EBV and Other Diseases

Hemophagocytic Lymphohistiocytosis

Hemophagocytic syndrome in Epstein-Barr virus-associated T-lymphoproliferative disorders: disease spectrum, pathogenesis, and management. IJ Su, CH Wang, AL Cheng, RL Chen. Leuk Lymphoma 1995 Nov;19(5-6):401-406. Review.

Su - Leuk Lymphoma 1995 abstract / PubMed

Polymerase chain reaction amplification of archival material for Epstein-Barr virus, cytomegalovirus, human herpesvirus6, and parvovirus B19 in children with bone marrow hemophagocytosis. MP Hoang, DB Dawson, ZR Rogers, RH Scheuermann, BB Rogers. Hum Pathol 1998 Oct;29(10):1074-1077.

Hoang - Hum Pathol 1998 abstract / PubMed

Haematological associations of Epstein-Barr virus infection. M Okano. Baillieres Best Pract Res Clin Haematol 2000 Jun;13(2):199-214. Review.

Okano - Baillieres Best Pract Res Clin Haematol 2000 abstract / PubMed

Hemophagocytic syndromes and infection. DN Fisman. Emerging Infectious Diseases 2000 Nov-Dec;6(6):601-608. Review. In this disorder, macrophages engulf the other blood cell types. "HLH may be diagnosed in association with malignant, genetic, or autoimmune diseases but is also prominently linked with Epstein-Barr (EBV) virus infection."

Fisman / EID 2000 full article

Lytic infection of Epstein-Barr virus (EBV) in hemophagocytic syndrome associated with EBV-induced lymphoproliferative disorder. T Yamamoto, A Shirakawa, M Kawaguchi, A Masuda, T Nishikawa, M Kobayashi. Ann Hematol 2004 Feb;83(2):127-132. 3 females, aged 52 to 87. "Atypical lymphocytes in all cases showed a positive reaction for both EBV-encoded small RNA (EBER) indicating latent infection with EBV and immediate early mRNAs of the Bam HI fragment of lower stranded frame (BHLF), indicating lytic infection by in situ hybridization. Interestingly, BHLF-positive cells were predominant in all cases. It is possible that reactivation of EBV infection may be involved in triggering the induction of cytokines and abnormal activation of histiocytes."

Yamamoto - Ann Hematol 2004 abstract / PubMed

Severe Epstein-Barr virus-associated hemophagocytic syndrome in six adult patients. AS Elazary, DG Wolf, G Amir, B Avni, D Rund, DB Yehuda, S Sviri. J Clin Virol 2007 Oct;40(2):156-159. There were six cases in three years in healthy adults in Israel. "EBV associated HPS may be more prevalent in non-Japanese adults than was previously considered."

Elazary - J Clin Virol 2007 abstract / PubMed

Viral markers in patients with hemophagocytosis: a prospective study in a tertiary care hospital. B Mishra, N Varma, S Appannanavar, P Malhotra, M Sharma, A Bhatnagar, RK Ratho, S Varma. Indian J Pathol Microbiol 2012 Apr-Jun;55(2):215-217. In north India. "Among the 14 HPS cases 43% (6/14) were positive for at least one viral marker tested, of which EBV was found to be the most prevalent (3/6: 50%) followed by parvovirus B19(2/6: 33%) and cytomegalovirus (1/6: 17%). Mortality was noted in 33% of virus associated HPS patients."

Mishra - Indian J Pathol Microbiol 2012 abstract / PubMed

Immune Disorder Rapidly Fatal in Cancer. By Ed Sussman. MedPage Today, Dec. 12, 2012. 63 patients at Mayo Clinic from 1996-2011. Re: Parikh S, et al "Outcome of adult patients with hemophagocytic syndrome: A tertiary care center experience." ASH 2012; Abstract 1040. "Aside from malignancy, the underlying etiology for hemophagocytic lymphohistiocytosis was mainly due to infections – 22 cases were infection-based. Of those, seven patients had Epstein-Barr, four had histoplasmosis, three had cytomegalovirus, and the rest had a variety of other infections. In addition to the infection-based cases, the investigators identified five autoimmune cases of the syndrome, four idiopathic cases, and one primary case, Parikh said. Of the 31 malignancies, 19 were T-cell lymphomas; six other cases were B-cell lymphomas, he said."

Immune Disorder Rapidly Fatal in Cancer / MedPage Today 2012

Demonstration of type II latency in T lymphocytes of Epstein-Barr Virus-associated hemophagocytic lymphohistiocytosis. Y Ito, Y Kawamura, S Iwata, J Kawada, T Yoshikawa, H Kimura. Pediatr Blood Cancer 2013 Feb;60(2):326-328. Case report. "EBV-positive lymphocytes were detected as CD5(+) , CD8(+) , and/or HLA DR(+) lymphocytes on Day 25 of the disease, mostly disappearing thereafter. CD8(+) cells specific for lytic antigen BRLF1 were detected, but cells specific for latent antigens EBNA3 and LMP2 were not. EBV genes EBNA1, LMP1, LMP2, EBER1, BARTs were detected, suggesting a latency type II gene expression pattern in this case."

Ito - Pediatr Blood Cancer 2013 abstract / PubMed

Immunologic Difference between Hypersensitivity to Mosquito Bite and Hemophagocytic Lymphohistiocytosis Associated with Epstein-Barr Virus Infection. WI Lee, JJ Lin, MY Hsieh, SJ Lin, TH Jaing, SH Chen, IJ Hung, CP Yang, CJ Chen, YC Huang, SP Li, JL Huang. PLoS One 2013 Oct 18;8(10):e76711. 12 episodes in 12 HLH patients and 14 episodes in 4 HMB patients. "[T]here were both decreased percentages of CD4+ and CD8+ and increased memory CD4+ and activated (CD2+HLADR+) lymphocytes. In contrast to HMB episodes that had higher IgE levels and EBV virus load predominantly in NK cells, those HLH episodes with virus load predominantly in CD3+ lymphocyte had decreased perforin expression and cytotoxicity that were recovered in the convalescence period. However, there was neither significant difference of total virus load in these episodes nor candidate genetic mutations responsible for hereditary HLH."

Lee - PLoS One 2013 full article / PubMed Central
Lee / PLoS One 2013 full article

[Analysis of clinical and laboratory features of 217 pediatric hemophagocytic lymphohistiocytosis]. L Xiao, X Guan, Y Meng, Y Su, Y Xian, J Xiao, Y Cui, J Yu. Zhonghua Xue Ye Xue Za Zhi 2014 Jul 14;35(7):628-632. 217 pediatric patients. "The most common causes of HLH was infection, especially Epstein-Barr virus-associated HLH (71.0%). Other causes included malignant hemophagocytic syndrome (MAHS), macrophage activation syndrome (MAS) and so on."

Xiao - Zhonghua Xue Ye Xue Za Zhi 2014 abstract / PubMed
Xiao / Zhonghua Xue Ye Xue Za Zhi 2014 full article landing (in Chinese)

Clinical features, genetics, and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in Korea: report of a nationwide survey from Korea Histiocytosis Working Party. KN Koh, HJ Im, NG Chung, B Cho, HJ Kang, HY Shin, CJ Lyu, KH Yoo, HH Koo, HJ Kim, HJ Baek, H Kook, HS Yoon, YT Lim, HS Kim, KH Ryu, JJ Seo; the Korea Histiocytosis Working Party. Eur J Haematol 2015 Jan;94(1):51-59. 25 cases with familial HLH, 64 with presumed secondary HLH, and 162 with unspecified HLH. "Of 217 evaluable patients, 91 (42%) had concomitant Epstein-Barr virus infection. Of 238 evaluable patients, central nervous system (CNS) involvement, which was more frequent in the familial group, was evident in 81 cases (34%). Genetic tests revealed a predominant UNC13D mutation with a high incidence of two recurrent splicing mutations (c.118-308C>T and c.754-1G>C). The 5-yr overall survival rate was 68% (38% in the familial group and 81% in the presumed secondary group)."

Koh - Eur J Haematol 2015 abstract / PubMed

[Treatment outcomes and prognostic analysis of 61 Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis]. X Zeng, N Wei, Y Wang, J Wang, J Zhang, L Wu, W Huang, Z Gao, R Pei, J Chen, Z Jin, Z Wang. Zhonghua Xue Ye Xue Za Zhi 2015 Jun 14;36(6):507-510. 102 out of 246 HLH cases were associated with EBV infection, including 61 EBV-HLH, 36 lymphoma associated HLH, and 5 primary HLH.

Zeng - Zhonghua Xue Ye Xue Za Zhi 2015 abstract / PubMed

Viral etiology, clinical and laboratory features of adult hemophagocytic lymphohistiocytosis. J Chen, X Wang, P He, Y Li, M Si, Z Fan, X Chang, Q Xie, X Jiao. J Med Virol 2016 Mar;88(3):541-549. 54 patients. "Twenty-four SHLH patients had viraemia, whereas 30 SHLH patients were secondary to other diseases. Epstein-Barr virus (EBV) was the most common virus that associated SHLH among all viruses studied. Severe SHLH patients with EBV-viraemia presented significantly high levels of ferritin, lactate dehydrogenase, aspartate transaminase (AST), and alanine transaminase (ALT). Positively relationships existed between EBV DNA titers and levels of AST and ALT (P < 0.05). The prognosis of SHLH patients with EBV viraemia was worse than that of non-EBV SHLH and non-viral SHLH."

Chen - J Med Virol 2016 abstract / PubMed

Clinical presentation of hemophagocytic lymphohistiocytosis in adults is less typical than in children. Z Zhang, J Wang, B Ji, Tv Bahr Greenwood, Y Zhang, Y Wang, D Kong, A Li, Y Jiang, Y Guo, X Liu, Y Wang, A Dou, N Li, JI Henter, G Sun, C Zheng. Clinics (Sao Paulo) 2016 Apr;71(4):205-209. 34 adults and 16 children. "2.9% of the adults (1/34) had EBV infection, which was much lower than the rate in the children (31.3%, or 5/16)."

Zhang - Clinics (Sao Paulo) 2016 full article / PubMed Central

Clinical presentation and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in China: A retrospective multicenter study. XJ Xu, HS Wang, XL Ju, PF Xiao, Y Xiao, HM Xue, HY Shi, YJ Gao, GC Jia, XR Li, WH Zhao, NL Wang, YM Tang; Histiocytosis Study Group of the Chinese Pediatric Society. Pediatr Blood Cancer 2016 Oct 26 [Epub ahead of print]. 323 patients. "Epstein-Barr virus (EBV) infection was the major condition related to HLH, which was documented in 74.4% (201/270) of the patients who underwent EBV detection."

Xu - Pediatr Blood Cancer 2016 abstract / PubMed

Severe Mosquito Bite Reaction

Characterization of Epstein-Barr virus (EBV)-infected natural killer (NK) cell proliferation in patients with severe mosquito allergy; establishment of an IL-2-dependent NK-like cell line. I Tsuge, T Morishima, M Morita, H Kimura, K Kuzushima, H Matsuoka. Clin Exp Immunol 1999 Mar;115(3):385-392. There is a clonal expansion of EBV-infected NK cells in severe hypersensitivity to mosquito bites.

Tsuge - Clin Exp Immunol 1999 abstract / PubMed
Tsuge - Clin Exp Immunol 1999 Full Article

Hypersensitivity to mosquito bites is not an allergic disease, but an Epstein-Barr virus-associated lymphoproliferative disease. S Ishihara, R Yabuta, Y Tokura, K Ohshima, S Tagawa. Int J Hematol 2000 Aug;72(2):223-228. "Although the symptoms of HMB have been supposed to derive from Arthus phenomenon, it has become apparent that this unique disorder has the potential to develop into so-called malignant histiocytosis or related disorders."

Ishihara - Int J Hematol 2000 abstract / PubMed

Hypersensitivity to mosquito bites as the primary clinical manifestation of a juvenile type of Epstein-Barr virus-associated natural killer cell leukemia/lymphoma. Y Tokura, S Ishihara, S Tagawa, N Seo, K Ohshima, M Tajigawa. J Am Acad Dermatol 2001 Oct;45(4):569-578.

Tokura - J Am Acad Dermatol 2001 abstract / PubMed

Epstein-Barr virus reactivation is induced, but abortive, in cutaneous lesions of systemic hydroa vacciniforme and hypersensitivity to mosquito bites. T Yamamoto, Y Hirai, T Miyake, T Hamada, O Yamasaki, S Morizane, W Fujimoto, K Iwatsuki. J Dermatol Sci 2016 Jun;82(3):153-159. "In the tissue, BZLF1 mRNA was detected in 5 of 6 (83%) samples of EBV+ epithelial neoplasms, 16 of 21 (76%) of EBV+ lymphomas, and 5 of 15 (33%) of systemic HV and/or HMB, but negative in all 15 patients with classical HV. In the blood, BZLF1 mRNA was detected in only one of 19 (5.3%) samples of EBV-associated T/NK-LPDs. A down-stream reactivation signal, BDRF1 mRNA was expressed in all 6 samples of EBV+ epithelial neoplasms, but it was positive in only one of 15 (6.7%) samples from systemic HV and HMB in the tissue."

Yamamoto - J Dermatol Sci 2016 abstract / PubMed

EBV and Ataxia-Telangiectasia

A-T patients are unusually susceptible to Epstein-Barr virus, and are at high risk of lymphomas; while A-T heterozygotes are at increased risk of breast and gastric cancers.

Unusual Prevalence of Epstein-Barr Virus Early Antigen (EBV-EA) Antibodies in Ataxia Telangiectasia. J Joncas, N Lapointe, F Gervais, M Leyritz. J Immunol 1977 Nov;119(5):1857-1859. 16 patients. "[A] high prevalence of Epstein-Barr virus early antigen (EBV-EA) antibodies was found in patients with ataxia telangiectasia (AT) in whom the incidence of lymphoma is increased."

Joncas / J Immunol 1977 abstract

Epstein-Barr virus-related antibody patterns in ataxia-telangiectasia. AI Berkel, W Henle, G Henle, G Klein, F Ersoy, O Sanal. Clin Exp Immunol 1979 Feb;35(2):196-201. 22 A-T patients and 22 healthy family members, 22 patients with other diseases and 15 healthy family members, and 23 unrelated healthy controls. "The AT patients showed an increased incidence (55.6%) of high antibody titres (greater than or equal to 1:320) to viral capsid antigen (VCA), and also a high incidence (48.2%) of antibodies to Epstein-Barr virus (EBV) induced early antigens (EA), but low titres (less than 1:10) of antibodies to the EBV-associated nuclear antigen (EBNA) in 44.2% of the cases. The geometric means of anti-VCA were three-to four-fold higher, and of anti-EBNA six-fold lower, than those of the control groups... AT patients with low anti-EBNA titres tended to have more advanced T cell deficiencies than AT patients with moderate anti-EBNA titres..."

Berkel - Clin Exp Immunol 1979 full article / PubMed Central

Epstein-Barr virus antibodies in patients with ataxia-telangiectasia and other immunodeficiency diseases. JH Joncas, A Wills, E Reece, Z Fox. Can Med Assoc J 1981 Oct 15;125(8):845-849. 16 patients, with review of the literature. "As in patients with ataxia-telangiectasia, EA antibodies are prevalent and persistent in patients with EBV-associated tumours, such as Burkitt's lymphoma and nasopharyngeal carcinoma. As well, the incidence of lymphoma in patients with ataxia-telangiectasia is high." EA antibodies persisted more than two years among some patients.

Joncas - Can Med Assoc J 1981 full article / PubMed Central

Disorders of B cells and helper T cells in the pathogenesis of the immunoglobulin deficiency of patients with ataxia telangiectasia. TA Waldmann, S Broder, CK Goldman, K Frost, SJ Korsmeyer, MA Medici. J Clin Invest 1983 Feb;71(2):282-295. 20 patients, 17 controls. "The immunoglobulin synthesis was below the lower limit of the normal 95% confidence interval for IgM in 5 patients, for IgG in 8, and for IgA in 14. The mononuclear cells from 9 of the 10 patients with a serum IgA concentration less than 0.1 mg/ml failed to synthesize IgA in vitro..."

Waldmann - J Clin Invest 1983 full article / PubMed Central

Epstein-Barr serology in immunodeficiencies: an attempt to correlate with immune abnormalities in Wiskott-Aldrich and Chediak-Higashi syndromes and ataxia telangiectasia. E Vilmer, GM Lenoir, JL Virelizier, C Griscelli. Clin Exp Immunol 1984 Feb;55(2):249-256. "We confirmed a frequent absence of anti-EBNA antibody in ataxia telangiectasia (AT), and we showed a correlation between the level of anti-EBNA response and the mixed leucocyte response (MLR), i.e., an absence of anti-EBNA antibody correlated with a decreased MLR... In spite of previous infection with EB virus, none of the 41 patients exhibited clinical signs attributable to the virus, suggesting that residual or compensatory mechanisms must have limited activation of the virus."

Vilmer - Clin Exp Immunol 1984 full article / PubMed Central

Epstein-Barr virus (EBV)-specific cell-mediated and humoral immune responses in ataxia-telangectasia patients. G Masucci, I Berkel, MG Masucci, I Ernberg, R Szigeti, F Ersoy, O Sanal, O Yegin, G Henle, W Henle, et al. J Clin Immunol 1984 Sep;4(5):369-382. 16 Turkish patients with A-T. "Fifteen were EBV seropositive; one was seronegative. Among the seropositives, eight had no or only low anti-EBV-determined nuclear antigen (EBNA) antibody titers, while seven had normal anti-EBNA levels... The majority of the patients of the low-EBNA antibody group was IgA deficient and had high levels of alpha-fetoprotein (a-FP)... EBV-specific cell-mediated responses were defective in seven of eight patients in the low-anti-EBNA group and five of seven patients in the group with normal anti-EBNA titers."

Masucci - J Clin Immunol 1984 abstract / PubMed

Immune response to Epstein-Barr virus (EBV) in ataxia-telangiectasia: EBV-specific antibody patterns and their relation to cell-mediated immunity. AI Berkel, W Henle, G Henle, F Ersoy, O Sanal, G Klein, O Yeğin. Kroc Found Ser 1985;19:287-300. 60 patients with AT, 22 healthy family members. "The AT patients showed an increased incidence (66.6%) of high antibody titers (greater than or equal to 1:320) to viral capsid antigen (VCA) and also a high incidence (35%) of antibody titers to early antigens (EA), but low titers (less than 1:10) of antibodies to the EBV-associated nuclear antigen (EBNA) in 35% of the patients. The geometric mean titers (GMT) of antibodies to VCA were five to six times higher; those of anti-EBNA were five times lower in AT patients as compared with control groups."

Berkel - Kroc Found Ser 1985 abstract - PubMed

[Studies on Epstein-Barr virus (EBV) infection and reactivity of peripheral B lymphocytes to EBV in patients with ataxia telangiectasia]. M Okano. Hokkaido Igaku Zasshi 1986 Jul;61(4):584-592. 10 Japanese patients with AT. "All the AT patients had high EBV antibody titers of IgG to viral capsid antigen (VCA) and early antigen (EA), while low titers of IgG to EBV-associated nuclear antigen (EBNA), compared with age and sex matched healthy controls. However, significant differences were not apparent with antibodies to several other viruses between the AT patients and controls." EBV-specific T cell killer function was very low. Malignant transformation "easily occurred with some of AT lymphoblastoid cells."

Okano - Hokkaido Igaku Zasshi 1986 abstract / PubMed

Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. D Morrell, E Cromartie, M Swift. J Natl Cancer Inst 1986 Jul;77(1):89-92. 263 ataxia-telangiectasia (A-T) homozygotes. "For white and black A-T patients, respectively, all-cause mortality was 50 and 147 times higher than expected based on U.S. mortality rates. There were 52 primary cancers, representing a 61-fold cancer excess for white probands and a 184-fold excess for black probands. The cancer excess was most pronounced for lymphoma, with 252- and 750-fold excesses observed for whites and blacks, respectively."

Morrell - J Natl Cancer Inst 1986 abstract / PubMed

The incidence and gene frequency of ataxia-telangiectasia in the United States. M Swift, D Morrell, E Cromartie, AR Chamberlin, MH Skolnick, DT Bishop. Am J Hum Genet 1986 Nov;39(5):573-583. Pedigree analysis " estimated the most likely gene frequency to be .007 on the assumption that A-T is a single homogeneous genetic syndrome, with 95% confidence limits of .0012-.02. Given that complementation analysis has demonstrated the genetic heterogeneity of A-T, the A-T heterozygote frequency will probably fall between 0.68% and 7.7%, with 2.8% being the most likely estimate."

Chamberlin - Am J Hum Genet 1986 full article / PubMed Central

Incidence of cancer in 161 families affected by ataxia-telangiectasia. M Swift, D Morrell, RB Massey, CL Chase. N Engl J Med 1991 Dec 26;325(26):1831-1836. 91 cancers. "For obligate heterozygotes 20 to 79 years of age, the excess risk of cancer was directly estimated to be 3.9 times higher in men and 2.7 times higher in women than in noncarriers. The most frequent site of cancer was the breast, with 23 new breast cancers diagnosed in 20 blood relatives... Women heterozygous for ataxia—telangiectasia were estimated to be 5.1 times more likely to have breast cancer than noncarriers (P = 0.009." "As described elsewhere, risk estimates for heterozygotes and our previously published estimate that heterozygotes constitute 1.4 percent of the population can be used to estimate the effect of this gene on overall mortality or the incidence of cancer in the United States. For example, if heterozygotes have a true risk of the development of cancer from the ages of 20 through 79 that is 3.5 times that of noncarriers, then 4.7 percent of all cancers in the general population between those ages occur in heterozygotes."

Swift / N Engl J Med 1991 full article

Epstein-barr-virus hypersensitivity of lymphocytes from patients with ataxia-telangiectasia. M Okano, F Mizuno, T Aya, T Osato, Y Sakiyama, S Matsumoto. Int J Oncol 1993 Jun;2(6):1027-1031. "When the lymphoblastoid cells from patients with AT were exposed to P3HR-1 EBV, EA and VCA syntheses were approximately 6- and 12-fold higher, respectively, than those in the cells derived from the healthy controls. This evidence suggested B lymphocytes of patients with AT were highly susceptible to EBV infection and possibly linked to the development of EBV-induced LPD."

Okano - Int J Oncol 1993 abstract / PubMed

ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. A Broeks, JH Urbanus, AN Floore, EC Dahler, JG Klijn, EJ Rutgers, P Devilee, NS Russell, FE van Leeuwen, LJ van 't Veer. Am J Hum Genet 2000 Feb;66(2):494-500. 82 breast cancer cases in AT patients under 45, and 4 were bilateral. 7 (8.5%) had ATM germline mutations. "We conclude that ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival." "None of the tumors of the ATM heterozygotes tested for LOH showed LOH of the wild-type allele. Thus, it seems that a mutant ATM germline allele plays a role in tumor initiation but that complete loss of the normal protein is not a prerequisite for tumor initiation."

Broeks - Am J Hum Genet 2000 full article / PubMed Central

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. In cell sublines, "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. Thus, multiple cellular functions involved in the maintenance of genome integrity seem to be independently targeted by EBV, pointing to the induction of genomic instability as a critical event in viral oncogenesis."

Gruhne - Oncogene 2009 abstract - PubMed

Incidence, Presentation, and Prognosis of Malignancies in Ataxia-Telangiectasia: A Report From the French National Registry of Primary Immune Deficiencies. F Suarez, N Mahlaoui, D Canioni, C Andriamanga, CD d'Enghien, N Brousse, JP Jais, A Fischer, O Hermine, D Stoppa-Lyonnet. J Clin Oncol 2015 Jan 10;33(2):202-208. "Eight patients developed acute leukemias (including four T-cell acute lymphoblastic leukemias), 12 developed Hodgkin lymphoma (HL), 38 developed non-Hodgkin lymphoma (NHL), three developed T-cell prolymphocytic leukemia (T-PLL), and eight developed carcinoma at a median age of 8.3, 10.6, 9.7, 24.2, and 31.4 years, respectively (P < .001). The majority of NHLs were aggressive B-cell NHL. Epstein-Barr virus was associated with all of the HLs and 50% of the NHLs. Overall survival was shorter in patients with AT who developed cancer compared with those who did not develop cancer (15 v 24 years, respectively; P < .001)."

Suarez - J Clin Oncol 2015 abstract / PubMed

EBV and Breast Cancer

Epstein-Barr virus in epithelial cell tumors: a breast cancer study. LG Labrecque, DM Barnes, IS Fentiman and BE Griffin. Cancer Research 1995; 55(1):39-45. 19 of 91 (21%) cases of breast carcinoma were positive for EBV DNA, versus none of 21 samples from benign breast tumors or normal breast tissue.

Labrecque et al / Cancer Res 1995 abstract

Absence of Epstein-Barr virus EBER-1 transcripts in an epidemiologically diverse group of breast cancers. S Glaser, R Ambinder, J DiGiuseppe, P Horn-Ross, J Hsu. Int J Cancer 1998;75:555–558. No EBV was found by in situ hybridization for the EBER-1 transcript among 97 female and 28 male patients identified from a US population-based cancer registry.

Glaser - Int J Cancer 1998 abstract / PubMed

Detection of Epstein-Barr Virus in Invasive Breast Cancers. M Bonnet, J-M Guinebretiere, E Kremmer, V Grunewald, E Benhamou, G Contesso, I Joab. Journal of the National Cancer Institute 1999 Aug 18;91(16):1376-1381. "We were able to detect the EBV genome by PCR in 51% of the tumors, whereas, in 90% of the cases studied, the virus was not detected in healthy tissue adjacent to the tumor (P<.001). The presence of the EBV genome in breast tumors was confirmed by Southern blot analysis."

Bonnet et al. / JNCI 1999 full article

Breast Cancer: a New Epstein-Barr Virus-Associated Disease? I Magrath, K Bhatia. Journal of the National Cancer Institute 1999 Aug;91(16):1349-1350. (Editorial.) "The possibility that there is variable or absent expression of EBER in EBV-positive breast cancer cells may explain, at least in part, the apparently conflicting results in the literature. Two of the groups that reported a lack of association of EBV with breast cancer of various histologies used only EBER ISH to detect EBV. A third, in which only three cases were studied, obtained positive results by PCR and negative results by EBER ISH. The remaining two, which used several techniques to detect EBV, examined only medullary carcinoma of the breast (8,9), a rare tumor (there was one in the series by Bonnet et al.) that is histologically similar to lymphoepithelioma-like carcinoma, a group of tumors that is often, but not always, EBV associated. Thus, although more data are needed, it seems likely at this time that EBV is frequently associated with multiple histologic types of breast cancer. The variable expression of EBER in neoplastic epithelial cells also leaves open the possibility that EBV may be associated with a broader range of tumors than previously thought, because many investigators in recent years have relied upon EBER ISH as a means of assessing EBV association. EBER ISH, if positive, is meaningful; however, if it is negative, it does not prove the absence of EBV, particularly in epithelial cells."

Magrath & Bhatia / JNCI 1999 full article

Hypothesis. Breast Cancer Risk and "Delayed" Primary Epstein-Barr Virus Infection. Y Yasui, JD Potter, JL Stanford, MA Rossing, MD Winget, M Bronner, J Daling. Cancer Epidemiology Biomarkers & Prevention 2001 Jan;10:9-16. Populations with higher incidence rates of breast cancer corresponded to those with higher likelihood of delayed primary EBV infection. "Age-adjusted odds ratios of breast cancer in women who reported a history of IM, relative to women who did not, increased monotonically from 0.55 [95% confidence interval (CI), 0.05–6.17] for women with 0–9 years of age at IM onset to 2.67 (CI, 1.04–6.89) for women with 25 years of age at IM onset (P = 0.016)."

Yasui et al. / Cancer Epidemiol Biomarkers Prevent 2001 full article

Frequency and genome load of Epstein-Barr virus in 509 breast cancers from different geographical areas. F Fina, S Romain, L Ouafik, J Palmari, F Ben Ayed, S Benharkat, P Bonnier, F Spyratos, JA Foekens, C Rose, M Buisson, H Gerard, MO Reymond, JM Seigneurin, PM Martin PM. Br J Cancer 2001 Mar 23;84(6):783-790. 31.8% of 509 tumours contained the EBV genome.

Fina - Br J Cancer 2001 abstract / PubMed

No significant association of Epstein-Barr virus infection with invasive breast carcinoma. P Chu, K Chang, Y Chen, W Chen, L Weiss. Am J Pathol 2001;159:571–578. "Five of 48 cases (10%) of breast carcinoma showed focal EBER-positive tumor cells. Twelve cases (25%) were positive for EBNA-1 by immunohistochemistry, all but one different from the EBER-positive cases. None of the cases were positive for LMP-1 or ZEBRA protein by immunohistochemistry. PCR studies for EBNA-4 and LMP-1 were each positive in five cases (including three cases in common). However, Southern blot studies successfully performed in all but one of the PCR-positive cases were completely negative."

Chu - Am J Pathol 2001 abstract / PubMed

Demonstration of Epstein-Barr virus in carcinomas of various sites. S Grinstein, MV Preciado, P Gattuso, PA Chabay, WH Warren, E De Matteo, VE Gould. Cancer Res 2002 Sep 1;62(17):4876-4878. "In 14 of 33 (42%) carcinomas, convincing nuclear reactions were noted involving a range of 5–30% of neoplastic cells; ductal and lobular variants of carcinoma were similarly involved; foci of in situ carcinoma also showed focal nuclear staining. Proliferative variants of fibrocystic disease with variable degrees of atypia, and occasionally a lack thereof, including ductal and lobular hyperplasia and papillomas, also showed focal nuclear immunoreactivity. These changes were found in cases with and without an associated carcinoma. In a cellular fibroadenoma (phyllodes tumor), EBV-reactive nuclei were found in some epithelial and stromal cells. Twenty-one normal breast, nonproliferative variants of fibrocystic changes and benign fibroadenomas were negative. CD21 showed no reaction in any epithelial component. Our demonstration of EBV in breast carcinomas confirm and broaden earlier reports including the relative incidence of positive cases. However, our findings on EBV in typical and atypical ductal and lobular proliferations and in situ carcinomas represent novel observations and may reflect a possible etiological role of EBV in breast carcinogenesis. Notably, these observations in the breast, with a different EBV pattern of expression (EBER-, LMP-1-, and EBNA-1+), parallel findings and hypothesis advocated by Pathmanathan et al. in nasopharyngeal carcinomas involving dysplasia or preinvasive carcinoma in situ (EBER+, LMP-1+), both representing evidence that EBV may be a primary etiological agent in a multistep process that leads to the development of a carcinoma."

Grinstein / Cancer Res 2002 full article

Lack of expression of the Epstein-Barr Virus (EBV) gene products, EBERs, EBNA1, LMP1, and LMP2A, in breast cancer cells. C Deshpande, S Badve, N Kidwai, R Longnecker. Lab Invest 2002;82:1193–1199. No EBV was detected in 43 female breast cancer cases by in situ hybridization for EBV RNA (EBERs), or by immunohistochemistry, for EBV nuclear antigen 1 (EBNA1) and the latent membrane proteins (LMP1 and LMP2A.

Deshpande - Lab Invest 2002 abstract / PubMed

Reactivity with A monoclonal antibody to Epstein-Barr virus (EBV) nuclear antigen 1 defines a subset of aggressive breast cancers in the absence of the EBV genome. PG Murray, D Lissauer, J Junying, G Davies, S Moore, A Bell, J Timms, D Rowlands, C McConkey, GM Reynolds, S Ghataura, D England, R Caroll, LS Young. Cancer Res 2003 May 1;63(9):2338-2343. EBV DNA was detected in 19 of 92 (21%) tumors.

Murray / Cancer Res 2003 full article

Lack of evidence for an association of Epstein-Barr virus infection with breast carcinoma. K Herrmann, G Niedobitek. Breast Cancer Res 2003;5(1):R13-17. "EBV-encoded RNA-specific in situ hybridisation and EBV-encoded nuclear antigen 1 immunohistochemistry were negative in all cases. Using the PCR, EBV DNA was detected in four out of 59 cases. These cases were further studied by EBV DNA in situ hybridisation, showing an absence of viral DNA from the tumour cells."

Herrmann / Cancer Res 2003 full article
Herrmann - Cancer Res 2003 full article / PubMed Central

Epstein-Barr virus gene expression in human breast cancer: protagonist or passenger? SA Xue, IA Lampert, JS Haldane, JE Bridger, BE Griffin. Br J Cancer 2003 Jul 7;89(1):113-119. EBV genes were found in 40% of 15 mastectomy-removed breast cancer samples, mostly of ductal origin.

Xue - Br J Cancer 2003 abstract / PubMed

Epstein-Barr virus in breast carcinoma in Argentina. MV Preciado, PA Chabay, EN De Matteo, P Gonzalez, S Grinstein, A Actis, HD Gass. Arch Pathol Lab Med 2005 Mar;129(3):377-381. EBV was found by immunohistochemical analysis in 24 (35%) of 69 samples and by PCR analysis in 12 (31%) of 39 samples; none was found in in any of the control breast biopsy specimens (17 biopsy specimens of fibroadenomas, 9 of benign epithelial proliferation [adenosis and sclerosing adenosis], 4 of atypical ductal hyperplasia, and 10 of usual ductal hyperplasia).

Preciado / Arch Pathol Lab Med 2005 full article

Real-time PCR measures Epstein-Barr Virus DNA in archival breast adenocarcinomas. LB Thorne, JL Ryan, SH Elmore, SL Glaser, ML Gulley. Diagn Mol Pathol 2005 Mar;14(1):29-33. "In four tumors (7%), low level EBV DNA was detected by at least one of the assays, with levels of up to 11 copies of EBV DNA per 100,000 cells. Immunohistochemisty for viral BMRF1 and BZLF1 and in situ hybridization for lytic gene transcripts showed no evidence of replicative EBV gene expression. Lymphocytes and malignant cells were also negative for latent infection by EBER in situ hybridization."

Thorne - Diagn Mol Pathol 2005 abstract / PubMed

Epstein-Barr Virus (EBV) Genome and Expression in Breast Cancer Tissue: Effect of EBV Infection of Breast Cancer Cells on Resistance to Paclitaxel (Taxol). H Arbach, V Viglasky, F Lefeu, J-M Guinebretière, V Ramirez, N Bride, N Boualaga, T Bauchet, J-P Peyrat, M-C Mathieu, S Mourah, M-P Podgorniak, J-M Seignerin, K Takada, I Joab. J Virology 2006 Jan;80(2):845-853. "Our findings show that EBV genomes can be detected by Q-PCR in about half of tumor specimens, usually in low copy numbers. However, we also found that the viral load is highly variable from tumor to tumor. Moreover, EBV genomes are heterogeneously distributed in morphologically identical tumor cells, with some clusters of isolated tumor cells containing relatively high genome numbers while other tumor cells isolated from the same specimen may be negative for EBV DNA... Furthermore, we observed that in vitro EBV infection of breast carcinoma cells confers resistance to paclitaxel (taxol) and provokes overexpression of a multidrug resistance gene (MDR1). Consequently, even if a small number of breast cancer cells are EBV infected, the impact of EBV infection on the efficiency of anticancer treatment might be of importance."

Arbach / J Virology 2006 full article

[Detection of Epstein-Barr virus in breast cancers with lymphoid stroma]. A Trabelsi, S Rammeh, W Stita, M Mokni, A Mourou, S Korbi. Ann Biol Clin (Paris) 2008 Jan-Feb;66(1):59-62. 18 medullary carcinoma and 18 high grade invasive ductal carcinoma with lymphoid stroma, by immunohistochemistry with anti-LMP2 antibody and by hybridization in situ by oligonucleotides EBER1 and EBER1. "LMP1 as well as hybridization in situ were positive in 5 tumors (3 medullary carcinoma and 2 high grade invasive ductal carcinoma with lymphoid stroma). RESULTS: positivity was observed in tumor cells and neither in epithelial non tumoral ones nor in lymphoid cells."

Trabelsi - Ann Biol Clin (Paris) 2008 abstract / PubMed

Detection of Epstein-Barr virus in breast carcinoma in Egyptian women. S Fawzy, M Sallam, N Mohammad Awad. Clin Biochem 2008 May;41(7-8):486-92. 32 ductal and 8 lobular breast cancers, 20 controls with fibrocystic disease. "10/40 (25%) of the BC specimens stained positively for EBNA-1; EBNA-1 expression was restricted to a fraction 5%-60% of tumor epithelial cells. EBV-DNA was detected in 8/10 of BC specimens positive for EBNA-1. Control specimens were negative by both techniques."

Fawzy - Clin Biochem 2008 abstract / PubMed

Association of Epstein Barr virus infection (EBV) with breast cancer in rural Indian women. D Joshi, M Quadri, N Gangane, R Joshi, N Gangane. PLoS One 2009 Dec 4;4(12):e8180. 58 cases of malignant breast disease and 63 of benign breast disease (controls). "Mean antibody levels were significantly higher for cases (54.22 IU/ml) as compared to controls (18.68 IU/ml). IHC for EBNA-1 was positive in 28/51 cases (54.9%). No IHC positivity was noted in the tested 30 controls."

Joshi - PLoS One 2009 full article / PubMed Central
Joshi / PLoS One 2009 full article

Characterization of Epstein Barr virus latency pattern in Argentine breast carcinoma. MA Lorenzetti, De Matteo, H Gass, P Martinez Vazquez, J Lara, P Gonzalez, MV Preciado, PA Chabay. PLoS One 2010 Oct 22;5(10):e13603. 71 biopsies of breast carcinoma and 48 non-neoplastic breast controls. "EBV genomic DNA and EBNA1 expression were detected in 31% (22/71) of patients specifically restricted to tumor epithelial cells in breast carcinoma while all breast control samples were negative for both viral DNA and EBNA1 protein. LMP2A was detected in 73% of EBNA1 positive cases, none of which expressed either LMP1 protein or EBERs transcripts."

Lorenzetti - PLoS One 2010 full article / PubMed Central
Lorenzetti / PLoS One 2010 full article

Association between Epstein-Barr virus infection and risk for development of pregnancy-associated breast cancer: joint effect with vitamin D? CB Agborsangaya, T Lehtinen, AT Toriola, E Pukkala, HM Surcel, R Tedeschi, M Lehtinen. Eur J Cancer 2011 Jan;47(1):116-120. 108 cases, 208 controls. "EBV seropositivity was generally not associated with the risk of PABC. Among individuals with sufficient (≥75 nmol/l) levels of vitamin D, we, however, found similar increased risk estimates for PABC associated with serum immunoglobulin G (IgG) antibodies to EBV early antigens [odds ratio (OR)=7.7, 95% (confidence interval) CI 1.4-42.3] and the viral reactivator protein, ZEBRA (OR=7.8, 95% CI 1.1-61.2)."

Agborsangaya - Eur J Cancer 2011 abstract / PubMed

Epstein-Barr virus as a marker of biological aggressiveness in breast cancer. C Mazouni, F Fina, S Romain, L Ouafik, P Bonnier, JM Brandone, PM Martin. Br J Cancer 2011 Jan 18;104(2):332-337. "EBV DNA was present in 65 of the 196 (33.2%) cases studied. EBV-positive BCs tended to be tumours with a more aggressive phenotype, more frequently oestrogen receptor negative (P=0.05) and with high histological grade (P=0.01). Overexpression of thymidine kinase activity was higher in EBV-infected BC (P=0.007). The presence of EBV was weakly associated with HER2 gene amplification (P=0.08)."

Mazouni - Br J Cancer 2011 abstract / PubMed

Deliberate scientific fraud in the British Medical Journal, funded by the U.S. National Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services. (Association of active and passive smoking with risk of breast cancer among postmenopausal women: a prospective cohort study. J Luo, KL Margolis, J Wactawski-Wende, K Horn, C Messina, ML Stefanick, HA Tindle, E Tong, TE Rohan. BMJ 2011 Mar 1;342:d1016. doi: 10.1136/bmj.d1016.) This study IS based on lifestyle questionnaires, which ignored the role of Epstein-Barr virus infection on order to falsely pretend to find a risk associated with smoking. It is supposed to be a basic principle of epidemiology that larger risks should be properly accounted for before making claims about smaller ones, but the authors and the editors of the BMJ have simply ignored this fundamental principle. The very design of this study makes its purposes clear. It is for lifestyle propaganda only, and not research on the real causes of disease. It epitomizes the agenda and methods of the ultra-politically-connected, unaccountable oligarchy of the Harvard School of Public Health, which secretly rules this country, its media and all the politicians. The fact that they commandeered the unprecedented sum of $625 million for this study, the Women's Health Initiative, is definitive proof of their power and influence. It proves that science is thoroughly corrupted by RELIGIOUS INTERESTS, who cynically disguise their theological agenda under a flimsy veneer of pseudo-science in order to force it on unwilling victims, in gross violation of our Constitutional rights to freedom of religion. These charlatans are so smugly confident that they will never be held accountable that they make no secret of their bias: "The addition of breast cancer to the list of diseases causally related to active or secondhand tobacco smoking would probably be a powerful argument for women to stop smoking or avoid taking it up." And they perform a cynical charade of pretending to consider the issue of confounding, without mentioning the word "virus." (Is breast cancer associated with tobacco smoking? P Boffetta, P Autier. BMJ 342:doi:10.1136/bmj.d1093.) It proves beyond a shadow of doubt that our so-called "science" is actually controlled by a theocracy!

Luo / BMJ 2011 abstract

Human papillomavirus and Epstein-Barr virus infections in breast cancer from chile. F Aguayo, N Khan, C Koriyama, C González, S Ampuero, O Padilla, L Solís, Y Eizuru, A Corvalán, S Akiba. Infect Agent Cancer 2011 Jun 23;6(1):7. "The amplification of a housekeeping gene showed that 46/55 samples (84%) had amplifiable DNA. HPV-16 was detected in 4/46 BCs (8.7%) and EBV [EBER-1] was detected in 3/46 (6.5%) BCs. The analysis of HPV-16 physical status showed that this virus was integrated in all of the tumors with a relatively low viral load (range: 0.14 to 33.8 copies/cell). E6 and E7 transcripts, however, were not detected in any HPV-16 positive specimens."

Aguayo / Infect Agent Cancer 2011 full article
Aguayo - Infect Agent Cancer 2011 full article / PubMed Central

Localization of Epstein-Barr virus to infiltrating lymphocytes in breast carcinomas and not malignant cells. G Khan, PS Philip, M Al Ashari, Y Houcinat, S Daoud. Exp Mol Pathol 2011 Aug;91(1):466-470. 47.5% of 61 breast cancer cases were EBV positive, "but the virus was localized to occasional infiltrating lymphocytes and not in the malignant cells."

Khan - Exp Mol Pathol 2011 abstract / PubMed

Epstein-Barr Virus and Breast Cancer: Lack of Evidence for an Association in Iranian Women. M Kadivar, A Monabati, A Joulaee, N Hosseini. Pathol Oncol Res 2011 Sep;17(3):489-492. 100 breast carcinoma and 42 control biopsies. EBNA-2 and LMP-1 were negative by IHC in all specimens, and no EBV DNA was found by PCR.

Kadivar - Pathol Oncol Res 2011 abstract / PubMed

Investigation of Epstein-Barr virus in breast carcinomas in Tunisia. M Hachana, K Amara, S Ziadi, E Romdhane, RB Gacem, M Trimeche. Pathol Res Pract 2011 Nov 15;207(11):695-700. "Using specific PCR assays, EBV DNA was found in 33 (27%) out of 123 breast carcinoma cases. EBV-encoded small RNAs (EBERs) in situ hybridization was negative in the neoplastic cells, but stomal lymphocytes were positive in 4 cases. Immunohistochemistry for latent membrane protein 1 (LMP1) was negative in all cases. None of the normal breast tissues showed positive results for EBV using PCR, in situ hybridization, and immunohistochemistry. A correlation was found between EBV DNA presence and the negativity of estrogen receptor (P=0.008)."

Hachana - Pathol Res Pract 2011 abstract / PubMed

Epstein-Barr virus is seldom found in mammary epithelium of breast cancer tissue using in situ molecular methods. K Baltzell, GC Buehring, S Krishnamurthy, H Kuerer, HM Shen, JD Sison. Breast Cancer Res Treat 2012 Feb;132(1):267-274. By ISH and IS-PCR, "EBV was found in mammary epithelial cells, the cell type from which most breast cancers arise, in 2/70 (2.9%) of specimens using IS-PCR and in none of the specimens using ISH."

Baltzell - Breast Cancer Res Treat 2012 abstract / PubMed

Epstein-Barr virus and breast cancer: Epidemiological and Molecular study on Egyptian and Iraqi women. AR Zekri, AA Bahnassy, WS Mohamed, FA El-Kassem, SJ El-Khalidi, MM Hafez, ZK Hassan. J Egypt Natl Canc Inst 2012 Sep;24(3):123-131. "Our gold standard for EBV reactivity in breast cancer cases was positivity of both EBNA1 by PCR and EBER by in situ hybridization. EBV was detected in 18/40 (45%) and 14/50 (28%) of Egyptian and Iraqi women; respectively where p=0.073, compared to 0/20 (0%) of their control groups (p<0.05)."

Zekri - J Egypt Natl Canc Inst 2012 abstract / PubMed

Identification of Transmembrane Protein 134 as a Novel LMP1-Binding Protein Using Bimolecular Fluorescence Complementation and an Enhanced Retroviral Mutagen. P Talaty, A Emery, K Holthusen, DN Everly Jr. J Virol 2012 Oct;86(20):11345-11355. "Our screen identified a novel LMP1-binding protein, transmembrane protein 134, Tmem134. Tmem134 is a candidate oncogene that is amplified in breast cancer cells lines. Binding, co-localization, and co-fractionation between LMP1 and Tmem134 were confirmed. Finally, Tmem134 affected LMP1-induced NF-κB induction."

Talaty - J Virol 2012 abstract / PubMed

Association of Epstein-Barr virus infection and breast carcinoma. MN Khabaz. Arch Med Sci 2013 Aug 30;9(4):745-751. 92 breast cancer samples, and 49 normal controls. "Twenty-four out of 92 breast carcinoma specimens was found to be infected with EBV as compared to 3 out of 49 control group specimens, which represented a statistically significant difference (p-value using χ(2) = 0.008). Immunohistochemically, 24 (26%) of the 92 studied samples were found to be positive, showing EBNA-1 granular nuclear staining in tumor epithelial cells."

Khabaz - Arch Med Sci 2013 abstract / PubMed

No association between Epstein-Barr Virus and Mouse Mammary Tumor Virus with Breast Cancer in Mexican Women. A Morales-Sánchez, T Molina-Muñoz, JL Martínez-López, P Hernández-Sancén, A Mantilla, YA Leal, J Torres, EN Fuentes-Pananá. Sci Rep 2013 Oct 17;3:2970. 86 tumor and 65 adjacent tissues. "Neither tumor samples nor adjacent tissue were positive for either virus in a first round PCR and only 4 tumor samples were EBV positive by a more sensitive nested PCR."

Morales-Sánchez - Sci Rep 2013 full article / PubMed Central
Morales-Sánchez / Sci Rep 2013 full article

Epstein Barr virus: a prime candidate of breast cancer aetiology in Sudanese patients. ZA Yahia, AA Adam, M Elgizouli, A Hussein, MA Masri, M Kamal, HS Mohamed, K Alzaki, AM Elhassan, K Hamad, ME Ibrahim. Infect Agent Cancer 2014 Mar 7;9(1):9. "EBV genome was detected in 55.5% (n = 90) of breast cancer tissues as compared to 23% in control tissue samples (p = 0.0001). Using ISH, EBV signal was detected in all 18 breast cancer biopsies examined while all five normal breast tissue biopsies tested were negative for EBV. Of six tumour suppressor genes investigated BRCA1, BRCA2, and p14 appeared to be under strong epigenetic silencing."

Yahia / Infect Agent Cancer 2014 full article

Association of Epstein-Barr virus with invasive breast carcinoma and its impact on well-known clinicopathologic parameters in Iranian women. F Mohammadizadeh, M Zarean, M Abbasi. Adv Biomed Res 2014 Jun 25;3:141. 80 cases. "LMP-1 expression was seen in 6 cases (7.5%) of breast carcinoma whereas normal breast tissue adjacent to carcinoma was negative for LMP-1 in all of the cases. A statistically significant association was seen between EBV and invasive breast carcinoma (P = 0.03)."

Mohammadizadeh - Adv Biomed Res 2014 full article / PubMed Central

Epstein-Barr virus infection and clinical outcome in breast cancer patients correlate with immune cell TNF-alpha/IFN-gamma response. G Marrão, M Habib, A Paiva, D Bicout, C Fallecker, S Franco, S Fafi-Kremer, T Simões da Silva, P Morand, C Freire de Oliveira, E Drouet. BMC Cancer 2014 Sep 11;14(1):665. 85 patients. "No correlation was found between: (i) EBV detection in tumor or PBMCs and tumor characteristics; (ii) EBV and other prognostic factors. Notably, patients exhibiting anti-ZEBRA antibodies at high titers experienced poorer overall survival (p = 0.002). Those who recovered from their disease were found to have a measurable EBV DNA load, together with a high frequency of IFN-gamma and TNF-alpha producing PBMCs (p = 0.04), which indicates the existence of a Th1-type polarized immune response in both the tumor and its surrounding tissue."

Marrão - BMC Cancer 2014 abstract / PubMed

Multiplex PCR/mass spectrometry screening of biological carcinogenic agents in human mammary tumors. J Peng, T Wang, H Zhu, J Guo, K Li, Q Yao, Y Lv, J Zhang, C He, J Chen, L Wang, Q Jin. J Clin Virol 2014 Oct;61(2):255-259. 100 breast cancer patients, 50 benign breast disease patients, 96 blood donors. "EBV, Merkel cell polyomavirus (MCPyV) and HPV-18 were detected in 60, 14 and 2 breast cancer patients, respectively, and EBV and MCPyV were detected in 16 and 1 benign breast disease patients, respectively. EBV and MCPyV were more prevalent in group 1 than in group 2 (EBV: 60.0% vs. 32.0%, p=0.0012; MCPyV: 14.0% vs. 2.0%; p=0.02). In contrast, there was no difference in the prevalence of EBV and MCPyV in blood samples between group 1 and group 2, group 1 and group 3. EBV was detected in malignant breast tissue and its presence was confined to the malignant cells using in situ hybridization."

Peng - J Clin Virol 2014 abstract / PubMed

Cytomegalovirus and epstein-barr virus in breast cancer. AK Richardson, MJ Currie, BA Robinson, H Morrin, Y Phung, JF Pearson, TP Anderson, JD Potter, LC Walker. PLoS One 2015 Feb 27;10(2):e0118989. Tumor vs. normal tissue of 70 patients. "Of the serology samples, 67 of 70 (96%) were EBV IgG positive and 49 of 70 (70%) were CMV IgG positive. QPCR detected EBV in 24 (34%) of the tumour and 9 (13%) of the paired normal specimens and CMV in 0 (0%) of the tumour and 2 (3%) of the paired normal specimens."

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

No significant viral transcription detected in whole breast cancer transcriptomes. D Fimereli, D Gacquer, D Fumagalli, R Salgado, F Rothé, D Larsimont, C Sotiriou, V Detours. BMC Cancer 2015 Mar 18;15:147. 58 breast cancers. "We identified a small number of viral sequences belonging to human herpesvirus 4 and 6 and Merkel cell polyomavirus... Our results show that no viral sequences are expressed in significant amounts in the BC investigated. The presence of non-transcribed viral DNA cannot be excluded."

Fimereli - BMC Cancer 2015 full article / PubMed Central
Fimereli / BMC Cancer 2015 full article

Incidence of Epstein-Barr virus in Syrian women with breast cancer: A tissue microarray study. T Aboulkassim, A Yasmeen, N Akil, G Batist, AE Moustafa. Hum Vaccin Immunother 2015 Apr 3;11(4):951-955. 56 (51.85%) of 108 breast cancer samples were positive for EBV, by PCR and tissue microarray (TMA) analysis.

Aboulkassim - Hum Vaccin Immunother 2015 abstract / PubMed

Evaluation Frequency of Merkel Cell Polyoma, Epstein-Barr and Mouse Mammary Tumor Viruses in Patients with Breast Cancer in Kerman, Southeast of Iran. MA Reza, MH Reza, L Mahdiyeh, F Mehdi, ZN Hamid. Asian Pac J Cancer Prev 2015;16(16):7351-7357. 100 patients. "EBV was detected in 8/100 (8%), MMTV in 12/100 (12%), MPy in 3/100 (3%) and EBER RNA in 18/100 (18%) cases. None of the control samples demonstrated any of the viruses."

Reza / Asian Pac J Cancer Prev 2015 full article landing

Epstein-Barr virus infection is equally distributed across the invasive ductal and invasive lobular forms of breast cancer. AJ Ballard. Pathol Res Pract 2015 Dec;211(12):1003-1005. 80 cases of invasive ductal carcinoma, and 80 cases of invasive lobular carcinoma. "EBNA1 staining was evident in the tumor cells of 63 cases (39.4% of tumor cases). By tumor type (ductal/lobular) EBV infection was noted in 34 (42.5%) cases of invasive ductal carcinoma and 29 (36.2%) cases of invasive lobular carcinoma, this difference was not found to be significant (P=0.518)."

Ballard - Pathol Res Pract 2015 abstract / PubMed

EBV and Leukemia

Epstein-Barr virus in patients with chronic lymphocytic leukemia: a pilot study. AM Tsimberidou, MJ Keating, CE Bueso-Ramos, R Kurzrock. Leuk Lymphoma 2006 May;47(5):827-836. "EBERs were detected in the bone marrow of 12 of 32 (38%) CLL/SLL marrows vs 0 of 20 normal marrows (p = 0.002). EBERs were observed in sporadic granulocytes alone or in addition to its presence in lymphocytes in nine of the 12 EBV-positive patients. EBERs were detected less frequently in patients with Rai stage 0 - 1 disease (20%) compared with Rai stage 2 - 4 (66%; p = 0.008). EBER-positive patients tended to have higher lactate dehydrogenase levels (p = 0.053). The 10-year survival rate was 22% vs 58% for patients with and without discernible EBERs (log-rank, p = 0.08). Evidence of EBV infection was found in 38% of patients with CLL/SLL."

Tsimberidou - Leuk Lymphoma 2006 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. "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

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors. E Kostareli, A Hadzidimitriou, N Stavroyianni, N Darzentas, A Athanasiadou, M Gounari, V Bikos, A Agathagelidis, T Touloumenidou, I Zorbas, A Kouvatsi, N Laoutaris, A Fassas, A Anagnostopoulos, C Belessi, K Stamatopoulos. Leukemia 2009 May;23(5):919-924. 93 CLL cases with an intentional bias for the IGHV4-34 [immunoglobulin heavy-chain variable 4-34 (IGHV4-34)] gene. 9/25 cases positive for EBV but not CMV, and all nine double positives, utilized the IGHV4-34 gene. Seven of the latter expressed the stereotyped B-cell receptors.

Kostareli - Leukemia 2009 abstract / PubMed

Epstein-Barr virus latent membrane protein 1 mRNA is expressed in a significant proportion of patients with chronic lymphocytic leukemia. JJ Tarrand, MJ Keating, AM Tsimberidou, S O'Brien, RP LaSala, XY Han, CE Bueso-Ramos. Cancer 2010 Feb 15;116(4):880-887. "EBV LMP1 mRNA transcripts were found in 19 of 135 (14%) of the CLL cases, but only 1% of the healthy controls (P < .0001). In contrast, 23 solid tumor patients tested negative for EBV LMP1 transcripts. In a later cohort of patients after hematopoietic stem cell transplantation, 4 of 7 patients with Hodgkin lymphoma or Burkitt lymphoma had EBV LMP1 detected. In a preliminary analysis, outcome data were available for 88 of the 135 patients with CLL. EBV LMP1 mRNA positivity was associated with a significantly increased degree of histologically demonstrated bone marrow involvement by CLL (P = .003, Mann-Whitney U test)."

Tarrand - Cancer 2010 abstract / PubMed

A prospective study of Epstein-Barr virus antibodies and risk of non-Hodgkin lymphoma. KA Bertrand, BM Birmann, ET Chang, D Spiegelman, JC Aster, SM Zhang, F Laden. Blood 2010 Nov 4;116(18):3547-3553. Case-control study nested in the Physicians' Health Study and Nurses' Health Study. "For chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), suggestive associations were noted for elevated anti-EBNA-2 (RR: 1.74; 95% CI: 0.99, 3.05), anti-VCA (RR: 1.58; 95% CI: 0.79, 3.14), and EBNA-1:EBNA-2 ratio </= 1.0 (RR: 1.52; 95% CI: 0.91, 2.55)."

Bertrand - Blood 2010 abstract / PubMed

Epstein-Barr virus infection and chronic lymphocytic leukemia: a possible progression factor? R Dolcetti, A Carbone. Infect Agent Cancer 2010 Nov 22;5:22. REVIEW. "Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the United States and Western Europe..." Some patients also develop EBV-related lymphomas.

Dolcetti - Infect Agent Cancer 2010 full article / PubMed Central

Single nucleotide polymorphisms of matrix metalloproteinase 9 (MMP9) and tumor protein 73 (TP73) interact with Epstein-Barr virus in chronic lymphocytic leukemia: results from the European case-control study EpiLymph. D Casabonne, O Reina, Y Benavente, N Becker, M Maynadié, L Foretová, P Cocco, A González-Neira, A Nieters, P Boffetta, JM Middeldorp, S de Sanjose. Haematologica 2011 Feb;96(2):323-237. 240 cases and 513 controls from five European centers. "In a recessive model, patients positive to aberrant antibody pattern and homozygous for rare genotypes in rs8113877T>G or rs17576A>G of the MMP9 gene were at highest risk of chronic lymphocytic leukemia. In a dominant model, TP73 showed the highest risk in patients positive to aberrant antibody pattern and homozygous for the wild-type genotype in rs1885859G>C or rs3765701A>T. All interactions were additive and no main effect was observed." "Overall, the odds ratio of chronic lymphocytic leukemia in all ab_EBV positive patients compared to all ab_EBV negative patients was 2.76 (95% CI=1.91 to 3.98)."

Casabonne - Haematologica 2011 full article / PubMed Central
Casabonne / Haematologica 2011 full article

Infectious Mononucleosis

Epstein-Barr virus and infectious mononucleosis. National Center for Infectious Diseases, Centers for Disease Control and Prevention. (Updated: 05/16/2006.)

Epstein-Barr Virus and Infectious Mononucleosis / CDC

EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15. D Sauce, M Larsen, SJ Curnow, AM Leese, PA Moss, AD Hislop, M Salmon, AB Rickinson. Blood 2006 Jul 1;108(1):11-18. "30 individuals known to have been EBV and/or CMV carriers for at least 5 years and to have no prior history of IM, 30 individuals with no serologic evidence of prior EBV infection, and 5 individuals with no serologic evidence of prior CMV infection." IM patients were followed from primary infection to asymptomatic virus carrier state. "Expression of IL-7Rα was lost from all CD8+ T cells, including EBV epitope-specific populations, during acute IM. Thereafter, expression recovered quickly on total CD8+ cells but slowly and incompletely on EBV-specific memory cells. Expression of IL-15Rα was also lost in acute IM and remained undetectable thereafter not just on EBV-specific CD8+ populations but on the whole peripheral T- and natural killer (NK)-cell pool."

Sauce / Blood 2006 full article

Epstein-barr virus and hodgkin lymphoma. RF Ambinder. Hematology Am Soc Hematol Educ Program 2007;2007:204-209. Review. "Recognition of the viral etiology of infectious mononucleosis followed the serendipitous observation that a technician working in a laboratory studying the serology of African children with BL became EBV seropositive as she recovered from the illness. Studies of college students followed that helped better define the syndrome. In a recent cohort study from the United Kingdom, more than 500 seronegative university students were followed for 3 years. Seroconversion occurred in 46%. Among seroconverters, infectious mononucleosis developed in 25%. But why some primary infection is associated with symptoms in some but not others remains a matter of speculation. Sexual activity, host age, host immune response polymorphisms, infection with particular strains of virus, and the size of the primary innoculum are all possible determinants. Recently, it has been recognized that infection with multiple viral strains is the rule rather than the exception. Viral copy number in whole blood correlates with severity and duration of symptoms. Whole-blood measurements do not distinguish between viremia (virions) or latently infected lymphocytes. Fine mapping of the evolution of the specific cellular immune response to viral antigens has progressed, as has an appreciation of the importance of innate immunity. Investigators have reported that EBV infectious mononucleosis is associated with a lifelong 'immunologic scar.' Individuals with a history of primary symptomatic disease differ from other healthy EBV seronegative and EBV seropositive individuals in that they lack CD8 T cells and natural killer (NK) cells expressing IL-15 receptor (recognized by flow cytometry for IL-15R). Assays of IL-15 responsiveness indicate that the absence of these cells have functional correlates in vitro. Whether they have clinical correlates is unknown. Remarkably, the change in lymphocyte cell populations is sustained over years and perhaps decades. No similar sustained change in the phenotype of lymphocytes accompanies the infectious mononucleosis-like syndrome associated with primary cytomegalovirus infection (or acute viral illnesses such as influenza). But what is the significance of the scar? Are there long-standing consequences with regard to health? As discussed below, EBV+ HL may be one of the consequences." A history of infectious mononucleosis was first linked to HL in reports in the 1950s.

Ambinder / Hematology 2007 full article
EBV and Hodgkin's Disease

EBV-associated mononucleosis does not induce long-term global deficit in T-cell responsiveness to IL-15. J Giron-Michel, F Menard, S Negrini, A Devocelle, B Azzarone, C Besson. Blood 2009 May 7;113(19):4541-4547. 11 subjects with infectious mononucleosis between one and 30 years previously, and 12 volunteers. "We did not observe any quantitative (flow cytometry) or qualitative (Western blot) differences in the expression of the IL-15Rα subunit on different T-cell subsets derived from healthy subjects or from IM subjects. Indeed, Western blot analysis revealed that T cells from both groups expressed the same panel of isoforms for the IL-15Rα chain, which were detected at the T-cell surface with similar mean fluorescence intensity... In addition, T cells of both groups of subjects display a similar responsiveness to low concentrations of recombinant IL-15 (1 ng/mL) concerning signal transduction, induction of long-term survival proliferative response, and induction of the CD69 early activation marker."

Giron-Michel / Blood 2009 full article

Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary epstein-barr virus infection in university students. HH Balfour Jr, OA Odumade, DO Schmeling, BD Mullan, JA Ed, JA Knight, HE Vezina, W Thomas, KA Hogquist. J Infect Dis 2013 Jan;207(1):80-88. 66/143 (46%) students experienced primary EBV infection in 3 years. "Of these, 77% had infectious mononucleosis, 12% had atypical symptoms, and 11% were asymptomatic. Subjects reporting deep kissing with or without coitus had the same higher risk of infection than those reporting no kissing (P < .01). Viremia was transient, but median oral shedding was 175 days. Increases were observed in numbers of NK cells and CD8(+) T-cells but not in numbers of CD4(+) T-cells during acute infection. Severity of illness correlated positively with both blood EBV load (P = .015) and CD8(+) lymphocytosis (P = .0003)."

Balfour - J Infect Dis 2013 abstract / PubMed

The levels of liver enzymes and atypical lymphocytes are higher in youth patients with infectious mononucleosis than in preschool children. Y Wang, J Li, YY Ren, H Zhao. Clin Mol Hepatol 2013 Dec;19(4):382-388. "IM was diagnosed in 287 patients during this 10-year period, with incidence peaks among preschool children (≤7 years old, 130/287, 45.3%) and youth patients (>15 and <24 years old, 101/287, 35.2%). Although the complaints at admission did not differ between these two patient groups, the incidence of clinical signs (tonsillopharyngitis, lymphadenopathy, hepatomegaly, and edema of the eyelids) was much higher in preschool children. The incidence of liver lesion and percentage of atypical lymphocytes were significantly higher in the youth group (P<0.001), and the average hospital stay was longer in this group. Pneumonia was the most common complication, and there was no case of mortality."

Wang - Clin Mol Hepatol 2013 full article / PubMed Central

Primary EBV Infection Induces an Expression Profile Distinct from Other Viruses but Similar to Hemophagocytic Syndromes. SK Dunmire, OA Odumade, JL Porter, J Reyes-Genere, DO Schmeling, H Bilgic, D Fan, EC Baechler, HH Balfour Jr, KA Hogquist. PLoS One 2014 Jan 17;9(1):e85422. 546 EBV-naïve college students. EBV was similar only to Dengue fever virus, but not to IAV, RSV, HRV, or YFV. "The signature shared by EBV and DENV was also present in patients with hemophagocytic syndromes, suggesting these two viruses cause uncontrolled inflammatory responses. Interestingly, while EBV induced a strong type I interferon response, a subset of interferon induced genes, including MX1, HERC5, and OAS1, were not upregulated, suggesting a mechanism by which viral antagonism of immunity results in a profound inflammatory response." "A hallmark of infectious mononucleosis is the dramatic expansion of CD8 T cells... The upregulation of three individual genes correlated very significantly with CD8 lymphocytosis. These three: OASL, (Pearson r = 0.6059, p<0.0001) TYMS (r = 0.5019, p = 0.0006), and SLAMF8 (r = 0.6028, p<0.0001), are all upregulated by IFNγ consistent with the known effects of IFNγ when given as therapy. Interestingly, OASL in particular has been hypothesized to cause fatigue through antagonism of the thyroid receptor."

Dunmire - PLoS One 2014 full article / PubMed Central
Dunmire / PLoS One 2014 full article

Role for early-differentiated natural killer cells in infectious mononucleosis. T Azzi, A Lünemann, A Murer, S Ueda, V Béziat, KJ Malmberg, G Staubli, C Gysin, C Berger, C Münz, O Chijioke, D Nadal. Blood 2014 Oct 16;124(16):2533-2543. "Here, we longitudinally assessed the kinetics, the differentiation and the proliferation of subsets of NK cells in pediatric IM patients. Our results indicate that acute IM is characterized by the preferential proliferation of early-differentiated CD56dim NKG2A+ KIR- NK cells. Moreover, this NK cell subset exhibits features of terminal differentiation and persists at higher frequency over at least the first 6 months after acute IM. Finally, we demonstrate that this NK cell subset preferentially degranulates and proliferates upon exposure to EBV-infected B cells expressing lytic antigens. Thus, early-differentiated NK cells might play a key role in the immune control of primary infection with this persistent tumor-associated virus."

Azzi - Blood 2014 abstract / PubMed

Early Virological and Immunological Events in Asymptomatic Epstein-Barr Virus Infection in African Children. S Jayasooriya, TI de Silva, J Njie-jobe, C Sanyang, AM Leese, AI Bell, KA McAulay, P Yanchun, HM Long, T Dong, HC Whittle, AB Rickinson, SL Rowland-Jones, AD Hislop, KL Flanagan. PLoS Pathog 2015;11(3): e1004746. 99 children aged 14-18 months followed for six months. "Focusing on IgM-positive children with very recent EBV infection but no history of symptoms, we found that they carried a virus load equivalent to that seen in AIM patients and also mounted a classical virus-specific CD8+ T-cell response. However, that response, though it could occupy at least 15% of the circulating CD8+ T-cell pool, occurred without the huge global expansion of CD8 numbers seen in AIM. This work reinforces the idea that the host’s exaggerated CD8+ T-cell response, rather than the virus load per se, leads to the symptoms of AIM."

Jayasooriya / PLoS Pathog 2015 full article

Prospective studies of infectious mononucleosis in university students. JM Grimm, DO Schmeling, SK Dunmire, JA Knight, BD Mullan, JA Ed, RC Brundage, KA Hogquist, HH Balfour Jr. Clin Transl Immunology 2016 Aug 12;5(8):e94. "During a median 8 months of observation, 14/85 subjects experienced primary EBV infections (24 cases/100 person-years). The only significant risk factor for acquisition of EBV infection was deep kissing (P=0.02)." Two were hospitalized.

Grimm - Clin Transl Immunology 2016 full article / PubMed Central

X-Linked Lymphoproliferative Syndrome

Lymphoproliferative Syndrome, X-Linked, 1; XLP1; also known as XLP; EBV Susceptibility, etc. "X-linked lymphoproliferative syndrome is caused by mutation in the SHD2D1A gene encoding SLAM-associated protein (SAP)... X-linked lymphoproliferative syndrome, or Duncan disease, is characterized by extreme sensitivity to infection with Epstein-Barr virus, which results in a complex phenotype manifested by severe or fatal mononucleosis, acquired hypogammaglobulinema, and malignant lymphoma. Other features may include aplastic anemia, red cell aplasia, and lymphomatoid granulomatosis... Coffey et al. (1998) noted that the average age of disease onset in XLP is 2.5 years, with 100% mortality by the age of 40 years. Following infection with EBV, patients mount a vigorous, uncontrolled polyclonal expansion of T and B cells. The primary cause of death is hepatic necrosis and bone marrow failure. The extensive tissue destruction of the liver and bone marrow appears to stem from the uncontrolled cytotoxic T-cell response."

#308240 Lymphoproliferative Syndrome, X-Linked / OMIM

Innate immune control of EBV-infected B cells by invariant natural killer T cells. BK Chung, K Tsai, LL Allan, DJ Zheng, JC Nie, CM Biggs, MR Hasan, FK Kozak, P van den Elzen, JJ Priatel, R Tan. Blood 2013 Oct 10;122(15):2600-2608. "Individuals with X-linked lymphoproliferative disease (XLP) lack invariant natural killer T (iNKT) cells and are exquisitely susceptible to Epstein-Barr virus (EBV) infection... These data indicate that iNKT cells may be important for early, innate control of B cell infection by EBV and that downregulation of CD1d may allow EBV to circumvent iNKT-mediated immune recognition."

Chung - Blood 2013 abstract / PubMed

See Also:

Epstein-Barr Virus Causes Nasopharyngeal Cancer
Epstein-Barr Virus Causes Lymphomas
EBV Causes Interstitial Lung Disease
Epstein-Barr Virus Causes Gastric Carcinoma
EBV Causes Lymphoepithelioma-like Lung Cancer
EBV Causes Mental Impairment in Children
EBV & Socioeconomic Status
EBV Causes Lupus
EBV Causes Multiple Sclerosis
Epstein-Barr Virus Causes Sjogren’s Syndrome

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cast 11-21-16