Phenotype and frequency of Epstein–Barr virus‐infected cells in pretreatment blood samples from patients with Hodgkin lymphoma

Khan, Gulfaraz; Lake, Annette; Shield, Lesley; Freeland, June; Andrew, Linda; Alexander, Freda E.; Jackson, Robert M.; Taylor, Pennie; Mccruden, E. A. B.; Jarrett, Ruth F.

doi:10.1111/j.1365-2141.2005.05483.x

Cited by 23 publications

(22 citation statements)

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“…The frequency of circulating EBV-infected cells seems to be higher in EBV-associated HL than non-EBV-associated cases (11). EBV genome is also detectable in the serum and plasma of EBV-associated HL patients, as ''naked'' DNA, rather than virions (12), consistent with the notion that cell-free viral DNA may be shed from malignant cells of the tumor tissue.…”

Section: Introductionsupporting

confidence: 64%

The Viral Load of Epstein–Barr Virus (EBV) DNA in Peripheral Blood Predicts for Biological and Clinical Characteristics in Hodgkin Lymphoma

Hohaus

Santangelo

Giachelia

et al. 2011

Clinical Cancer Research

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Purpose: The Epstein-Barr virus (EBV) is present in the malignant Hodgkin/Reed-Sternberg (HRS) cells of 20% to 40% cases of Hodgkin lymphoma (HL) in Western countries. We were interested in the detection and quantification of cell-free plasma EBV-DNA as an indicator of biological and clinical characteristics in EBV-associated HL.Experimental Design: EBV was detected in peripheral blood compartments (whole blood, plasma, and mononuclear cells) at diagnosis by real-time PCR for the EBNA (EB nuclear antigen) region (n ¼ 93) and in HRS cells by in situ hybridization for EBV-encoded small RNAs (EBER; n ¼ 63). These data were correlated to histological and clinical characteristics, EBV serology, circulating cell-free DNA, and interleukin (IL)-6 levels.Results: Detection of EBV-DNA in plasma had a high specificity (90%), but a relatively low sensitivity (65%) to predict for EBV association. The viral load was higher in patients with advanced stage disease, older age in the presence of B-symptoms, and international prognostic score more than 2. The presence of EBV in HRS cells and higher plasma EBV-DNA copy numbers correlated to an increased frequency of tumor-infiltrating CD68þ macrophages in lymph node biopsies. Plasma EBV-DNA load correlated to circulating cell-free DNA and IL-6 levels, and inversely correlated to lymphocyte counts and EBNA1 antibody titers.Conclusion: Although the presence of EBV-DNA in peripheral blood cannot be regarded as a surrogate marker for EBER, the plasma EBV-DNA load at HL diagnosis is an indicator of disease activity and biological characteristics associated with negative prognosis. Moreover, the inverse correlation to EBNA1 antibody titers and lymphocyte counts may indicate a reduction in immunosurveillance, favoring the expansion of EBV-HRS cells in HL. Clin Cancer Res; 17(9); 2885-92. Ó2011 AACR.

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Section: Introductionsupporting

confidence: 64%

The Viral Load of Epstein–Barr Virus (EBV) DNA in Peripheral Blood Predicts for Biological and Clinical Characteristics in Hodgkin Lymphoma

Hohaus

Santangelo

Giachelia

et al. 2011

Clinical Cancer Research

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“…Acute IM is associated with high numbers of EBVinfected B cells, which gradually decrease over time (38). Patients with EBV-related HL have been shown to have a higher frequency of circulating EBV-infected B cells than patients with EBVunrelated HL at diagnosis (39). We, therefore, propose a disease model in which the number of EBV-infected B cells is a critical determinant of risk of EBV-related HL.…”

Section: Discussionmentioning

confidence: 99%

HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma

Hjalgrim

Rostgaard

Johnson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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104

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A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60-2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51-0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBVrelated HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74-6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL.case series | epidemiology

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“…They argued that elevated levels of EBV-infected B cells within the peripheral blood is a risk factor for developing EBV ϩ HL. 41 Based on the functional link of HLA-A alleles in the context of presentation of EBV-derived peptides, this gene represents the most likely causal association with EBV ϩ HL. However, the associated HLA class I region also includes 9 pseudogenes and the protein-coding HCG9 gene.…”

Section: Discussionmentioning

confidence: 99%

HLA-A02 is associated with a reduced risk and HLA-A01 with an increased risk of developing EBV+ Hodgkin lymphoma

Niens

Jarrett

Hepkema

et al. 2007

Blood

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132

107

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Phenotype and frequency of Epstein–Barr virus‐infected cells in pretreatment blood samples from patients with Hodgkin lymphoma

Cited by 23 publications

References 51 publications

The Viral Load of Epstein–Barr Virus (EBV) DNA in Peripheral Blood Predicts for Biological and Clinical Characteristics in Hodgkin Lymphoma

The Viral Load of Epstein–Barr Virus (EBV) DNA in Peripheral Blood Predicts for Biological and Clinical Characteristics in Hodgkin Lymphoma

HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma

HLA-A02 is associated with a reduced risk and HLA-A01 with an increased risk of developing EBV+ Hodgkin lymphoma

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Phenotype and frequency of Epstein–Barr virus‐infected cells in pretreatment blood samples from patients with Hodgkin lymphoma

Cited by 23 publications

References 51 publications

The Viral Load of Epstein–Barr Virus (EBV) DNA in Peripheral Blood Predicts for Biological and Clinical Characteristics in Hodgkin Lymphoma

The Viral Load of Epstein–Barr Virus (EBV) DNA in Peripheral Blood Predicts for Biological and Clinical Characteristics in Hodgkin Lymphoma

HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma

HLA-A*02 is associated with a reduced risk and HLA-A*01 with an increased risk of developing EBV+ Hodgkin lymphoma

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HLA-A02 is associated with a reduced risk and HLA-A01 with an increased risk of developing EBV+ Hodgkin lymphoma