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      Frequent traces of EBV infection in Hodgkin and non-Hodgkin lymphomas classified as EBV-negative by routine methods: expanding the landscape of EBV-related lymphomas

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          Abstract

          The Epstein–Barr virus (EBV) is linked to various B-cell lymphomas, including Burkitt lymphoma (BL), classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) at frequencies ranging, by routine techniques, from 5 to 10% of cases in DLBCL to >95% in endemic BL. Using higher-sensitivity methods, we recently detected EBV traces in a few EBV-negative BL cases, possibly suggesting a “ hit-and-run” mechanism. Here, we used routine and higher-sensitivity methods (qPCR and ddPCR for conserved EBV genomic regions and miRNAs on microdissected tumor cells; EBNA1 mRNA In situ detection by RNAscope) to assess EBV infection in a larger lymphoma cohort [19 BL, 34 DLBCL, 44 cHL, 50 follicular lymphomas (FL), 10 T-lymphoblastic lymphomas (T-LL), 20 hairy cell leukemias (HCL), 10 mantle cell lymphomas (MCL)], as well as in several lymphoma cell lines (9 cHL and 6 BL). qPCR, ddPCR, and RNAscope consistently documented the presence of multiple EBV nucleic acids in rare tumor cells of several cases EBV-negative by conventional methods that all belonged to lymphoma entities clearly related to EBV (BL, 6/9 cases; cHL, 16/32 cases; DLBCL, 11/30 cases), in contrast to fewer cases (3/47 cases) of FL (where the role of EBV is more elusive) and no cases (0/40) of control lymphomas unrelated to EBV (HCL, T-LL, MCL). Similarly, we revealed traces of EBV infection in 4/5 BL and 6/7 HL cell lines otherwise conventionally classified as EBV negative. Interestingly, additional EBV-positive cases (1 DLBCL, 2 cHL) relapsed as EBV-negative by routine methods while showing EBNA1 expression in rare tumor cells by RNAscope. The relapse specimens were clonally identical to their onset biopsies, indicating that the lymphoma clone can largely loose the EBV genome over time but traces of EBV infection are still detectable by high-sensitivity methods. We suggest EBV may contribute to lymphoma pathogenesis more widely than currently acknowledged.

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          Most cited references 54

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          Epstein-Barr virus: exploiting the immune system.

          In vitro, Epstein-Barr virus (EBV) will infect any resting B cell, driving it out of the resting state to become an activated proliferating lymphoblast. Paradoxically, EBV persists in vivo in a quiescent state in resting memory B cells that circulate in the peripheral blood. How does the virus get there, and with such specificity for the memory compartment? An explanation comes from the idea that two genes encoded by the virus--LMP1 and LMP2A--allow EBV to exploit the normal pathways of B-cell differentiation so that the EBV-infected B blast can become a resting memory cell.
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            Epstein-Barr virus: more than 50 years old and still providing surprises.

            It is more than 50 years since the Epstein-Barr virus (EBV), the first human tumour virus, was discovered. EBV has subsequently been found to be associated with a diverse range of tumours of both lymphoid and epithelial origin. Progress in the molecular analysis of EBV has revealed fundamental mechanisms of more general relevance to the oncogenic process. This Timeline article highlights key milestones in the 50-year history of EBV and discusses how this virus provides a paradigm for exploiting insights at the molecular level in the diagnosis, treatment and prevention of cancer.
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              RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues.

              In situ analysis of biomarkers is highly desirable in molecular pathology because it allows the examination of biomarker status within the histopathological context of clinical specimens. Immunohistochemistry and DNA in situ hybridization (ISH) are widely used in clinical settings to assess protein and DNA biomarkers, respectively, but clinical use of in situ RNA analysis is rare. This disparity is especially notable when considering the abundance of RNA biomarkers discovered through whole-genome expression profiling. This is largely due to the high degree of technical complexity and insufficient sensitivity and specificity of current RNA ISH techniques. Here, we describe RNAscope, a novel RNA ISH technology with a unique probe design strategy that allows simultaneous signal amplification and background suppression to achieve single-molecule visualization while preserving tissue morphology. RNAscope is compatible with routine formalin-fixed, paraffin-embedded tissue specimens and can use either conventional chromogenic dyes for bright-field microscopy or fluorescent dyes for multiplex analysis. Unlike grind-and-bind RNA analysis methods such as real-time RT-PCR, RNAscope brings the benefits of in situ analysis to RNA biomarkers and may enable rapid development of RNA ISH-based molecular diagnostic assays. Copyright © 2012 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                enrico.tiacci@unipg.it
                lazzi2@unisi.it
                Journal
                Mod Pathol
                Mod Pathol
                Modern Pathology
                Nature Publishing Group US (New York )
                0893-3952
                1530-0285
                1 June 2020
                1 June 2020
                2020
                : 33
                : 12
                : 2407-2421
                Affiliations
                [1 ]GRID grid.9024.f, ISNI 0000 0004 1757 4641, Section of Pathology, Department of Medical Biotechnology, , University of Siena, ; Siena, Italy
                [2 ]GRID grid.8404.8, ISNI 0000 0004 1757 2304, Section of Pathology, , University of Florence, ; Florence, Italy
                [3 ]GRID grid.10049.3c, ISNI 0000 0004 1936 9692, BioMaterials Cluster, Bernal Institute, , University of Limerick, ; Limerick, Ireland
                [4 ]GRID grid.10049.3c, ISNI 0000 0004 1936 9692, Ireland, Health Research Institute (HRI), , University of Limerick, ; Limerick, Ireland
                [5 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Institute of immunology and Immunotherapy, , University of Birmingham, ; Birmingham, UK
                [6 ]GRID grid.417287.f, ISNI 0000 0004 1760 3158, Section of Haematology and Clinical Immunology, Department of Medicine, , University and Hospital of Perugia, ; Perugia, Italy
                [7 ]GRID grid.10604.33, ISNI 0000 0001 2019 0495, Department of Clinical Medicine and Therapeutics, Unit of Medical Oncology, , University of Nairobi, ; Nairobi, Kenya
                [8 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Department of Anatomical Pathology, , University of Charité Berlin, ; Berlin, Germany
                Article
                575
                10.1038/s41379-020-0575-3
                7685982
                32483241
                © The Author(s), under exclusive licence to United States & Canadian Academy of Pathology 2020, Corrected Publication June 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                © The Author(s), under exclusive licence to United States & Canadian Academy of Pathology 2020

                Pathology

                molecular biology, tumour virus infections

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