EBV and cancer risk

EBV and cancer risk

Dr. Weeks’ Comment:   mono,  yuppie flu and Epstein-Barr virus (all are the same illness) are typically treated with as cavalier an attitude as that demonstrated by the surgeon who removes a gall bladder and fails to advise the patient that by removing that amazing organ which generates bile (an emulsifying agent) he has left the patient unable to digest and absorb oils (including fat-soluble vitamins like vitamin D, A, E !!!!!) .  If you get mono,  ask your doctor to assess your immune system function and, if it is not optimal, we recommend you buff it up!

Blood. 2010 Nov 18. [Epub ahead of print]

Lymphomas differ in their dependence on Epstein-Barr virus.

Vereide DT, Sugden B.

McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, United States.

Abstract

Epstein-Barr virus (EBV) encodes oncogenic information and, oftentimes concomitant with host immunosuppresssion, gives rise to malignancies in all major categories of lymphoma defined by the World Health Organization. Here, we conditionally evicted the viral extrachromosomal genome from tumor cells in vitro to examine the role of EBV in different lymphomas including Burkitt’s lymphoma (BL) and post-transplant lymphoproliferative disorder (PTLD). Cells derived from two canonical BLs were found to have the least dependence on the virus; some required EBV to prevent the inefficient induction of apoptosis. In contrast, cells derived from a subset of Burkitt’s lymphoma, Wp-restricted BL, required EBV to block a robust apoptotic program that involves the up-regulation of the pro-apoptotic protein Bim. Wp-restricted BL cells also relied on the virus to promote efficient proliferation, a distinction that highlights the multiple contributions EBV makes to affect proliferation of its host cells. Like Wp-BL cells, PTLD cells depended on the virus to inhibit apoptosis. They furthermore required the virus to drive them out of G(1)/G(0). Together, these results reveal a graded dependence on EBV among tumor cells that directly correlates with the number of viral genes expressed in the tumor cell.

PMID: 21088132 [PubMed – as supplied by publisher]

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2.

Adv Cancer Res. 2010;108:1-19.

Insights into the evolution of lymphomas induced by Epstein-Barr virus.

Vereide D, Sugden B.

McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Abstract

Epstein-Barr virus (EBV) encodes a wealth of oncogenic instructions, including the abilities to drive a resting normal B cell to proliferate and to override apoptotic stimuli. EBV is found in almost all types of lymphomas at varying frequencies. However, the particular viral genes expressed differ considerably among tumors. We have examined the role of EBV in several lymphomas by conditionally evicting the extrachromosomal viral genome from tumor cells in vitro and have found a graded dependence on the virus. Tumor cells that express all the known latent viral genes have been found to depend on the virus to drive proliferation and to block apoptosis at least in part by repressing the proapoptotic protein Bim. Other tumor cells, which express fewer viral genes, also depend on the virus to block apoptosis, but rely on the virus to promote but not to drive proliferation. Lastly, tumor cells with the fewest viral genes expressed have been found to require EBV to prevent the inefficient induction of a Bim-independent apoptosis. We present a model for the evolution of EBV-induced lymphomas in which tumors are initially “addicted” to the virus for almost all oncogenic functions. These tumors are targets for the immune system because they express multiple immunogenic viral proteins. Therefore, EBV-induced tumors are under selective pressure to acquire cellular mutations that can replace viral functions. We posit that the heterogeneity in viral gene expression among different EBV-associated lymphomas reflects a dynamic process by which tumors evolve to be less dependent on the virus.

Copyright © 2010 Elsevier Inc. All rights reserved.

PMID: 21034964 [PubMed – in process]

3.

J Virol. 2010 Oct 27. [Epub ahead of print]

A new model of EBV infection reveals an important role for early lytic viral protein expression in the development of lymphomas.

Ma SD, Hegde S, Young KH, Sullivan R, Rajesh D, Zhou Y, Jankowska-Gan E, Burlingham WJ, Sun X, Gulley ML, Tang W, Gumperz JE, Kenney SC.

Departments of Oncology and Medicine, McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, U.S.A.; Department of Medical Microbiology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, U.S.A.; Pathology & Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, U.S.A.; Research Animal Resources Center and UW Comprehensive Cancer Center, Graduate School and School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, U.S.A.; Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, U.S.A.; and Department of Pathology, University of North Carolina, Chapel Hill, North Carolina, U.S.A.

Abstract

Epstein-Barr virus (EBV) infects cells in latent or lytic forms, but the role of lytic infection in EBV-induced lymphomas is unclear. Here we have used a new humanized mouse model, in which both human fetal CD34(+) hematopoietic stem cells and thymus/liver tissue are transplanted, to compare EBV pathogenesis and lymphoma formation following infection with a lytic-defective BZLF1-deleted (Z-KO) virus or a lytically active BZLF1(+) control. Both the control and Z-KO viruses established long-term viral latency in all infected animals. 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. Specific immune responses against EBV-infected B cells were generated in mice infected with either control or Z-KO virus. In both cases forms of viral latency (type I and type IIB) were observed that are less immunogenic than the highly transforming form (type III) commonly found in tumors of immunocompromised hosts, suggesting that immune pressure contributed to the outcome of the infection. These results point to an important role for lytic EBV infection in the development of B-cell lymphomas in the context of an active host immune response.

PMID: 20980506 [PubMed – as supplied by publisher]

J Oncol. 2010;2010. pii: 516047. Epub 2010 Oct 5.

Burkitt lymphoma: pathogenesis and immune evasion.

God JM, Haque A.

Department of Microbiology and Immunology, Charles Darby Children’s Research Institute, Hollings Cancer Center, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.

Abstract

B-cell lymphomas arise at distinct stages of cellular development and maturation, potentially influencing antigen (Ag) presentation and T-cell recognition. Burkitt lymphoma (BL) is a highly malignant B-cell tumor associated with Epstein-Barr Virus (EBV) infection. Although BL can be effectively treated in adults and children, leading to high survival rates, its ability to mask itself from the immune system makes BL an intriguing disease to study. In this paper, we will provide an overview of BL and its association with EBV and the c-myc oncogene. The contributions of EBV and c-myc to B-cell transformation, proliferation, or attenuation of cellular network and immune recognition or evasion will be summarized. We will also discuss the various pathways by which BL escapes immune detection by inhibiting both HLA class I- and II-mediated Ag presentation to T cells. Finally, we will provide an overview of recent developments suggesting the existence of BL-associated inhibitory molecules that may block HLA class II-mediated Ag presentation to CD4+ T cells, facilitating immune escape of BL.

PMID: 20953370 [PubMed – in process]PMCID: PMC2952908Free PMC Article

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2.

Anticancer Res. 2010 Sep;30(9):3473-8.

Epstein-Barr virus-infected cell line TCC36B derived from B lymphocytes infiltrating renal pelvis urothelial carcinoma.

Chuang CK, Chuang KL, Hsieh CH, Shen YC, Liao SK.

Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University Taoyuan 333, Taiwan, ROC.

Abstract

This study reports an initial analysis of an EBV-infected B cell line (TCC36B), established from an urothelial carcinoma (UC) lesion of the renal pelvis.

MATERIALS AND METHODS: Cytofluorometric and G-banding analyses were performed for phenotyping and cytogenetics. PCR was used to detect EBV DNA, and sequence analysis to investigate mutations and deletions of the latent membrane protein (LMP)-1 gene of EBV.

RESULTS: TCC36B cells proliferated in vitro and showed positivity for surface CD19, CD20, HLA-DR and IgG(λ), indicating that they belong to B-cells. Cytogenetic analysis showed 46,XX with a unique clonal abnormality of dup(2)(p13p25). EBV DNA was detected in TCC36B cells. Sequence analysis revealed a 30-bp deletion and 7 point mutations on the LMP-1 gene in TCC36B cells.

CONCLUSION: These results suggest the involvement of an EBV variant in the pathogenesis of UC. This cell line should thus facilitate further investigations on the aetiological role of EBV in urothelial cancer.

PMID: 20944125 [PubMed – indexed for MEDLINE]

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3.

Clin Oncol (R Coll Radiol). 2010 Oct 11. [Epub ahead of print]

Different Clinical Significance of Pre- and Post-treatment Plasma Epstein-Barr Virus DNA Load in Nasopharyngeal Carcinoma Treated with Radiotherapy.

Hou X, Zhao C, Guo Y, Han F, Lu LX, Wu SX, Li S, Huang PY, Huang H, Zhang L.

Shanghai Lung Tumour Clinical Medical Center, Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China; Department of Medical Oncology, Cancer Center of Sun Yat-Sen University, Guangzhou, China.

Abstract

AIMS: To correlate the pre-treatment plasma Epstein-Barr virus (EBV) DNA with tumour burden and to explore the prognostic implications of pre- and post-treatment plasma EBV DNA load in nasopharyngeal carcinoma patients treated with radiotherapy.

MATERIALS AND METHODS: Plasma EBV DNA load was measured using a real-time quantitative polymerase chain reaction assay in 69 patients with nasopharyngeal carcinoma before and after radiation treatment and correlated with tumour volume and treatment outcome. Tumour volume was calculated by multiplying the sum of the areas of gross extent of the primary tumour and regional lymph nodes shown by computed tomography images and/or magnetic resonance imaging. Prognostic models for distant metastasis and overall survival were constructed using a multivariable fractional polynomial algorithm.

RESULTS: The pre-treatment plasma EBV DNA concentration was significantly associated with tumour volume (Spearman correlation coefficient, 0.61; P<0.001). The multivariable fractional polynomial algorithm selected post-treatment EBV DNA and administration of chemotherapy as prognostic factors for distant metastasis (P<0.001, P=0.021, respectively), as well as for overall survival (P<0.001, P=0.018, respectively).

CONCLUSIONS: Pre- and post-treatment plasma EBV DNA load have important clinical significance. Pre-treatment plasma EBV DNA concentration reflects tumour burden, whereas clearance of circulating plasma EBV DNA after treatment predicts the risk of distant metastasis and overall survival.

Copyright © 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

PMID: 20943358 [PubMed – as supplied by publisher]

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4.

Infect Agent Cancer. 2010 Oct 12;5:18.

Risk of classical Kaposi sarcoma by plasma levels of Epstein-Barr virus antibodies, sCD26, sCD23 and sCD30.

Pelser C, Middeldorp J, Mbulaiteye SM, Lauria C, Messina A, Viviano E, Romano N, Vitale F, Goedert JJ.

Infections & Immunoepidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA. goedertj@mail.nih.gov.

Abstract

ABSTRACT:

BACKGROUND: To clarify the immunological alterations leading to classical Kaposi sarcoma (cKS) among people infected with KS-associated herpesvirus (KSHV).

METHODS: In a population-based study of 119 cKS cases, 105 KSHV-seropositive controls, and 155 KSHV-seronegative controls, we quantified plasma soluble cluster of differentiation (sCD) levels and antibodies against Epstein-Barr virus nuclear antigen-1 (anti-EBNA-1) and viral capsid antigen (anti-VCA). Differences between groups in prevalence of low-tertile anti-EBNA-1 and high-tertile anti-VCA were compared by logistic regression. Continuous levels between groups and by presence of cKS co-factors among controls were compared by linear regression and Mann-Whitney-Wilcoxon methods.

RESULTS: Comparisons of cKS cases to seropositive controls and of seropositive to seronegative controls revealed no significant differences. However, controls with known cKS cofactors (male sex, nonsmoking, diabetes and cortisone use) had significantly lower levels of anti-EBNA (P = 0.0001 – 0.07) and anti-VCA (P = 0.0001 – 0.03). Levels of sCD26 were significantly lower for male and non-smoking controls (Padj ≤ 0.03), and they were marginally lower with older age and cortisone use (Padj ≤ 0.09).

CONCLUSIONS: Anti-EBV and sCD26 levels were associated with cofactors for cKS, but they did not differ between cKS cases and matched controls. Novel approaches and broader panels of assays are needed to investigate immunological contributions to cKS.

PMID: 20939920 [PubMed – in process]PMCID: PMC2964600Free PMC Article

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5.

Anal Cell Pathol (Amst). 2010 Sep 8. [Epub ahead of print]

EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1.

Geddert H, Zur Hausen A, Gabbert HE, Sarbia M.

Institute of Pathology, University Hospital of Düsseldorf, Düsseldorf, Germany.

Abstract

Background: Epstein-Barr virus (EBV)-associated gastric carcinomas (GC) constitute a distinct clinicopathological entity of gastric cancer. In order to determine underlying distinct aberrant promoter methylation we tested cardiac and non-cardiac GC with regard to the presence of EBV.Methods: One hundred GC were tested by RNA-in situ hybridization for the presence of EBV by EBV-encoded small RNA (EBER). Aberrant promoter methylation was investigated by methylation-specific real-time PCR for p16, p14, APC and hMLH1. P16 protein expression was assessed by immunohistochemistry.Results: In our selected study cohort, EBER-transcripts were detected in 19.6% (18/92) of GC. EBV-positive GC revealed significantly more often gene hypermethylation of p16, p14 and APC (p<0.0001, p<0.0001 and p=0.02, respectively) than EBV-negative GC. The majority of GC with p16 hypermethylation showed a p16 protein loss (22/28). In contrast, no correlation between the presence of EBV and hMLH1 hypermethylation was found (p=0.7). EBV-positive GC showed a trend towards non-cardiac location (p=0.06) and lower stages (I/II) according to the WHO (p=0.05).Conclusions: Hypermethylation of tumor suppressor genes is significantly more frequent in EBV-associated GC compared to EBV-negative GC. Our data add new insights to the role of EBV in gastric carcinogenesis and underline that EBV associated GC comprise a distinct molecular-pathologic as well as a distinct clinicopathological entity of GC.

PMID: 20890024 [PubMed – as supplied by publisher]

J Oncol. 2010;2010. pii: 516047. Epub 2010 Oct 5.

Burkitt lymphoma: pathogenesis and immune evasion.

God JM, Haque A.

Department of Microbiology and Immunology, Charles Darby Children’s Research Institute, Hollings Cancer Center, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.

Abstract

B-cell lymphomas arise at distinct stages of cellular development and maturation, potentially influencing antigen (Ag) presentation and T-cell recognition. Burkitt lymphoma (BL) is a highly malignant B-cell tumor associated with Epstein-Barr Virus (EBV) infection. Although BL can be effectively treated in adults and children, leading to high survival rates, its ability to mask itself from the immune system makes BL an intriguing disease to study. In this paper, we will provide an overview of BL and its association with EBV and the c-myc oncogene. The contributions of EBV and c-myc to B-cell transformation, proliferation, or attenuation of cellular network and immune recognition or evasion will be summarized. We will also discuss the various pathways by which BL escapes immune detection by inhibiting both HLA class I- and II-mediated Ag presentation to T cells. Finally, we will provide an overview of recent developments suggesting the existence of BL-associated inhibitory molecules that may block HLA class II-mediated Ag presentation to CD4+ T cells, facilitating immune escape of BL.

PMID: 20953370 [PubMed – in process]PMCID: PMC2952908Free PMC Article

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Click here to read
2.

Anticancer Res. 2010 Sep;30(9):3473-8.

Epstein-Barr virus-infected cell line TCC36B derived from B lymphocytes infiltrating renal pelvis urothelial carcinoma.

Chuang CK, Chuang KL, Hsieh CH, Shen YC, Liao SK.

Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University Taoyuan 333, Taiwan, ROC.

Abstract

This study reports an initial analysis of an EBV-infected B cell line (TCC36B), established from an urothelial carcinoma (UC) lesion of the renal pelvis.

MATERIALS AND METHODS: Cytofluorometric and G-banding analyses were performed for phenotyping and cytogenetics. PCR was used to detect EBV DNA, and sequence analysis to investigate mutations and deletions of the latent membrane protein (LMP)-1 gene of EBV.

RESULTS: TCC36B cells proliferated in vitro and showed positivity for surface CD19, CD20, HLA-DR and IgG(λ), indicating that they belong to B-cells. Cytogenetic analysis showed 46,XX with a unique clonal abnormality of dup(2)(p13p25). EBV DNA was detected in TCC36B cells. Sequence analysis revealed a 30-bp deletion and 7 point mutations on the LMP-1 gene in TCC36B cells.

CONCLUSION: These results suggest the involvement of an EBV variant in the pathogenesis of UC. This cell line should thus facilitate further investigations on the aetiological role of EBV in urothelial cancer.

PMID: 20944125 [PubMed – indexed for MEDLINE]

Related citations

Click here to read
3.

Clin Oncol (R Coll Radiol). 2010 Oct 11. [Epub ahead of print]

Different Clinical Significance of Pre- and Post-treatment Plasma Epstein-Barr Virus DNA Load in Nasopharyngeal Carcinoma Treated with Radiotherapy.

Hou X, Zhao C, Guo Y, Han F, Lu LX, Wu SX, Li S, Huang PY, Huang H, Zhang L.

Shanghai Lung Tumour Clinical Medical Center, Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China; Department of Medical Oncology, Cancer Center of Sun Yat-Sen University, Guangzhou, China.

Abstract

AIMS: To correlate the pre-treatment plasma Epstein-Barr virus (EBV) DNA with tumour burden and to explore the prognostic implications of pre- and post-treatment plasma EBV DNA load in nasopharyngeal carcinoma patients treated with radiotherapy.

MATERIALS AND METHODS: Plasma EBV DNA load was measured using a real-time quantitative polymerase chain reaction assay in 69 patients with nasopharyngeal carcinoma before and after radiation treatment and correlated with tumour volume and treatment outcome. Tumour volume was calculated by multiplying the sum of the areas of gross extent of the primary tumour and regional lymph nodes shown by computed tomography images and/or magnetic resonance imaging. Prognostic models for distant metastasis and overall survival were constructed using a multivariable fractional polynomial algorithm.

RESULTS: The pre-treatment plasma EBV DNA concentration was significantly associated with tumour volume (Spearman correlation coefficient, 0.61; P<0.001). The multivariable fractional polynomial algorithm selected post-treatment EBV DNA and administration of chemotherapy as prognostic factors for distant metastasis (P<0.001, P=0.021, respectively), as well as for overall survival (P<0.001, P=0.018, respectively).

CONCLUSIONS: Pre- and post-treatment plasma EBV DNA load have important clinical significance. Pre-treatment plasma EBV DNA concentration reflects tumour burden, whereas clearance of circulating plasma EBV DNA after treatment predicts the risk of distant metastasis and overall survival.

Copyright © 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

PMID: 20943358 [PubMed – as supplied by publisher]

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Click here to read
4.

Infect Agent Cancer. 2010 Oct 12;5:18.

Risk of classical Kaposi sarcoma by plasma levels of Epstein-Barr virus antibodies, sCD26, sCD23 and sCD30.

Pelser C, Middeldorp J, Mbulaiteye SM, Lauria C, Messina A, Viviano E, Romano N, Vitale F, Goedert JJ.

Infections & Immunoepidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA. goedertj@mail.nih.gov.

Abstract

ABSTRACT:

BACKGROUND: To clarify the immunological alterations leading to classical Kaposi sarcoma (cKS) among people infected with KS-associated herpesvirus (KSHV).

METHODS: In a population-based study of 119 cKS cases, 105 KSHV-seropositive controls, and 155 KSHV-seronegative controls, we quantified plasma soluble cluster of differentiation (sCD) levels and antibodies against Epstein-Barr virus nuclear antigen-1 (anti-EBNA-1) and viral capsid antigen (anti-VCA). Differences between groups in prevalence of low-tertile anti-EBNA-1 and high-tertile anti-VCA were compared by logistic regression. Continuous levels between groups and by presence of cKS co-factors among controls were compared by linear regression and Mann-Whitney-Wilcoxon methods.

RESULTS: Comparisons of cKS cases to seropositive controls and of seropositive to seronegative controls revealed no significant differences. However, controls with known cKS cofactors (male sex, nonsmoking, diabetes and cortisone use) had significantly lower levels of anti-EBNA (P = 0.0001 – 0.07) and anti-VCA (P = 0.0001 – 0.03). Levels of sCD26 were significantly lower for male and non-smoking controls (Padj ≤ 0.03), and they were marginally lower with older age and cortisone use (Padj ≤ 0.09).

CONCLUSIONS: Anti-EBV and sCD26 levels were associated with cofactors for cKS, but they did not differ between cKS cases and matched controls. Novel approaches and broader panels of assays are needed to investigate immunological contributions to cKS.

PMID: 20939920 [PubMed – in process]PMCID: PMC2964600Free PMC Article

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5.

Anal Cell Pathol (Amst). 2010 Sep 8. [Epub ahead of print]

EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1.

Geddert H, Zur Hausen A, Gabbert HE, Sarbia M.

Institute of Pathology, University Hospital of Düsseldorf, Düsseldorf, Germany.

Abstract

Background: Epstein-Barr virus (EBV)-associated gastric carcinomas (GC) constitute a distinct clinicopathological entity of gastric cancer. In order to determine underlying distinct aberrant promoter methylation we tested cardiac and non-cardiac GC with regard to the presence of EBV.Methods: One hundred GC were tested by RNA-in situ hybridization for the presence of EBV by EBV-encoded small RNA (EBER). Aberrant promoter methylation was investigated by methylation-specific real-time PCR for p16, p14, APC and hMLH1. P16 protein expression was assessed by immunohistochemistry.Results: In our selected study cohort, EBER-transcripts were detected in 19.6% (18/92) of GC. EBV-positive GC revealed significantly more often gene hypermethylation of p16, p14 and APC (p<0.0001, p<0.0001 and p=0.02, respectively) than EBV-negative GC. The majority of GC with p16 hypermethylation showed a p16 protein loss (22/28). In contrast, no correlation between the presence of EBV and hMLH1 hypermethylation was found (p=0.7). EBV-positive GC showed a trend towards non-cardiac location (p=0.06) and lower stages (I/II) according to the WHO (p=0.05).Conclusions: Hypermethylation of tumor suppressor genes is significantly more frequent in EBV-associated GC compared to EBV-negative GC. Our data add new insights to the role of EBV in gastric carcinogenesis and underline that EBV associated GC comprise a distinct molecular-pathologic as well as a distinct clinicopathological entity of GC.

PMID: 20890024 [PubMed – as supplied by publisher]

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6.

Am J Surg Pathol. 2010 Nov;34(11):1715-9.

Anorectal Epstein-Barr virus infection mimicking Hodgkin lymphoma in an immunocompetent man.

Vasiliu V, Suarez F, Canioni D, Hermine O, Varet B, Brousse N.

Departments of Pathology, Necker-Enfants Malades Hospital and Paris-Descartes University, Paris, France.

Abstract

Anorectal Hodgkin lymphoma (HL) is rare, mainly described in human immunodeficiency virus (HIV) patients with exceptional cases reported in immunocompetents. We report the case of a middle age HIV male, presenting with intestinal occlusion. Rectosigmoidoscopy showed multiple anorectal nodular and ulceronecrotic masses. The biopsy specimens revealed a diffuse polymorphous inflammatory infiltrate in the lamina propria, associated with CD30, CD20, CD3, CD15, and ALK1 scattered large Hodgkin and/or Reed Sternberg -like cells stained by LMP1 antibody and EBER. A diagnosis of EBV-associated atypical lymphoproliferative disease mimicking HL was made. These lesions remained stable for 2 years without treatment then disappeared leaving a mucosal scar. A later control biopsy showed a condylomatous lesion, without lymphoid lesion, suggesting a sexually acquired infection. Eight years later, the complete resolution of the lesion without any treatment is a strong argument against a malignant lymphoid process and raises doubts as to the reality of isolated anorectal HL in immunocompetent participants.

PMID: 20861713 [PubMed – indexed for MEDLINE]

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7.

Tumori. 2010 May-Jun;96(3):465-72.

Gene analysis of Epstein-Barr virus-associated lymphomas in Hu-Pbl/SCID chimeras.

Gan R, Xie X, He J, Liu X, Hong L, Tang Y, Liu F, Xie H.

Cancer Research Institute, University of South China, Hengyang City, China. gan998@yahoo.com

Abstract

AIMS AND BACKGROUND: The mechanisms of Epstein-Barr virus (EBV)-associated tumor development are incompletely understood. The aim of this study was to investigate the gene expression of EBV-associated lymphomas in hu-PBL/SCID mice.

METHODS: Human peripheral blood lymphocytes (hu-PBL) from EBV-seropositive donors were transplanted into severe combined immunodeficiency (SCID) mice. In situ hybridization was used to detect EBV-encoded small RNA- 1 (EBER1) in tumor tissues. Mutation of TP53 exons 5-8 in EBV-induced lymphomas was analyzed by PCR-SSCP. Immunohistochemical staining was used to examine EBV gene products and cellular oncoproteins.

RESULTS: Twenty-one of 29 mice developed tumors. EBER1 was positive in the nuclei of almost all tumor cells. Immunohistochemistry showed positive staining of LMP1, EBNA2 and ZEBRA in a small number of tumor cells. Immunohistochemically detectable p53 protein expression was common (85.7%), but TP53 gene mutations were identified in only four cases (19.1%) of EBV-associated lymphomas. Positivity rates of C-myc, Bcl-2 and Bax expression were 100%, 95.2%, and 90.5%, respectively, in the 21 cases of EBV-associated lymphomas.

CONCLUSIONS: Our preliminary findings suggest that EBV-associated lymphomas in hu-PBL/SCID chimeras show EBV infection, expression of oncogenic viral genes, and overexpression of cellular oncogenes. TP53 gene mutations are rare but p53 protein is commonly expressed in EBV-associated lymphomas.

PMID: 20845810 [PubMed – indexed for MEDLINE]

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8.

Mol Cancer. 2010 Sep 15;9:241.

Epstein-Barr virus-encoded EBNA1 enhances RNA polymerase III-dependent EBER expression through induction of EBER-associated cellular transcription factors.

Owen TJ, O’Neil JD, Dawson CW, Hu C, Chen X, Yao Y, Wood VH, Mitchell LE, White RJ, Young LS, Arrand JR.

School of Cancer Sciences, University of Birmingham, Birmingham, UK.

Abstract

BACKGROUND: Epstein-Barr Virus (EBV)-encoded RNAs (EBERs) are non-polyadenylated RNA molecules transcribed from the EBV genome by RNA polymerase III (pol III). EBERs are the most abundant viral latent gene products, although the precise mechanisms by which EBV is able to achieve such high levels of EBER expression are not fully understood. Previously EBV has been demonstrated to induce transcription factors associated with EBER expression, including pol III transcription factors and ATF-2. We have recently demonstrated that EBV-encoded nuclear antigen-1 (EBNA1) induces cellular transcription factors, and given these findings, we investigated the role of EBNA1 in induction of EBER-associated transcription factors.

RESULTS: Our data confirm that in epithelial cells EBNA1 can enhance cellular pol III transcription. Transient expression of EBNA1 in Ad/AH cells stably expressing the EBERs led to induction of both EBER1 and EBER2 and conversely, expression of a dominant negative EBNA1 led to reduced EBER expression in EBV-infected Ad/AH cells. EBNA1 can induce transcription factors used by EBER genes, including TFIIIC, ATF-2 and c-Myc. A variant chromatin precipitation procedure showed that EBNA1 is associated with the promoters of these genes but not with the promoters of pol III-transcribed genes, including the EBERs themselves. Using shRNA knock-down, we confirm the significance of both ATF-2 and c-Myc in EBER expression. Further, functional induction of a c-Myc fusion protein led to increased EBER expression, providing c-Myc binding sites upstream of EBER1 were intact. In vivo studies confirm elevated levels of the 102 kD subunit of TFIIIC in the tumour cells of EBV-positive nasopharyngeal carcinoma biopsies.

CONCLUSIONS: Our findings reveal that EBNA1 is able to enhance EBER expression through induction of cellular transcription factors and add to the repertoire of EBNA1’s transcription-regulatory properties.

PMID: 20843307 [PubMed – in process]PMCID: PMC2945964Free PMC Article

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9.

J Med Virol. 2010 Oct;82(10):1711-23.

Expression of Epstein-Barr virus-encoded LMP1 and hTERT extends the life span and immortalizes primary cultures of nasopharyngeal epithelial cells.

Yip YL, Tsang CM, Deng W, Cheung PY, Jin Y, Cheung AL, Lung ML, Tsao SW.

Cancer Biology Laboratory, Li Ka Shing Faculty of Medicine, Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

Abstract

Cell immortalization is regarded as an early and pre-requisite step in tumor development. Defining the specific genetic events involved in cell immortalization may provide insights into the early events of carcinogenesis. Nasopharyngeal carcinoma is common among the Southern Chinese population. Epstein-Barr virus (EBV) infection is associated closely with nasopharyngeal carcinoma. The involvement of LMP1 (an EBV-encoded oncogene) has been implicated in the pathogenesis of nasopharyngeal carcinoma. In this study, LMP1 expression, in combination with ectopic expression of hTERT (catalytic unit of human telomerase), was shown to extend the life span of primary cultures of nasopharyngeal epithelial cells and facilitate the immortalization of one of the cell lines (NP446). This is the first report on the successful immortalization of nasopharyngeal epithelial cells involving LMP1. The events associated with the immortalization of nasopharyngeal epithelial cells by LMP1/hTERT were characterized. Expression of c-Myc, Bmi-1, and Id-1 were upregulated at an early stage of immortalization. At a later stage of immortalization, downregulation of p21 and p16 expression were observed. Upregulation of EGFR expression and activation of MAPK signaling pathway were observed in LMP1/hTERT-immortalized nasopharyngeal epithelial cells. The LMP1/hTERT-immortalized NP446 cells were non-tumorigenic in immunosuppressed nude mice and retained anchorage-dependent growth, suggesting that additional events are required for tumorigenic transformation. The ability of the EBV-encoded LMP1, in the presence of hTERT expression, to extend the life span and immortalize primary cultures of nasopharyngeal epithelial cells supports the involvement of EBV infection and its viral products in the early stage of pathogenesis of nasopharyngeal carcinoma.

(c) 2010 Wiley-Liss, Inc.

PMID: 20827769 [PubMed – in process]

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10.

World J Gastroenterol. 2010 Sep 7;16(33):4130-4.

Epstein-Barr virus: silent companion or causative agent of chronic liver disease?

Petrova M, Kamburov V.

Clinic of Gastroenterology, Ministry of Interior, MI, 79, “Skobelev” Blvd, Sofia 1606, Bulgaria. mpetrova@gmail.com

Abstract

The Epstein-Barr virus (EBV) has an important and multifaceted role in liver pathology. As a member of the herpes virus family, EBV establishes a persistent infection in more than 90% of adults. Besides acute hepatitis during primary infection, many clinical syndromes of interest for the hepatologist are associated with EBV infection. The role of EBV in the evolution of chronic hepatitis from hepatotropic viruses is considered. Chronic EBV-associated hepatitis is suspected in immunocompetent adults with compatible serology, suggestive histology and detection of the viral genome in the liver and/or increase of specific circulating cytotoxic T-lymphocytes. EBV is the main cause of post-transplant lymphoproliferative disorders which occur in up to 30% of cases. EBV-driven lymphoproliferative diseases are also recognized in non-immunocompromised patients and liver is involved in up to a third of the cases. Directly implicated in the pathogenesis of different tumors, EBV has a disputable role in hepatocellular carcinoma carcinogenesis. Further research is required in order to establish or reject the role of EBV in human liver cancer. This paper attempts to discuss the range of EBV-associated chronic liver diseases in immunocompetent patients, from mild, self-limiting mononuclear hepatitis to liver cancer.

PMID: 20806428 [PubMed – in process]PMCID: PMC2932915Free PMC Article

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11.

Pediatr Blood Cancer. 2010 Oct;55(4):754-6.

Spontaneous resolution of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.

Belyea B, Hinson A, Moran C, Hwang E, Heath J, Barfield R.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. brian.belyea@duke.edu

Abstract

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a reactive, proliferative disorder of the immune system resulting in lymphohistiocytic proliferation, hemophagocytosis, and cytokine dysregulation. The most common infectious trigger in sHLH is Epstein-Barr virus (EBV-HLH). Current treatment protocols for EBV-HLH have a cure rate of approximately 75%; however, there are significant toxicities associated with these therapies. We present two patients with EBV-HLH who experienced spontaneous resolution of their disease prior to the initiation of therapy, suggesting there may be a subgroup of patients with EBV-HLH who do well with conservative management and can avoid potentially toxic therapies.

Copyright 2010 Wiley-Liss, Inc.

PMID: 20806367 [PubMed – indexed for MEDLINE]

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Dr. Weeks’ Comment:   mono,  yuppie flu and Epstein-Barr virus (all are the same illness) are typically treated with as cavalier an attitude as that demonstrated by the surgeon who removes a gall bladder and fails to advise the patient that by removing that amazing organ which generates bile (an emulsifying agent) he has left the…
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