected with the control virus developed tumors more frequently than Z-KO virus-infected animals."

Ma - J Virol 2011 abstract / PubMed

Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression. S Maruo, B Zhao, E Johannsen, E Kieff, J Zou, K Takada. Proc Natl Acad Sci USA 2011 Feb 1;108(5):1919-1924. "In the absence of EBNA3C or EBNA3A, p16(INK4A) and p14(ARF) expression increased and cell growth ceased. EBNA3C inactivation did not alter p16(INK4A) promoter CpG methylation, but reduced already low H3K27me3, relative to resting B cells, and increased H3K4me3 and H3-acetylation, linking EBNA3C inactivation to histone modifications associated with increased transcription."

Maruo - Proc Natl Acad Sci USA 2011 abstract / PubMed

The H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over-expressed in Hodgkin's Lymphoma. JA Anderton, S Bose, M Vockerodt, K Vrzalikova, W Wei, M Kuo, K Helin, J Christensen, M Rowe, PG Murray, CB Woodman. Oncogene 2011 Apr 28;30(17):2037-2043. "KDM6B is over-expressed in primary HL and induced by the EBV oncogene, latent membrane protein (LMP1) in GC B cells, the presumptive progenitors of HL. Consistent with these observations, we found that KDM6B transcriptional targets in GC B cells are enriched for genes differentially expressed in HL, and that KDM6B depletion can restore the tri-methylation of H3K27 on these genes."

Anderton - Oncogene 2011 abstract / PubMed

Specific infiltration of langerin-positive dendritic cells in EBV-infected tonsil, Hodgkin lymphoma and nasopharyngeal carcinoma. PH Braz-Silva, S Vitale, C Butori, N Guevara, J Santini, M Magalhăes, P Hofman, A Doglio. Int J Cancer 2011 May 1;128(10):2501-2508. "We report here the existence of a novel subset of langerin (CD207)-positive, immature dendritic cells (DCs) (CD83(neg)) abundantly infiltrating Epstein Barr virus (EBV)-infected areas in tonsil, Hodgkin lymphoma and nasopharyngeal carcinoma. These CD207(+) DCs differ from conventional epidermal Langerhans cells in their lack of CD1a and CCR6 and their unusual tissue localization. CD207(+) DC infiltration strongly correlates with EBV infection because it was neither detected in EBV negative specimens nor in tissues infected with other human viruses. These immature DCs might represent good candidates for induction of the EBV-specific immune response."

Braz-Silva - Int J Cancer 2011 abstract / PubMed

The Epstein-Barr virus nuclear antigen-1 promotes telomere dysfunction via induction of oxidative stress. SA Kamranvar, MG Masucci. Leukemia 2011 Jun;25(6):1017-1025. "Stable or conditional expression of EBNA1 induced telomere abnormalities including loss or gain of telomere signals, telomere fusion and heterogeneous length of telomeres. This was accompanied by the accumulation of extrachromosomal telomeres, telomere dysfunction-induced foci (TIFs) containing phosphorylated histone H2AX and the DNA damage response protein 53BP1, telomere-associated promyelocytic leukemia nuclear bodies (APBs), telomeric-sister chromatid exchanges and displacement of the shelterin protein TRF2."

Kamranvar - Leukemia 2011 abstract / PubMed
Kamranvar - Leukemia 2011 full article / PubMed Central

A novel persistence associated EBV miRNA expression profile is disrupted in neoplasia. J Qiu, K Cosmopoulos, M Pegtel, E Hopmans, P Murray, J Middeldorp, M Shapiro, DA Thorley-Lawson. PLoS Pathog 2011 Aug;7(8):e1002193. "In the generally accepted model of EBV persistence, newly infected naďve B lymphoblasts (LCL) expressing Latency III, switch to Latency II when transiting the germinal center (GCB) to become resting memory B (MemB) cells, the site of long term persistence where viral latent protein expression is extinguished. Our results here suggest that the transit from EBV driven growth into more restricted forms of latency in GCB and MemB cells is associated with turning off expression of the Latency III associated BARTs and up regulation of the remaining BART miRNAs by 5–10 fold. This is not simply related to the cessation of proliferation because latently infected GCB are, like LCL cells, proliferating. Since proliferation in the GC is not driven by Latency III, the viral growth program, we may conclude that the Latency III BART profile (presence of the Latency III associated BARTs and reduced expression of the remaining BARTs) is specifically associated with EBV driven growth." Also, the miRNA expression profiles of tumor cell lines were not representative of the tumors.

Qiu - PLoS Pathog 2011 full article / PubMed Central

Epigenetic and transcriptional changes which follow Epstein-Barr virus infection of germinal centre B cells and their relevance to the pathogenesis of Hodgkin's lymphoma. S Leonard, W Wei, J Anderton, M Vockerodt, M Rowe, PG Murray, CB Woodman. J Virol 2011 Sep;85(18):9568-9577. "We show that EBV infection of GC B cells is followed by up-regulation of the DNA methyltransferase, DNMT3A and down-regulation of DNMT3B and of DNMT1. We show that the EBV oncogene, LMP1, down-regulates DNMT1, and that DNMT3A binds to the viral promoter Wp. Genome-wide promoter arrays performed on these cells showed that EBV-associated methylation changes in cellular genes were not randomly distributed across the genome but clustered at chromosomal locations consistent with an instructive pattern of methylation and were in part determined by promoter CpG content. Both DNMT3B and DNMT1 were down-regulated and DNMT3A up-regulated in HL cell lines, recapitulating the pattern of expression observed following EBV infection of GC B cells. We also found using gene expression profiling, that genes differentially expressed following EBV infection of GC B cells were significantly enriched for those reported to be differentially expressed in HL. These observations suggest that EBV-infected GC B cells are a useful model for studying virus associated changes contributing to the pathogenesis of HL."

Leonard - J Virol 2011 abstract / PubMed

Epstein-Barr virus nuclear antigen 3C stabilizes Gemin3 to block p53-mediated apoptosis. Q Cai, Y Guo, B Xiao, S Banerjee, A Saha, J Lu, T Glisovic, ES Robertson. PLoS Pathog 2011 Dec;7(12):e1002418. "Here, we report that EBNA3C directly interacts with Gemin3 through its C-terminal domains. This interaction results in increased stability of Gemin3 and its accumulation in both B lymphoma cells and EBV transformed lymphoblastoid cell lines (LCLs). Moreover, EBNA3C promotes formation of a complex with p53 and Gemin3 which blocks the DNA-binding affinity of p53. Small hairpin RNA based knockdown of Gemin3 in B lymphoma or LCL cells remarkably attenuates the ability of EBNA3C to inhibit the transcription activity of p53 on its downstream genes p21 and Bax, as well as apoptosis. These findings provide the first evidence that Gemin3 may be a common target of oncogenic viruses for driving cell proliferation and anti-apoptotic activities."

Cai - PLoS Pathog 2011 full article / PubMed Central
Cai / PLoS Pathog 2011 full article

Epstein-Barr Virus Infection of Naďve B Cells In Vitro Frequently Selects Clones with Mutated Immunoglobulin Genotypes: Implications for Virus Biology. E Heath, N Begue-Pastor, S Chaganti, D Croom-Carter, C Shannon-Lowe, D Kube, R Feederle, H-J Delecluse, AB Rickinson, AI Bell. PLoS Pathog 2012;8(5): e1002697. "We find that EBV does not induce Ig class switching (though the infected cells remain responsive to exogenous switch signals) but can induce Ig gene mutation. Thus, within 4 weeks of infecting naive B cell preparations, one can often detect cells carrying Ig mutations which appear to have arisen by somatic hypermutation in vitro. Furthermore, in many cases such cells become dominant during clonal evolution of the emergent EBV-transformed cell line. Overall these findings suggest a possible explanation as to why EBV is selectively found in memory B cell populations in vivo and why EBV-positive lymphoproliferative lesions/lymphomas so frequently involve clones with mutated Ig genotypes."

Heath / PLoS Pathog 2012 full article

Induction of p16INK4a Is the Major Barrier to Proliferation when Epstein-Barr Virus (EBV) Transforms Primary B Cells into Lymphoblastoid Cell Lines. L Skalska, RE White, GA Parker, AJ Sinclair, K Paschos, MJ Allday. PLoS Pathog 2013;9(2): e1003187. "Infections of normal primary B cells with recombinant EBV-BAC virus from which EBNA3C is deleted or with 3CHT EBV in the absence of activating ligand 4-hydroxytamoxifen, revealed that EBNA3C is necessary to overcome an EBV-driven increase in p16INK4a expression and concomitant block to proliferation 2–4 weeks post-infection. If cells are p16INK4a-null, functional EBNA3C is dispensable for the outgrowth of LCLs."

Skalska / PLoS Pathog 2013 full article

Epstein-Barr Virus Transforming Protein LMP-1 Alters B Cells Gene Expression by Promoting Accumulation of the Oncoprotein ΔNp73α. R Accardi, I Fathallah, H Gruffat, G Mariggiň, F Le Calvez-Kelm, C Voegele, B Bartosch, H Hernandez-Vargas, J McKay, BS Sylla, E Manet, M Tommasino. PLoS Pathog 2013;9(3): e1003186. "Here we show that Epstein-Barr virus (EBV), via the oncoprotein LMP-1, induces the expression of ΔNp73α, a strong antagonist of p53. This phenomenon is mediated by the LMP-1 dependent activation of c-Jun NH2-terminal kinase 1 (JNK-1) which in turn favours the recruitment of p73 to ΔNp73α promoter."

Accardi / PLoS Pathog 2013 full article

Telomere dysfunction and activation of alternative lengthening of telomeres in B-lymphocytes infected by Epstein-Barr virus. SA Kamranvar, X Chen, MG Masucci. Oncogene 2013 Dec 5;32(49):5522-5530. "Here we show that newly EBV-infected cells exhibit multiple signs of telomere dysfunction, including the occurrence of extra-chromosomal telomeres, telomere fusion and telomere length heterogeneity, and undergo progressive increase in telomere length without a parallel increase in telomerase activity. This phenotype is accompanied by the accumulation of telomere-associated promyelocytic leukemia nuclear bodies and telomeric-sister chromatid exchange, suggesting that EBV infection promotes the activation of ALT. Newly infected cells also display a significant reduction of telomere-associated TRF2 and express low levels of TRF1, TRF2, POT1 and ATRX, pointing to telomere de-protection as an important correlate of ALT activation."

Kamranvar - Oncogene 2013 abstract / PubMed

The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1. FZ Cader, M Vockerodt, S Bose, E Nagy, MA Brundler, P Kearns, PG Murray. Blood 2013 Dec 19;122(26):4237-4245. "We show that expression of the EBV-encoded latent membrane protein-1 (LMP1) in primary human germinal centre B cells, the presumed progenitors of HRS cells, up-regulates discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen. We also show that HRS cells intimately associated with collagen frequently over-express DDR1 and that short-term exposure to collagen is sufficient to activate DDR1 in Hodgkin lymphoma-derived cell lines. The ectopic expression of DDR1 significantly increased the survival of collagen-treated DG75, Burkitt lymphoma cells, following etoposide treatment. Conversely, knockdown of DDR1 significantly decreased the survival of collagen-treated L428 Hodgkin lymphoma cells in the absence of specific apoptotic stimulus suggesting that DDR1 also influences baseline survival."

Cader - Blood 2013 abstract / PubMed

Epstein-Barr virus Type 2 latently infects T-cells inducing an atypical activation characterized by expression of lymphotactic cytokines. CB Coleman, EM Wohlford, NA Smith, CA King, JA Ritchie, PC Baresel, H Kimura, R Rochford. J Virol 2015 Feb;89(4):2301-2312. "We report here that the EBV type 2 (EBV-2) strain displays a unique cell tropism for T-cells. In remarkable contrast to EBV-1, EBV-2 readily infects primary T-cells in vitro, demonstrating a propensity for CD8+ T-cells. EBV-2 infection of purified T-cells results in expression of latency genes and ultimately leads to T-cell activation, substantial proliferation, and profound alteration of cytokine expression. The pattern of cytokine production is strikingly skewed towards chemokines with roles in lymphocyte migration, demonstrating that EBV-2 has the ability to modulate normal T-cell process."

Coleman - J Virol 2015 abstract / PubMed

Epstein-Barr Virus Proteins EBNA3A and EBNA3C Together Induce Expression of the Oncogenic MicroRNA Cluster miR-221/miR-222 and Ablate Expression of Its Target p57KIP2. Q Bazot, K Paschos, L Skalska, JS Kalchschmidt, GA Parker, MJ Allday. PLoS Pathog 2015 Jul 8;11(7):e1005031. "...EBNA3A and EBNA3C are both required for transactivation of the oncogenic miR-221/miR-222 cluster that is expressed at high levels in multiple human tumours - including lymphoma/leukemia. ChIP, ChIP-seq, and chromosome conformation capture analyses indicate that this activation results from direct targeting of both EBV proteins to chromatin at the miR-221/miR-222 genomic locus... In contrast, EBNA3A and EBNA3C are necessary to silence the tumour suppressor cluster miR-143/miR-145, but here ChIP-seq suggests that repression is probably indirect."

Bazot / PLoS Pathog 2015 full article

See Also:

Confounding By Infection
Epstein-Barr Virus Causes Nasopharyngeal Cancer
EBV Causes Lymphoepithelioma-like Lung Cancer
Epstein-Barr Virus Causes Gastric Carcinoma
EBV & Socioeconomic Status
EBV Causes Interstitial Lung Disease
EBV and Other Diseases
EBV Causes Multiple Sclerosis
Epstein-Barr Virus Causes Sjogren’s Syndrome
EBV Causes Lupus

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cast 09-17-16