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1
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Sneyers F, Rocha‐Iraizos A, Vergote VKJ, Dierickx D. Delving deeper into the pathogenesis and genomics of posttransplant diffuse large B-cell lymphoma. Hemasphere 2025; 9:e70123. [PMID: 40236504 PMCID: PMC11997454 DOI: 10.1002/hem3.70123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 02/13/2025] [Accepted: 03/14/2025] [Indexed: 04/17/2025] Open
Abstract
Posttransplant lymphoproliferative disorders (PTLDs) are a well-known complication of solid organ transplantation and allogeneic hematopoietic stem cell transplantation. The diffuse large B-cell lymphoma subtype (PT-DLBCL) is the most frequent monomorphic PTLD and is associated with poor prognosis. Transplant recipients have an increased risk of abnormal proliferation of lymphoid cells because of diminished immune surveillance. In about 60% of the cases, Epstein-Barr virus infection seems to contribute to the cancer phenotype. Although clinical and research interest in the disorder has increased during the last two decades, the pathology of the disease remains largely elusive. In this review, we summarize current knowledge of PT-DLBCL pathogenesis, and we discuss how a better understanding of PT-DLBCL can lead to improved diagnostics and therapeutic strategies.
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Affiliation(s)
- Flore Sneyers
- Department of OncologyLaboratory of Experimental HematologyKU LeuvenLeuvenBelgium
- Department of Human GeneticsLaboratory of Molecular Biology of LeukemiaKU LeuvenLeuvenBelgium
- Center for Cancer Biology, VIBLeuvenBelgium
- Leuven Kankerinstituut (LKI), KU Leuven – UZ LeuvenLeuvenBelgium
| | - Ana‐Lucía Rocha‐Iraizos
- Department of OncologyLaboratory of Experimental HematologyKU LeuvenLeuvenBelgium
- Department of Human GeneticsLaboratory of Molecular Biology of LeukemiaKU LeuvenLeuvenBelgium
- Center for Cancer Biology, VIBLeuvenBelgium
- Leuven Kankerinstituut (LKI), KU Leuven – UZ LeuvenLeuvenBelgium
| | - Vibeke K. J. Vergote
- Leuven Kankerinstituut (LKI), KU Leuven – UZ LeuvenLeuvenBelgium
- Department of HematologyUZ LeuvenLeuvenBelgium
| | - Daan Dierickx
- Department of OncologyLaboratory of Experimental HematologyKU LeuvenLeuvenBelgium
- Leuven Kankerinstituut (LKI), KU Leuven – UZ LeuvenLeuvenBelgium
- Department of HematologyUZ LeuvenLeuvenBelgium
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2
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Carbone A, Chadburn A, Gloghini A, Vaccher E, Bower M. Immune deficiency/dysregulation -associated lymphoproliferative disorders. Revised classification and management. Blood Rev 2024; 64:101167. [PMID: 38195294 DOI: 10.1016/j.blre.2023.101167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 12/13/2023] [Accepted: 12/30/2023] [Indexed: 01/11/2024]
Abstract
Significant advances in the field of lymphoma have resulted in two recent classification proposals, the International Consensus Classification (ICC) and the 5th edition WHO. A few entities are categorized differently in the ICC compared to the WHO. Nowhere is this more apparent than the immunodeficiency lymphoproliferative disorders. The three previous versions of the WHO classification (3rd, 4th and revised 4th editions) and the ICC focused on four clinical settings in which these lesions arise for primary categorization. In contrast the 2023 WHO 5th edition includes pathologic characteristics including morphology and viral status, in addition to clinical setting, as important information for lesion classification. In addition, the 2023 WHO recognizes a broader number of clinical scenarios in which these lesions arise, including not only traditional types of immune deficiency but also immune dysregulation. With this classification it is hoped that new treatment strategies will be developed leading to better patient outcomes.
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Affiliation(s)
- Antonino Carbone
- Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, Aviano, Italy.
| | - Amy Chadburn
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, United States of America.
| | - Annunziata Gloghini
- Department of Advanced Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
| | - Emanuela Vaccher
- Infectious Diseases and Tumors Unit, Department of Medical Oncology, Centro di Riferimento Oncologico (CRO), IRCCS, National Cancer Institute, Aviano, Italy.
| | - Mark Bower
- Department of Oncology and National Centre for HIV Malignancy, Chelsea & Westminster Hospital, London SW109NH, UK.
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3
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Bednarska K, Chowdhury R, Tobin JWD, Swain F, Keane C, Boyle S, Khanna R, Gandhi MK. Epstein-Barr virus-associated lymphomas decoded. Br J Haematol 2024; 204:415-433. [PMID: 38155519 DOI: 10.1111/bjh.19255] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 11/15/2023] [Accepted: 11/29/2023] [Indexed: 12/30/2023]
Abstract
Epstein-Barr virus (EBV)-associated lymphomas cover a range of histological B- and T-cell non-Hodgkin and Hodgkin lymphoma subtypes. The role of EBV on B-cell malignant pathogenesis and its impact on the tumour microenvironment are intriguing but incompletely understood. Both the International Consensus Classification (ICC) and 5th Edition of the World Health Organization (WHO-HAEM5) proposals give prominence to the distinct clinical, prognostic, genetic and tumour microenvironmental features of EBV in lymphoproliferative disorders. There have been major advances in our biological understanding, in how to harness features of EBV and its host immune response for targeted therapy, and in using EBV as a method to monitor disease response. In this article, we showcase the latest developments and how they may be integrated to stimulate new and innovative approaches for further lines of investigation and therapy.
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Affiliation(s)
- Karolina Bednarska
- Mater Research Institute, University of Queensland, Brisbane, Queensland, Australia
| | - Rakin Chowdhury
- Frazer Institute, University of Queensland, Brisbane, Queensland, Australia
- Department of Haematology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Joshua W D Tobin
- Mater Research Institute, University of Queensland, Brisbane, Queensland, Australia
- Department of Haematology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Fiona Swain
- Frazer Institute, University of Queensland, Brisbane, Queensland, Australia
- Department of Haematology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Colm Keane
- Frazer Institute, University of Queensland, Brisbane, Queensland, Australia
- Department of Haematology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Stephen Boyle
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Rajiv Khanna
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Maher K Gandhi
- Mater Research Institute, University of Queensland, Brisbane, Queensland, Australia
- Department of Haematology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
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4
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Salmerón-Villalobos J, Castrejón-de-Anta N, Guerra-García P, Ramis-Zaldivar JE, López-Guerra M, Mato S, Colomer D, Diaz-Crespo F, Menarguez J, Garrido-Pontnou M, Andrés M, García-Fernández E, Llavador M, Frigola G, García N, González-Farré B, Martín-Guerrero I, Garrido-Colino C, Astigarraga I, Fernández A, Verdú-Amorós J, González-Muñíz S, González B, Celis V, Campo E, Balagué O, Salaverria I. Decoding the molecular heterogeneity of pediatric monomorphic post-solid organ transplant lymphoproliferative disorders. Blood 2023; 142:434-445. [PMID: 37053555 DOI: 10.1182/blood.2022019543] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/28/2023] [Accepted: 03/31/2023] [Indexed: 04/15/2023] Open
Abstract
Posttransplant lymphoproliferative disorders (PTLDs) represent a broad spectrum of lymphoid proliferations, frequently associated with Epstein-Barr virus (EBV) infection. The molecular profile of pediatric monomorphic PTLDs (mPTLDs) has not been elucidated, and it is unknown whether they display similar genetic features as their counterpart in adult and immunocompetent (IMC) pediatric patients. In this study, we investigated 31 cases of pediatric mPTLD after solid organ transplantation, including 24 diffuse large B-cell lymphomas (DLBCLs), mostly classified as activated B cell, and 7 cases of Burkitt lymphoma (BL), 93% of which were EBV positive. We performed an integrated molecular approach, including fluorescence in situ hybridization, targeted gene sequencing, and copy number (CN) arrays. Overall, PTLD-BL carried mutations in MYC, ID3, DDX3X, ARID1A, or CCND3 resembling IMC-BL, higher mutational burden than PTLD-DLBCL, and lesser CN alterations than IMC-BL. PTLD-DLBCL showed a very heterogeneous genomic profile with fewer mutations and CN alterations than IMC-DLBCL. Epigenetic modifiers and genes of the Notch pathway were the most recurrently mutated in PTLD-DLBCL (both 28%). Mutations in cell cycle and Notch pathways correlated with a worse outcome. All 7 patients with PTLD-BL were alive after treatment with pediatric B-cell non-Hodgkin lymphoma protocols, whereas 54% of patients with DLBCL were cured with immunosuppression reduction, rituximab, and/or low-dose chemotherapy. These findings highlight the low complexity of pediatric PTLD-DLBCL, their good response to low-intensity treatment, and the shared pathogenesis between PTLD-BL and EBV-positive IMC-BL. We also suggest new potential parameters that could help in the diagnosis and the design of better therapeutic strategies for these patients.
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Affiliation(s)
- Julia Salmerón-Villalobos
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigación Biomédica en Red-Oncología, Madrid, Spain
| | - Natalia Castrejón-de-Anta
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Hematopathology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Pilar Guerra-García
- Pediatric Hematology and Oncology Department, Hospital Universitario La Paz, Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, Instituto de Investigación Sanitaria del Hospital Universitario La Paz - IdiPAZ, Madrid, Spain
| | - Joan Enric Ramis-Zaldivar
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigación Biomédica en Red-Oncología, Madrid, Spain
| | - Mónica López-Guerra
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigación Biomédica en Red-Oncología, Madrid, Spain
- Hematopathology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Sara Mato
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigación Biomédica en Red-Oncología, Madrid, Spain
| | - Dolors Colomer
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigación Biomédica en Red-Oncología, Madrid, Spain
- Hematopathology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Francisco Diaz-Crespo
- Pathology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Javier Menarguez
- Pathology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | | | - Mara Andrés
- Pediatric Hematology and Oncology Department, Hospital Universitario y Politécnico La Fe de Valencia, Valencia, Spain
| | | | - Margarita Llavador
- Pathology Department, Hospital Universitario y Politécnico La Fe de Valencia, Valencia, Spain
| | - Gerard Frigola
- Hematopathology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Noelia García
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Blanca González-Farré
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigación Biomédica en Red-Oncología, Madrid, Spain
- Hematopathology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Idoia Martín-Guerrero
- Department of Genetics, Physics Anthropology and Animal Physiology, Faculty of Science and Technology, Universidad del Pais Vasco/Euskal Herriko Unibertsitatea, Leioa, Spain
- Department of Pediatrics, Osakidetza, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain
- Departament of Pediatrics, Universidad del Pais Vasco/Euskal Herriko Unibertsitatea, Leioa, Spain
| | - Carmen Garrido-Colino
- Pediatric Oncology and Hematology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Itziar Astigarraga
- Department of Pediatrics, Osakidetza, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain
- Departament of Pediatrics, Universidad del Pais Vasco/Euskal Herriko Unibertsitatea, Leioa, Spain
| | - Alba Fernández
- Pediatric Oncology and Hematology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Jaime Verdú-Amorós
- Pediatric Oncology and Hematology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Soledad González-Muñíz
- Pediatric Oncology and Hematology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Berta González
- Pediatric Hematology and Oncology Department, Hospital Universitario La Paz, Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, Instituto de Investigación Sanitaria del Hospital Universitario La Paz - IdiPAZ, Madrid, Spain
| | - Verónica Celis
- Pediatric Oncology and Hematology Department, Hospital Sant Joan de Déu, Barcelona, Spain
| | - Elías Campo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigación Biomédica en Red-Oncología, Madrid, Spain
- Hematopathology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Olga Balagué
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigación Biomédica en Red-Oncología, Madrid, Spain
- Hematopathology Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Itziar Salaverria
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigación Biomédica en Red-Oncología, Madrid, Spain
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5
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Post-Transplant Lymphoproliferative Disease (PTLD) after Allogeneic Hematopoietic Stem Cell Transplantation: Biology and Treatment Options. J Clin Med 2022; 11:jcm11247542. [PMID: 36556158 PMCID: PMC9784583 DOI: 10.3390/jcm11247542] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/15/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Post-transplant lymphoproliferative disease (PTLD) is a serious complication occurring as a consequence of immunosuppression in the setting of allogeneic hematopoietic stem cell transplantation (alloHSCT) or solid organ transplantation (SOT). The majority of PTLD arises from B-cells, and Epstein-Barr virus (EBV) infection is present in 60-80% of the cases, revealing the central role played by the latent infection in the pathogenesis of the disease. Therefore, EBV serological status is considered the most important risk factor associated with PTLDs, together with the depth of T-cell immunosuppression pre- and post-transplant. However, despite the advances in pathogenesis understanding and the introduction of novel treatment options, PTLD arising after alloHSCT remains a particularly challenging disease, and there is a need for consensus on how to treat rituximab-refractory cases. This review aims to explore the pathogenesis, risk factors, and treatment options of PTLD in the alloHSCT setting, finally focusing on adoptive immunotherapy options, namely EBV-specific cytotoxic T-lymphocytes (EBV-CTL) and chimeric antigen receptor T-cells (CAR T).
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6
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Markouli M, Ullah F, Omar N, Apostolopoulou A, Dhillon P, Diamantopoulos P, Dower J, Gurnari C, Ahmed S, Dima D. Recent Advances in Adult Post-Transplant Lymphoproliferative Disorder. Cancers (Basel) 2022; 14:cancers14235949. [PMID: 36497432 PMCID: PMC9740763 DOI: 10.3390/cancers14235949] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 11/24/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022] Open
Abstract
PTLD is a rare but severe complication of hematopoietic or solid organ transplant recipients, with variable incidence and timing of occurrence depending on different patient-, therapy-, and transplant-related factors. The pathogenesis of PTLD is complex, with most cases of early PLTD having a strong association with Epstein-Barr virus (EBV) infection and the iatrogenic, immunosuppression-related decrease in T-cell immune surveillance. Without appropriate T-cell response, EBV-infected B cells persist and proliferate, resulting in malignant transformation. Classification is based on the histologic subtype and ranges from nondestructive hyperplasias to monoclonal aggressive lymphomas, with the most common subtype being diffuse large B-cell lymphoma-like PTLD. Management focuses on prevention of PTLD development, as well as therapy for active disease. Treatment is largely based on the histologic subtype. However, given lack of clinical trials providing evidence-based data on PLTD therapy-related outcomes, there are no specific management guidelines. In this review, we discuss the pathogenesis, histologic classification, and risk factors of PTLD. We further focus on common preventive and frontline treatment modalities, as well as describe the application of novel therapies for PLTD and elaborate on potential challenges in therapy.
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Affiliation(s)
- Mariam Markouli
- Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Fauzia Ullah
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Najiullah Omar
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Anna Apostolopoulou
- Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Puneet Dhillon
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Panagiotis Diamantopoulos
- Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Joshua Dower
- Department of Hematology and Medical Oncology, Tufts Medical Center, Boston, MA 02111, USA
| | - Carmelo Gurnari
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Sairah Ahmed
- Department of Lymphoma-Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Danai Dima
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
- Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland Clinic, Cleveland, OH 44195, USA
- Correspondence:
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7
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de Leval L, Alizadeh AA, Bergsagel PL, Campo E, Davies A, Dogan A, Fitzgibbon J, Horwitz SM, Melnick AM, Morice WG, Morin RD, Nadel B, Pileri SA, Rosenquist R, Rossi D, Salaverria I, Steidl C, Treon SP, Zelenetz AD, Advani RH, Allen CE, Ansell SM, Chan WC, Cook JR, Cook LB, d’Amore F, Dirnhofer S, Dreyling M, Dunleavy K, Feldman AL, Fend F, Gaulard P, Ghia P, Gribben JG, Hermine O, Hodson DJ, Hsi ED, Inghirami G, Jaffe ES, Karube K, Kataoka K, Klapper W, Kim WS, King RL, Ko YH, LaCasce AS, Lenz G, Martin-Subero JI, Piris MA, Pittaluga S, Pasqualucci L, Quintanilla-Martinez L, Rodig SJ, Rosenwald A, Salles GA, San-Miguel J, Savage KJ, Sehn LH, Semenzato G, Staudt LM, Swerdlow SH, Tam CS, Trotman J, Vose JM, Weigert O, Wilson WH, Winter JN, Wu CJ, Zinzani PL, Zucca E, Bagg A, Scott DW. Genomic profiling for clinical decision making in lymphoid neoplasms. Blood 2022; 140:2193-2227. [PMID: 36001803 PMCID: PMC9837456 DOI: 10.1182/blood.2022015854] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/15/2022] [Indexed: 01/28/2023] Open
Abstract
With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.
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Affiliation(s)
- Laurence de Leval
- Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland
| | - Ash A. Alizadeh
- Division of Oncology, Department of Medicine, Stanford University, Stanford, CA
- Stanford Cancer Institute, Stanford University, Stanford, CA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA
- Division of Hematology, Department of Medicine, Stanford University, Stanford, CA
| | - P. Leif Bergsagel
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Phoenix, AZ
| | - Elias Campo
- Haematopathology Section, Hospital Clínic, Institut d'Investigaciones Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Andrew Davies
- Centre for Cancer Immunology, University of Southampton, Southampton, United Kingdom
| | - Ahmet Dogan
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jude Fitzgibbon
- Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Steven M. Horwitz
- Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ari M. Melnick
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | - William G. Morice
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Ryan D. Morin
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
- Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
- BC Cancer Centre for Lymphoid Cancer, Vancouver, BC, Canada
| | - Bertrand Nadel
- Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
| | - Stefano A. Pileri
- Haematopathology Division, IRCCS, Istituto Europeo di Oncologia, IEO, Milan, Italy
| | - Richard Rosenquist
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Solna, Sweden
| | - Davide Rossi
- Institute of Oncology Research and Oncology Institute of Southern Switzerland, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, Switzerland
| | - Itziar Salaverria
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Christian Steidl
- Centre for Lymphoid Cancer, BC Cancer and University of British Columbia, Vancouver, Canada
| | | | - Andrew D. Zelenetz
- Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | - Ranjana H. Advani
- Division of Oncology, Department of Medicine, Stanford University, Stanford, CA
| | - Carl E. Allen
- Division of Pediatric Hematology-Oncology, Baylor College of Medicine, Houston, TX
| | | | - Wing C. Chan
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | - James R. Cook
- Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH
| | - Lucy B. Cook
- Centre for Haematology, Imperial College London, London, United Kingdom
| | - Francesco d’Amore
- Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
| | - Stefan Dirnhofer
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | | | - Kieron Dunleavy
- Division of Hematology and Oncology, Georgetown Lombardi Comprehensive Cancer Centre, Georgetown University Hospital, Washington, DC
| | - Andrew L. Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Falko Fend
- Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany
| | - Philippe Gaulard
- Department of Pathology, University Hospital Henri Mondor, AP-HP, Créteil, France
- Faculty of Medicine, IMRB, INSERM U955, University of Paris-Est Créteil, Créteil, France
| | - Paolo Ghia
- Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy
| | - John G. Gribben
- Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Olivier Hermine
- Service D’hématologie, Hôpital Universitaire Necker, Université René Descartes, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Daniel J. Hodson
- Wellcome MRC Cambridge Stem Cell Institute, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Eric D. Hsi
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC
| | - Giorgio Inghirami
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | - Elaine S. Jaffe
- Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Kennosuke Karube
- Department of Pathology and Laboratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keisuke Kataoka
- Division of Molecular Oncology, National Cancer Center Research Institute, Toyko, Japan
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Wolfram Klapper
- Hematopathology Section and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Won Seog Kim
- Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea
| | - Rebecca L. King
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Young H. Ko
- Department of Pathology, Cheju Halla General Hospital, Jeju, Korea
| | | | - Georg Lenz
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
| | - José I. Martin-Subero
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Miguel A. Piris
- Department of Pathology, Jiménez Díaz Foundation University Hospital, CIBERONC, Madrid, Spain
| | - Stefania Pittaluga
- Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Laura Pasqualucci
- Institute for Cancer Genetics, Columbia University, New York, NY
- Department of Pathology & Cell Biology, Columbia University, New York, NY
- The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
| | - Leticia Quintanilla-Martinez
- Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany
| | - Scott J. Rodig
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA
| | | | - Gilles A. Salles
- Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jesus San-Miguel
- Clínica Universidad de Navarra, Navarra, Cancer Center of University of Navarra, Cima Universidad de NavarraI, Instituto de Investigacion Sanitaria de Navarra, Centro de Investigación Biomédica en Red de Céncer, Pamplona, Spain
| | - Kerry J. Savage
- Centre for Lymphoid Cancer, BC Cancer and University of British Columbia, Vancouver, Canada
| | - Laurie H. Sehn
- Centre for Lymphoid Cancer, BC Cancer and University of British Columbia, Vancouver, Canada
| | - Gianpietro Semenzato
- Department of Medicine, University of Padua and Veneto Institute of Molecular Medicine, Padova, Italy
| | - Louis M. Staudt
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Steven H. Swerdlow
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | | | - Judith Trotman
- Haematology Department, Concord Repatriation General Hospital, Sydney, Australia
| | - Julie M. Vose
- Department of Internal Medicine, Division of Hematology-Oncology, University of Nebraska Medical Center, Omaha, NE
| | - Oliver Weigert
- Department of Medicine III, LMU Hospital, Munich, Germany
| | - Wyndham H. Wilson
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jane N. Winter
- Feinberg School of Medicine, Northwestern University, Chicago, IL
| | | | - Pier L. Zinzani
- IRCCS Azienda Ospedaliero-Universitaria di Bologna Istitudo di Ematologia “Seràgnoli” and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Università di Bologna, Bologna, Italy
| | - Emanuele Zucca
- Institute of Oncology Research and Oncology Institute of Southern Switzerland, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, Switzerland
| | - Adam Bagg
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - David W. Scott
- Centre for Lymphoid Cancer, BC Cancer and University of British Columbia, Vancouver, Canada
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8
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Leeman-Neill RJ, Soderquist CR, Montanari F, Raciti P, Park D, Radeski D, Mansukhani MM, Murty VV, Hsiao S, Alobeid B, Bhagat G. Phenogenomic heterogeneity of post-transplant plasmablastic lymphomas. Haematologica 2020; 107:201-210. [PMID: 33297669 PMCID: PMC8719101 DOI: 10.3324/haematol.2020.267294] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Indexed: 11/14/2022] Open
Abstract
Plasmablastic lymphoma (PBL) is a rare and clinically aggressive neoplasm that typically occurs in immunocompromised individuals, including those infected with human immunodeficiency virus (HIV) and solid organ allograft recipients. Most prior studies have focused on delineating the clinico-pathological features and genetic attributes of HIVrelated PBL, in which MYC deregulation, Epstein-Barr virus (EBV) infection and, more recently, mutations in JAK/STAT, MAP kinase, and NOTCH pathway genes have been implicated in disease pathogenesis. The phenotypic spectrum of post-transplant (PT)-PBL is not well characterized and data on underlying genetic alterations are limited. This led us to perform comprehensive histopathological and immunophenotypic evaluation and targeted sequencing of 18 samples from 11 patients (8 males, 3 females; age range, 12-76 years) with PT-PBL; eight de novo and three preceded by other types of post-transplant lymphoproliferative disorders. Post-transplant PBL displayed morphological and immunophenotypic heterogeneity and some features overlapped those of plasmablastic myeloma. Six (55%) cases were EBV positive and five (45%) showed MYC rearrangement by fluorescence in situ hybridization. Recurrent mutations in epigenetic regulators (KMT2/MLL family, TET2) and DNA damage repair and response (TP53, mismatch repair genes, FANCA, ATRX), MAP kinase (KRAS, NRAS, HRAS, BRAF), JAK/STAT (STAT3, STAT6, SOCS1), NOTCH (NOTCH1, NOTCH3, SPEN), and immune surveillance (FAS, CD58) pathway genes were observed, with the mutational profiles of EBV+ and EBV– cases exhibiting both similarities and differences. Clinical outcomes also varied, with survival ranging from 0-15.9 years after diagnosis. Besides uncovering the biological heterogeneity of PT-PBL, our study highlights similarities and distinctions between PT-PBL and PBL occurring in other settings and reveals potentially targetable oncogenic pathways in subsets of the disease.
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Affiliation(s)
| | | | - Francesca Montanari
- Division of Hematology/Oncology, Columbia University Irving Medical Center, NY Presbyterian Hospital, New York, NY
| | | | | | - Dejan Radeski
- Department of Haematology, Sir Charles Gairdner Hospital, Perth
| | | | - Vundavalli V Murty
- Department of Medicine, Division of Cytogenetics, Columbia University Irving Medical Center, NY Presbyterian Hospital, New York, NY
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9
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Cascione L, Aresu L, Baudis M, Bertoni F. DNA Copy Number Changes in Diffuse Large B Cell Lymphomas. Front Oncol 2020; 10:584095. [PMID: 33344238 PMCID: PMC7740002 DOI: 10.3389/fonc.2020.584095] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/29/2020] [Indexed: 12/24/2022] Open
Abstract
Copy number aberrations (CNV/CNA) represent a major contribution to the somatic mutation landscapes in cancers, and their identification can lead to the discovery of oncogenetic targets as well as improved disease (sub-) classification. Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma in Western Countries and up to 40% of the affected individuals still succumb to the disease. DLBCL is an heterogenous group of disorders, and we call DLBCL today is not necessarily the same disease of a few years ago. This review focuses on types and frequencies of regional DNA CNVs in DLBCL, not otherwise specified, and in two particular conditions, the transformation from indolent lymphomas and the DLBCL in individuals with immunodeficiency.
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Affiliation(s)
- Luciano Cascione
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland.,SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Luca Aresu
- Department of Veterinary Science, University of Turin, Grugliasco, Italy
| | - Michael Baudis
- SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.,Department of Molecular Life Science, University of Zurich, Zurich, Switzerland
| | - Francesco Bertoni
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland.,Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
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10
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Functional interplay of Epstein-Barr virus oncoproteins in a mouse model of B cell lymphomagenesis. Proc Natl Acad Sci U S A 2020; 117:14421-14432. [PMID: 32522871 DOI: 10.1073/pnas.1921139117] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Epstein-Barr virus (EBV) is a B cell transforming virus that causes B cell malignancies under conditions of immune suppression. EBV orchestrates B cell transformation through its latent membrane proteins (LMPs) and Epstein-Barr nuclear antigens (EBNAs). We here identify secondary mutations in mouse B cell lymphomas induced by LMP1, to predict and identify key functions of other EBV genes during transformation. We find aberrant activation of early B cell factor 1 (EBF1) to promote transformation of LMP1-expressing B cells by inhibiting their differentiation to plasma cells. EBV EBNA3A phenocopies EBF1 activities in LMP1-expressing B cells, promoting transformation while inhibiting differentiation. In cells expressing LMP1 together with LMP2A, EBNA3A only promotes lymphomagenesis when the EBNA2 target Myc is also overexpressed. Collectively, our data support a model where proproliferative activities of LMP1, LMP2A, and EBNA2 in combination with EBNA3A-mediated inhibition of terminal plasma cell differentiation critically control EBV-mediated B cell lymphomagenesis.
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11
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Post Transplant Lymphoproliferative Disorder. Indian J Hematol Blood Transfus 2020; 36:229-237. [PMID: 32425371 DOI: 10.1007/s12288-019-01182-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 09/05/2019] [Indexed: 12/12/2022] Open
Abstract
Posttransplant lymphoproliferative disorder is an extremely fatal complication arising in transplant recipients as a side effect of immunosuppression. PTLDs are seen after both solid organ and hematopoietic stem cell transplants though the incidence is much higher in the former. Primary Epstein-Barr virus (EBV) infection or reactivation due to a state of immune dysregulation along with intensity of immunosuppression used are of paramount importance in pathogenesis of PTLD. EBV associated PTLDs occur early in the post transplant period whereas late onset lymphomas are usually EBV negative. The uncontrolled B cell proliferation can create a spectrum of histological patterns from nondestructive lesions to destructive polymorphic or more aggressive monomorphic PTLDs. Early detection of seropositivity by serial monitoring in the recipient can prevent PTLD development by starting pre-emptive therapy. The mainstay treatment in established cases remains reduction of immunosuppression. Chemotherapeutic and immunomodulatory agents are added sequentially based on the type of PTLD and based on its response to initial therapy. Despite various treatment options available, the morbidity remains high and achieving state of disease remission without causing graft rejection can be quite challenging. Hence, a better understanding in pathobiology of EBV+ versus EBV- PTLDS may help prevent lymphomagenesis in transplant recipients.
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12
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Ferla V, Rossi FG, Goldaniga MC, Baldini L. Biological Difference Between Epstein-Barr Virus Positive and Negative Post-transplant Lymphoproliferative Disorders and Their Clinical Impact. Front Oncol 2020; 10:506. [PMID: 32457824 PMCID: PMC7225286 DOI: 10.3389/fonc.2020.00506] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 03/20/2020] [Indexed: 12/18/2022] Open
Abstract
Epstein–Barr virus (EBV) infection is correlated with several lymphoproliferative disorders, including Hodgkin disease, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and post-transplant lymphoproliferative disorder (PTLD). The oncogenic EBV is present in 80% of PTLD. EBV infection influences immune response and has a causative role in the oncogenic transformation of lymphocytes. The development of PTLD is the consequence of an imbalance between immunosurveillance and immunosuppression. Different approaches have been proposed to treat this disorder, including suppression of the EBV viral load, reduction of immune suppression, and malignant clone destruction. In some cases, upfront chemotherapy offers better and durable clinical responses. In this work, we elucidate the clinicopathological and molecular-genetic characteristics of PTLD to clarify the biological differences of EBV(+) and EBV(–) PTLD. Gene expression profiling, next-generation sequencing, and microRNA profiles have recently provided many data that explore PTLD pathogenic mechanisms and identify potential therapeutic targets. This article aims to explore new insights into clinical behavior and pathogenesis of EBV(–)/(+) PTLD with the hope to support future therapeutic studies.
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Affiliation(s)
- Valeria Ferla
- Hematology Division, IRCCS Ca' Granda-Maggiore Policlinico Hospital Foundation, Milan, Italy
| | - Francesca Gaia Rossi
- Hematology Division, IRCCS Ca' Granda-Maggiore Policlinico Hospital Foundation, Milan, Italy
| | - Maria Cecilia Goldaniga
- Hematology Division, IRCCS Ca' Granda-Maggiore Policlinico Hospital Foundation, Milan, Italy
| | - Luca Baldini
- Hematology Division, IRCCS Ca' Granda-Maggiore Policlinico Hospital Foundation, Milan, Italy.,University of Milan, Milan, Italy
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13
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Fujimoto A, Suzuki R. Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disorders after Hematopoietic Stem Cell Transplantation: Pathogenesis, Risk Factors and Clinical Outcomes. Cancers (Basel) 2020; 12:cancers12020328. [PMID: 32024048 PMCID: PMC7072403 DOI: 10.3390/cancers12020328] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 01/27/2020] [Accepted: 01/30/2020] [Indexed: 02/07/2023] Open
Abstract
Epstein-Barr virus (EBV) is a ubiquitous virus belonging to the human γ-herpes virus subfamily. After primary infection, EBV maintains a life-long latent infection. A major concern is that EBV can cause a diverse range of neoplasms and autoimmune diseases. In addition, patients undergoing hematopoietic stem cell transplantation or solid organ transplantation can experience post-transplant lymphoproliferative disorders (PTLDs) due to dysfunction or suppression of host’s immune system, or uncontrolled proliferation of EBV-infected cells. In recent years, the number of EBV-associated PTLD cases has increased. This review focuses on the current understandings of EBV-associated PTLD pathogenesis, as well as the risk factors and clinical outcomes for patients after allogeneic stem cell transplantation.
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Affiliation(s)
| | - Ritsuro Suzuki
- Correspondence: ; Tel.: +81-853-20-2517; Fax: +81-853-20-2525
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14
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Gonzalez-Farre B, Ramis-Zaldivar JE, Salmeron-Villalobos J, Balagué O, Celis V, Verdu-Amoros J, Nadeu F, Sábado C, Ferrández A, Garrido M, García-Bragado F, de la Maya MD, Vagace JM, Panizo CM, Astigarraga I, Andrés M, Jaffe ES, Campo E, Salaverria I. Burkitt-like lymphoma with 11q aberration: a germinal center-derived lymphoma genetically unrelated to Burkitt lymphoma. Haematologica 2019; 104:1822-1829. [PMID: 30733272 PMCID: PMC6717587 DOI: 10.3324/haematol.2018.207928] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 02/07/2019] [Indexed: 12/29/2022] Open
Abstract
Burkitt-like lymphoma with 11q aberration is characterized by pathological features and gene expression profile resembling those of Burkitt lymphoma but lacks the MYC rearrangement and carries an 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized entities is controversial. To improve the understanding of Burkitt-like lymphoma with 11q aberration we performed an analysis of copy number alterations and targeted sequencing of a large panel of B-cell lymphoma-related genes in 11 cases. Most patients had localized nodal disease and a favorable outcome after therapy. Histologically, they were high grade B-cell lymphoma, not otherwise specified (8 cases), diffuse large B-cell lymphoma (2 cases) and only one was considered as atypical Burkitt lymphoma. All cases had a germinal center B-cell signature and phenotype with frequent LMO2 expression. The patients with Burkitt-like lymphoma with 11q aberration had frequent gains of 12q12-q21.1 and losses of 6q12.1-q21, and lacked common Burkitt lymphoma or diffuse large B-cell lymphoma alterations. Potential driver mutations were found in 27 genes, particularly involving BTG2, DDX3X, ETS1, EP300, and GNA13. However, ID3, TCF3, or CCND3 mutations were absent in all cases. These results suggest that Burkitt-like lymphoma with 11q aberration is a germinal center-derived lymphoma closer to high-grade B-cell lymphoma or diffuse large B-cell lymphoma than to Burkitt lymphoma.
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Affiliation(s)
- Blanca Gonzalez-Farre
- Hematopathology Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Joan Enric Ramis-Zaldivar
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | | | - Olga Balagué
- Hematopathology Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Verónica Celis
- Pediatric Oncology Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Jaime Verdu-Amoros
- Pediatric Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Ferran Nadeu
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Constantino Sábado
- Pediatric Oncology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | | | - Marta Garrido
- Pathology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | | | | | - José Manuel Vagace
- Pediatric Hematology Department, Hospital Materno Infantil de Badajoz, Badajoz, Spain
| | - Carlos Manuel Panizo
- Department of Hematology, Clínica Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Itziar Astigarraga
- Pediatrics Department, Hospital Universitario Cruces, IIS Biocruces Bizkaia, UPV/EHU, Barakaldo, Spain
| | - Mara Andrés
- Pediatric Oncology Department, Hospital La Fe, Valencia, Spain
| | - Elaine S Jaffe
- Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Elias Campo
- Hematopathology Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Itziar Salaverria
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain .,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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15
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Stanley K, Friehling E, Ranganathan S, Mazariegos G, McAllister-Lucas LM, Sindhi R. Post-transplant lymphoproliferative disorder in pediatric intestinal transplant recipients: A literature review. Pediatr Transplant 2018; 22:e13211. [PMID: 29745058 DOI: 10.1111/petr.13211] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/31/2018] [Indexed: 12/14/2022]
Abstract
Intestinal transplantation is a successful treatment for children with intestinal failure, but has many potential complications. PTLD, a clinically and histologically diverse malignancy, occurs frequently after intestinal transplantation and can be fatal. The management of this disease is particularly challenging. The rejection-prone intestinal allograft requires high levels of immunosuppression, a precondition for PTLD. While EBV infection clearly plays a role in disease pathogenesis, the relatively naïve immune system of children is another likely contributor. As a result, pediatric intestine recipients have a higher risk of developing PTLD than other solid organ recipients. Other risk factors for disease development such as molecular and genomic changes that precipitate malignant transformation are not fully understood, especially among children. Studies on adults have started to describe the molecular pathogenesis of PTLD, but the genomic landscape of the malignancy remains largely undefined in pediatric intestinal transplant patients. In this review, we describe what is known about PTLD in pediatric patients after intestinal transplant and highlight current knowledge gaps to better direct future investigations in the pediatric population.
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Affiliation(s)
- Kaitlin Stanley
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
| | - Erika Friehling
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
| | | | - George Mazariegos
- Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
| | - Linda M McAllister-Lucas
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
| | - Rakesh Sindhi
- Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
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16
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Jin W, Chen F, Wang K, Song Y, Fei X, Wu B. miR-15a/miR-16 cluster inhibits invasion of prostate cancer cells by suppressing TGF-β signaling pathway. Biomed Pharmacother 2018; 104:637-644. [PMID: 29803177 DOI: 10.1016/j.biopha.2018.05.041] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 05/02/2018] [Accepted: 05/08/2018] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND To determine whether and how miR15a/16 regulate TGF-β signaling pathways during the progression of prostate cancer. METHODS We used bioinformatics prediction, reporter gene assay, real-time PCR, Matrigel invasion assay and Western blot to dissect the molecular mechanism of how miR-15a/miR-16 may cause metastasis in prostate tumor. RESULTS MiR-15a/16 targeted and inhibited the expression of endogenous Smad3 and ACVR2A proteins. The overexpression of miR15a/16 down-regulated p-smad3 expression, affected the expression of both MMP2 and E-cadherin, and down-regulated the expression of the EMT-mediated factors Snail and Twist in LNCaP prostate cancer cells. The overexpression of miR15a/16 decreased the invasion of LNCaP cells. MiR-15a/miR-16 cluster could reverse the invasion of activin A-mediated prostate cancer cells. After the inhibition of the activin/smad signaling pathway, the inhibitory effect of invasion in prostate cancer cells by miR-15a/miR-16 cluster disappeared. CONCLUSION Our data indicated that miR15a/16 inhibited the components of TGF-β signaling pathways in LNCaP cell line, which might relate to the progression and metastasis of prostate cancer.
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Affiliation(s)
- Wei Jin
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Fangjie Chen
- Department of Medical Genetics, China Medical University, Shenyang, 110122, China
| | - Kefeng Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Yan Song
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Xiang Fei
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Bin Wu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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17
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Margolskee E, Jobanputra V, Jain P, Chen J, Ganapathi K, Nahum O, Levy B, Morscio J, Murty V, Tousseyn T, Alobeid B, Mansukhani M, Bhagat G. Genetic landscape of T- and NK-cell post-transplant lymphoproliferative disorders. Oncotarget 2018; 7:37636-37648. [PMID: 27203213 PMCID: PMC5122338 DOI: 10.18632/oncotarget.9400] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 05/06/2016] [Indexed: 12/21/2022] Open
Abstract
Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/or deletion(n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development.
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Affiliation(s)
- Elizabeth Margolskee
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Vaidehi Jobanputra
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Preti Jain
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Jinli Chen
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Karthik Ganapathi
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Odelia Nahum
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Brynn Levy
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Julie Morscio
- Department of Pathology, Translational Cell and Tissue Research Laboratory, UZ Leuven/KU Leuven, Leuven, Belgium
| | - Vundavalli Murty
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Thomas Tousseyn
- Department of Pathology, Translational Cell and Tissue Research Laboratory, UZ Leuven/KU Leuven, Leuven, Belgium
| | - Bachir Alobeid
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Mahesh Mansukhani
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Govind Bhagat
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
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18
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Menter T, Juskevicius D, Alikian M, Steiger J, Dirnhofer S, Tzankov A, Naresh KN. Mutational landscape of B-cell post-transplant lymphoproliferative disorders. Br J Haematol 2017; 178:48-56. [PMID: 28419429 DOI: 10.1111/bjh.14633] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 12/31/2016] [Indexed: 12/14/2022]
Abstract
It is currently unclear whether post-transplant diffuse large B-cell lymphomas (PT-DLBCL) display a similar genomic landscape as DLBCL in immunocompetent patients (IC-DLBCL). We investigated 50 post-transplant lymphoproliferative disorders (PTLDs) including 37 PT-DLBCL samples for somatic mutations frequently observed in IC-DLBCL. Targeted Next Generation Sequencing (NGS) using the Ion Torrent platform and a customized panel of 68 genes was performed on genomic DNA. Non-tumoural tissue was sequenced to exclude germline variants in cases where available. A control cohort of 76 IC-DLBCL was available for comparative analyses. In comparison to IC-DLBCLs, PT-DLBCL showed more frequent mutations of TP53 (P = 0·004), and absence of ATM and B2M mutations (P = 0·004 and P = 0·016, respectively). In comparison to IC-DLBCLs, Epstein-Barr virus (EBV)+ PT-DLBCL had fewer mutated genes (P = 0·007) and particularly fewer mutations in nuclear factor-κB pathway-related genes (P = 0·044). TP53 mutations were more frequent in EBV- PT-DLBCL as compared to IC-DLBCL (P = 0·001). Germinal centre B cell (GCB) subtype of PT-DLBCL had fewer mutations and mutated genes than GCB-IC-DLBCLs (P = 0·048 and 0·04 respectively). Polymorphic PTLD displayed fewer mutations as compared to PT-DLBCL (P = 0·001). PT-DLBCL differs from IC-DLBCL with respect to mutations in genes related to DNA damage control and immune-surveillance, and EBV association is likely to have a bearing on the mutational pattern.
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Affiliation(s)
- Thomas Menter
- Department of Cellular and Molecular Pathology, Hammersmith Hospital Campus, Imperial College Healthcare NHS Trust, London, UK.,Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | | | - Mary Alikian
- Department of Cellular and Molecular Pathology, Hammersmith Hospital Campus, Imperial College Healthcare NHS Trust, London, UK
| | - Juerg Steiger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Stephan Dirnhofer
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Alexandar Tzankov
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Kikkeri N Naresh
- Department of Cellular and Molecular Pathology, Hammersmith Hospital Campus, Imperial College Healthcare NHS Trust, London, UK
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19
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Feng W, Chakraborty A. Fragility Extraordinaire: Unsolved Mysteries of Chromosome Fragile Sites. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1042:489-526. [PMID: 29357071 DOI: 10.1007/978-981-10-6955-0_21] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Chromosome fragile sites are a fascinating cytogenetic phenomenon now widely implicated in a slew of human diseases ranging from neurological disorders to cancer. Yet, the paths leading to these revelations were far from direct, and the number of fragile sites that have been molecularly cloned with known disease-associated genes remains modest. Moreover, as more fragile sites were being discovered, research interests in some of the earliest discovered fragile sites ebbed away, leaving a number of unsolved mysteries in chromosome biology. In this review we attempt to recount some of the early discoveries of fragile sites and highlight those phenomena that have eluded intense scrutiny but remain extremely relevant in our understanding of the mechanisms of chromosome fragility. We then survey the literature for disease association for a comprehensive list of fragile sites. We also review recent studies addressing the underlying cause of chromosome fragility while highlighting some ongoing debates. We report an observed enrichment for R-loop forming sequences in fragile site-associated genes than genomic average. Finally, we will leave the reader with some lingering questions to provoke discussion and inspire further scientific inquiries.
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Affiliation(s)
- Wenyi Feng
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA.
| | - Arijita Chakraborty
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
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20
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Morscio J, Tousseyn T. Recent insights in the pathogenesis of post-transplantation lymphoproliferative disorders. World J Transplant 2016; 6:505-516. [PMID: 27683629 PMCID: PMC5036120 DOI: 10.5500/wjt.v6.i3.505] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Revised: 06/30/2016] [Accepted: 08/18/2016] [Indexed: 02/05/2023] Open
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is an aggressive complication of solid organ and hematopoietic stem cell transplantation that arises in up to 20% of transplant recipients. Infection or reactivation of the Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, in combination with chronic immunosuppression are considered as the main predisposing factors, however insight in PTLD biology is fragmentary. The study of PTLD is complicated by its morphological heterogeneity and the lack of prospective trials, which also impede treatment optimization. Furthermore, the broad spectrum of underlying disorders and the graft type represent important confounding factors. PTLD encompasses different malignant subtypes that resemble histologically similar lymphomas in the general population. Post-transplant diffuse large B-cell lymphoma (PT-DLBCL), Burkitt lymphoma (PT-BL) and plasmablastic lymphoma (PT-PBL) occur most frequently. However, in many studies various EBV+ and EBV- PTLD subtypes are pooled, complicating the interpretation of the results. In this review, studies of the gene expression pattern, the microenvironment and the genetic profile of PT-DLBCL, PT-BL and PT-PBL are summarized to better understand the mechanisms underlying post-transplantation lymphomagenesis. Based on the available findings we propose stratification of PTLD according to the histological subtype and the EBV status to facilitate the interpretation of future studies and the establishment of clinical trials.
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21
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Radeski D, Montanari F, Alobeid B, O'Connor OA, Bhagat G. Post-transplant lymphoproliferative disorder: a heterogeneous conundrum - response to Weisenburger DD & Gross TG. Br J Haematol 2016; 179:856-857. [PMID: 27471184 DOI: 10.1111/bjh.14272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Dejan Radeski
- School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia
| | - Francesca Montanari
- NYU Cancer Institute, New York University School of Medicine, New York, NY, USA
| | - Bachir Alobeid
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Owen A O'Connor
- Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA
| | - Govind Bhagat
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
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22
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Bagheri H, Badduke C, Qiao Y, Colnaghi R, Abramowicz I, Alcantara D, Dunham C, Wen J, Wildin RS, Nowaczyk MJ, Eichmeyer J, Lehman A, Maranda B, Martell S, Shan X, Lewis SM, O’Driscoll M, Gregory-Evans CY, Rajcan-Separovic E. Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis. JCI Insight 2016; 1:e85461. [PMID: 27699255 PMCID: PMC5033885 DOI: 10.1172/jci.insight.85461] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 02/09/2016] [Indexed: 01/14/2023] Open
Abstract
The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome. Here, we describe 8 new patients with the 2p15p16.1 deletion and review all published cases to date. We demonstrate functional deficits for the above 4 candidate genes using patients' lymphoblast cell lines (LCLs) and knockdown of their orthologs in zebrafish. All genes were dosage sensitive on the basis of reduced protein expression in LCLs. In addition, deletion of XPO1, a nuclear exporter, cosegregated with nuclear accumulation of one of its cargo molecules (rpS5) in patients' LCLs. Other pathways associated with these genes (e.g., NF-κB and Wnt signaling as well as the DNA damage response) were not impaired in patients' LCLs. Knockdown of xpo1a, rel, bcl11aa, and bcl11ab resulted in abnormal zebrafish embryonic development including microcephaly, dysmorphic body, hindered growth, and small fins as well as structural brain abnormalities. Our multifaceted analysis strongly implicates XPO1, REL, and BCL11A as candidate genes for 2p15p16.1 microdeletion syndrome.
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Affiliation(s)
- Hani Bagheri
- Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada
- Child and Family Research Institute, Vancouver, British Columbia, Canada
| | - Chansonette Badduke
- Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada
- Child and Family Research Institute, Vancouver, British Columbia, Canada
| | - Ying Qiao
- Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada
- Child and Family Research Institute, Vancouver, British Columbia, Canada
| | - Rita Colnaghi
- Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom
| | - Iga Abramowicz
- Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom
| | - Diana Alcantara
- Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom
| | - Christopher Dunham
- Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada
| | - Jiadi Wen
- University of Texas at Dallas, Dallas, Texas, USA
| | | | - Malgorzata J.M. Nowaczyk
- Department of Pathology and Molecular Medicine, McMaster University Medical Centre, Hamilton, Ontario, Canada
| | | | - Anna Lehman
- Department of Medical Genetics, UBC, Vancouver, British Columbia, Canada
| | - Bruno Maranda
- Medical Genetics, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Sally Martell
- Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada
- Child and Family Research Institute, Vancouver, British Columbia, Canada
| | - Xianghong Shan
- Department of Ophthalmology, UBC, Vancouver, British Columbia, Canada
| | - Suzanne M.E. Lewis
- Department of Medical Genetics, UBC, Vancouver, British Columbia, Canada
| | - Mark O’Driscoll
- Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom
| | | | - Evica Rajcan-Separovic
- Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, British Columbia, Canada
- Child and Family Research Institute, Vancouver, British Columbia, Canada
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23
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Ferreiro JF, Morscio J, Dierickx D, Vandenberghe P, Gheysens O, Verhoef G, Zamani M, Tousseyn T, Wlodarska I. EBV-Positive and EBV-Negative Posttransplant Diffuse Large B Cell Lymphomas Have Distinct Genomic and Transcriptomic Features. Am J Transplant 2016; 16:414-25. [PMID: 26780579 DOI: 10.1111/ajt.13558] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 08/03/2015] [Accepted: 08/20/2015] [Indexed: 01/25/2023]
Abstract
The molecular pathogenesis of posttransplant diffuse large B cell lymphoma (PT-DLBCL) is largely unknown. We have recently shown that Epstein-Barr virus-positive (EBV(+)) and -negative (EBV(-)) PT-DLBCL have distinct gene expression profiles, and the transcriptomic profile of EBV(-) PT-DLBCL is similar to that of DLBCL in immunocompetent individuals (IC-DLBCL). To validate these observations at the genomic level, we performed array-comparative genome hybridization (aCGH) analysis of 21 EBV(+) PT-DLBCL, 6 EBV(-) PT-DLBCL, and 11 control IC-DLBCL, and subsequently combined genomic and transcriptomic data. The analysis showed that EBV(+) and EBV(-) PT-DLBCL have distinct aCGH profiles and shared only one recurrent imbalance. EBV(-) PT-DLBCL, however, displayed at least 10 aberrations recurrent in IC-DLBCL, among which characteristic gain of 3/3q and 18q, and loss of 6q23/TNFAIP3 as well as 9p21/CDKN2A. The most prevalent aberration in EBV(+) PT-DLBCL was gain/amplification of 9p24.1 targeting PDCD1LG2/PDL2. Our data indicate that the FOXP1 oncogene and the tumor suppressor CDKNA2 implicated in EBV(-) DLBCL, do not play a critical role in the pathogenesis of EBV(+) PT-DLBCL. Altogether, genomic profiling of PT-/IC-DLBCL confirms that EBV(-) and EBV(+) PT-DLBCL are distinct entities, while EBV(-) PT-DLBCL has features in common with IC-DLBCL. These findings support the hypothesis that EBV(-) PT-DLBCL are de novo lymphomas in transplant recipients.
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Affiliation(s)
| | - J Morscio
- Translational Cell and Tissue Research KU Leuven, Department of Pathology UZ Leuven, Leuven, Belgium
| | - D Dierickx
- Department of Hematology, UZ Leuven, Leuven, Belgium
| | | | - O Gheysens
- Department of Molecular Medicine, UZ Leuven, Leuven, Belgium
| | - G Verhoef
- Department of Hematology, UZ Leuven, Leuven, Belgium
| | - M Zamani
- Center for Human Genetics, KU Leuven, Leuven, Belgium
| | - T Tousseyn
- Translational Cell and Tissue Research KU Leuven, Department of Pathology UZ Leuven, Leuven, Belgium
| | - I Wlodarska
- Center for Human Genetics, KU Leuven, Leuven, Belgium
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24
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How I treat posttransplant lymphoproliferative disorders. Blood 2015; 126:2274-83. [PMID: 26384356 DOI: 10.1182/blood-2015-05-615872] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 09/13/2015] [Indexed: 01/13/2023] Open
Abstract
Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal disorder arising after solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). Iatrogenically impaired immune surveillance and Epstein-Barr virus (EBV) primary infection/reactivation are key factors in the pathogenesis. However, current knowledge on all aspects of PTLD is limited due to its rarity, morphologic heterogeneity, and the lack of prospective trials. Furthermore, the broad spectrum of underlying immune disorders and the type of graft represent important confounding factors. Despite these limitations, several reviews have been written aimed at offering a guide for pathologists and clinicians in diagnosing and treating PTLD. Rather than providing another classical review on PTLD, this "How I Treat" article, based on 2 case reports, focuses on specific challenges, different perspectives, and novel insights regarding the pathogenesis, diagnosis, and treatment of PTLD. These challenges include the wide variety of PTLD presentation (making treatment optimization difficult), the impact of EBV on pathogenesis and clinical behavior, and the controversial treatment of Burkitt lymphoma (BL)-PTLD.
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25
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Testoni M, Zucca E, Young KH, Bertoni F. Genetic lesions in diffuse large B-cell lymphomas. Ann Oncol 2015; 26:1069-1080. [PMID: 25605746 PMCID: PMC4542576 DOI: 10.1093/annonc/mdv019] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 12/05/2014] [Accepted: 12/15/2014] [Indexed: 01/04/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, accounting for 35%-40% of all cases. The combination of the anti-CD20 monoclonal antibody rituximab with anthracycline-based combination chemotherapy (R-CHOP, rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) lead to complete remission in most and can cure more than half of patients with DLBCL. The diversity in clinical presentation, as well as the pathologic and biologic heterogeneity, suggests that DLBCL comprises several disease entities that might ultimately benefit from different therapeutic approaches. In this review, we summarize the current literature focusing on the genetic lesions identified in DLBCL.
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Affiliation(s)
- M Testoni
- Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona
| | - E Zucca
- Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - K H Young
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - F Bertoni
- Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona; Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
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26
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Kinch A, Cavelier L, Bengtsson M, Baecklund E, Enblad G, Backlin C, Thunberg U, Sundström C, Pauksens K. Donor or recipient origin of posttransplant lymphoproliferative disorders following solid organ transplantation. Am J Transplant 2014; 14:2838-45. [PMID: 25307322 DOI: 10.1111/ajt.12990] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 08/25/2014] [Accepted: 08/25/2014] [Indexed: 01/25/2023]
Abstract
Previous studies of donor or recipient origin of posttransplant lymphoproliferative disorders (PTLDs) following solid organ transplantation (SOT) have either been small or with selected patient groups. We studied tumor origin in a population-based cohort of 93 patients with PTLD following SOT. Tumor origin of PTLD tissue was analyzed by fluorescence in situ hybridization of the sex chromosomes in cases of sex mismatch between donor and recipient (n = 41), or HLA genotyping in cases of identical sex but different HLA type (n = 52). Tumor origin of PTLD could be determined in 67 of the 93 cases. All 67 PTLDs were of recipient origin. They were found in recipients of kidney (n = 38), liver (n = 12), heart (n = 10) and lung (n = 7). The most common recipient-derived lymphomas were monomorphic B-cell PTLDs (n = 45), monomorphic T cell PTLDs (n = 9), indolent lymphomas (n = 6), and polymorphic PTLD (n = 4). Half of the recipient-derived PTLDs were Epstein-Barr virus-positive. Twelve of the recipient-derived PTLDs were located in the grafts: in four cases exclusively and in eight cases in combination with disseminated disease outside the graft. Tumor origin was indeterminable in 26 cases, probably due to low DNA quality. We conclude that the vast majority of PTLDs after SOT was of recipient origin.
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Affiliation(s)
- A Kinch
- Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden
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27
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Chigrinova E, Rinaldi A, Kwee I, Rossi D, Rancoita PMV, Strefford JC, Oscier D, Stamatopoulos K, Papadaki T, Berger F, Young KH, Murray F, Rosenquist R, Greiner TC, Chan WC, Orlandi EM, Lucioni M, Marasca R, Inghirami G, Ladetto M, Forconi F, Cogliatti S, Votavova H, Swerdlow SH, Stilgenbauer S, Piris MA, Matolcsy A, Spagnolo D, Nikitin E, Zamò A, Gattei V, Bhagat G, Ott G, Zucca E, Gaidano G, Bertoni F. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood 2013; 122:2673-2682. [PMID: 24004666 DOI: 10.1182/blood-2013-03-489518] [Citation(s) in RCA: 186] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). Although RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the preexisting CLL, the mechanisms leading to RS have not been clarified. To better understand the pathogenesis of RS, we analyzed a series of cases including 59 RS, 28 CLL phase of RS, 315 CLL, and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell-cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL phase, being present in approximately one half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. Although RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL phase preceding RS had not a generalized increase in genomic complexity compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions.
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MESH Headings
- Cell Transformation, Neoplastic/genetics
- Chromosomes, Human, Pair 12/genetics
- Disease Progression
- Female
- Gene Expression Regulation, Leukemic/genetics
- Genes, p16/physiology
- Genome-Wide Association Study
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/pathology
- Male
- Middle Aged
- Trisomy/genetics
- Tumor Suppressor Protein p53/genetics
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Affiliation(s)
- Ekaterina Chigrinova
- Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland
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28
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Hussein K, Tiede C, Maecker-Kolhoff B, Kreipe H. Posttransplant lymphoproliferative disorder in pediatric patients. Pathobiology 2013; 80:289-96. [PMID: 24013821 DOI: 10.1159/000350331] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Transplantation of solid organs and hematopoietic stem cells is accompanied by profound disturbance of immune function mediated by immunosuppressive drugs or delayed immune reconstitution. Disturbed T cell control of Epstein-Barr virus (EBV)-infected B cells leads to posttransplant lymphoproliferative disorder (PTLD) in up to 10% of patients. Children are at a higher risk because they are more often EBV-naïve before transplantation. Patients with PTLD often present with unspecific symptoms (pain and organ/graft dysfunction). Depending on the onset of PTLD, manifestations vary between mainly nodal (late PTLD) and extranodal sites (early PTLD). Histology, immunohistology, EBER in situ hybridization and molecular pathology are required for diagnosis and subclassification of PTLD. The three major types are early lesions (resembling reactive proliferations in immunocompetent patients), polymorphic PTLD (proliferation of B and T cells with effacement of histoarchitecture) and monomorphic PTLD (presenting as malignant lymphomas, mainly high-grade B cell lymphomas). In a subfraction of cases, including monomorphic PTLD, reduction of immunosuppressive medication alone is sufficient to induce remission. Surgical debulking of tumor mass and anti-CD20-antibody treatment with or without chemotherapy (usually at lower dosages than in immunocompetent patients) constitute the basis of additional therapy.
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Affiliation(s)
- Kais Hussein
- Institute of Pathology, Hannover Medical School, Hannover, Germany
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29
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Morscio J, Dierickx D, Tousseyn T. Molecular pathogenesis of B-cell posttransplant lymphoproliferative disorder: what do we know so far? Clin Dev Immunol 2013; 2013:150835. [PMID: 23690819 PMCID: PMC3649442 DOI: 10.1155/2013/150835] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 03/10/2013] [Accepted: 03/11/2013] [Indexed: 12/14/2022]
Abstract
Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal disease that arises in 2%-10% of solid organ and hematopoietic stem cell transplants and is most frequently of B-cell origin. This very heterogeneous disorder ranges from benign lymphoproliferations to malignant lymphomas, and despite the clear association with Epstein-Barr Virus (EBV) infection, its etiology is still obscure. Although a number of risk factors have been identified (EBV serostatus, graft type, and immunosuppressive regimen), it is currently not possible to predict which transplant patient will eventually develop PTLD. Genetic studies have linked translocations (involving C-MYC, IGH, BCL-2), various copy number variations, DNA mutations (PIM1, PAX5, C-MYC, RhoH/TTF), and polymorphisms in both the host (IFN-gamma, IL-10, TGF-beta, HLA) and the EBV genome to B-cell PTLD development. Furthermore, the tumor microenvironment seems to play an important role in the course of disease representing a local niche that can allow antitumor immune responses even in an immunocompromised host. Taken together, B-cell PTLD pathogenesis is very complex due to the interplay of many different (patient-dependent) factors and requires thorough molecular analysis for the development of novel tailored therapies. This review aims at giving a global overview of the currently known parameters that contribute to the development of B-cell PTLD.
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Affiliation(s)
- J. Morscio
- KU Leuven, Translational Cell and Tissue Research, Leuven, Belgium
| | - D. Dierickx
- UZ Leuven, Department of Hematology, University Hospitals KU Leuven, Leuven, Belgium
| | - T. Tousseyn
- KU Leuven, Translational Cell and Tissue Research, Leuven, Belgium
- UZ Leuven, Department of Pathology, University Hospitals KU Leuven, Leuven, Belgium
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30
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Genome-wide DNA profiling of HIV-related B-cell lymphomas. Methods Mol Biol 2013; 973:213-26. [PMID: 23412793 DOI: 10.1007/978-1-62703-281-0_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2023]
Abstract
Non-Hodgkin lymphomas represent a frequent complication of human immunodeficiency virus (HIV) infection, occurring at higher frequency than in immunocompetent individuals, and causing morbidity and mortality. Here, we present the method we have followed to analyze the genomic lesions in HIV-related and in other immunodeficiency-related lymphomas, as well in diffuse large B-cell lymphoma (DLBCL) samples derived from immunocompetent hosts. The technology we have used is represented by the GeneChip Human Mapping 250K NspI arrays (Affymetrix, Santa Clara, CA, USA), arrays based on 25mer oligonucleotides initially designed for large-scale genotyping, that is, the detection of thousands of single-nucleotide polymorphisms (SNPs), then shown to be applicable for the detection of cancer alterations. The protocol is shown in all its steps with suggestions and tips. Applications of the technology and obtained results are also briefly summarized.
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31
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Posttransplant lymphoproliferative disorders. Adv Hematol 2012; 2012:230173. [PMID: 22570658 PMCID: PMC3337580 DOI: 10.1155/2012/230173] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Accepted: 01/24/2012] [Indexed: 12/04/2022] Open
Abstract
Posttransplant lymphoproliferative disorders (PTLDs) are a group of diseases that range from benign polyclonal to malignant monoclonal lymphoid proliferations. They arise secondary to treatment with immunosuppressive drugs given to prevent transplant rejection. Three main pathologic subsets/stages of evolution are recognised: early, polymorphic, and monomorphic lesions. The pathogenesis of PTLDs seems to be multifactorial. Among possible infective aetiologies, the role of EBV has been studied in depth, and the virus is thought to play a central role in driving the proliferation of EBV-infected B cells that leads to subsequent development of the lymphoproliferative disorder. It is apparent, however, that EBV is not solely responsible for the “neoplastic” state. Accumulated genetic alterations of oncogenes and tumour suppressor genes (deletions, mutations, rearrangements, and amplifications) and epigenetic changes (aberrant hypermethylation) that involve tumour suppressor genes are integral to the pathogenesis. Antigenic stimulation also plays an evident role in the pathogenesis of PTLDs. Plasmacytoid dendritic cells (PDCs) that are critical to fight viral infections have been thought to play a pathogenetically relevant role in PTLDs. Furthermore, regulatory T cells (Treg cells), which are modulators of immune reactions once incited, seem to have an important role in PTLDs where antigenic stimulation is key for the pathogenesis.
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Capello D, Gloghini A, Baldanzi G, Martini M, Deambrogi C, Lucioni M, Piranda D, Famà R, Graziani A, Spina M, Tirelli U, Paulli M, Larocca LM, Gaidano G, Carbone A, Sinigaglia F. Alterations of negative regulators of cytokine signalling in immunodeficiency-related non-Hodgkin lymphoma. Hematol Oncol 2012; 31:22-8. [PMID: 22488585 DOI: 10.1002/hon.2010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 02/07/2012] [Accepted: 02/20/2012] [Indexed: 12/19/2022]
Abstract
We investigated immunodeficiency-related non-Hodgkin lymphoma for the presence of molecular alterations affecting negative regulators of the Janus family protein tyrosine kinase/signal transducer and activator of transcription pathway. Protein tyrosine phosphatase, non-receptor type 6/Src homology 2-containing tyrosine phosphatase-1 epigenetic silencing was recurrent in primary effusion lymphoma (100%), and diffuse large B-cell lymphoma (63%), with a higher prevalence in the non-germinal centre subtype, and was associated with the activation of the Janus family protein tyrosine kinase/signal transducer and activator of transcription 3 pathway. Suppressor of cytokine signalling (SOCS)1 and SOCS3 epigenetic silencing were occasionally detected, whereas SOCS1 was frequently mutated in diffuse large B-cell lymphoma and polymorphic post-transplant lymphoproliferative disorders, possibly as a cause of aberrant somatic hypermutation. However, the mutation profile of the coding region of the gene was different from that expected from the aberrant somatic hypermutation process, suggesting that, at least in some cases, SOCS1 mutations may have been selected for their functional activity.
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Affiliation(s)
- Daniela Capello
- Division of Hematology, 'Amedeo Avogadro' University of Eastern Piedmont, Novara, Italy.
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33
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Mian M, Scandurra M, Chigrinova E, Shen Y, Inghirami G, Greiner TC, Chan WC, Vose JM, Testoni M, Chiappella A, Baldini L, Ponzoni M, Ferreri AJM, Franceschetti S, Gaidano G, Montes-Moreno S, Piris MA, Facchetti F, Tucci A, Nomdedeu JF, Lazure T, Uccella S, Tibiletti MG, Zucca E, Kwee I, Bertoni F. Clinical and molecular characterization of diffuse large B-cell lymphomas with 13q14.3 deletion. Ann Oncol 2012; 23:729-735. [PMID: 21693768 DOI: 10.1093/annonc/mdr289] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Deletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21). PATIENTS AND METHODS Affymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years. RESULTS Deletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21. CONCLUSIONS Cases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulation.
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Affiliation(s)
- M Mian
- Laboratory of Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Division of Hematology, Azienda Ospedaliera S. Maurizio, Bolzano/Bozen, Italy
| | - M Scandurra
- Laboratory of Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - E Chigrinova
- Laboratory of Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Y Shen
- Department of Pathology and Microbiology, University of Nebraska, Omaha, USA
| | - G Inghirami
- Department of Pathology and Center for Experimental Research and Medical Studies, University of Turin, Turin
| | - T C Greiner
- Department of Pathology and Microbiology, University of Nebraska, Omaha, USA
| | - W C Chan
- Department of Pathology and Microbiology, University of Nebraska, Omaha, USA
| | - J M Vose
- Department of Pathology and Microbiology, University of Nebraska, Omaha, USA
| | - M Testoni
- Laboratory of Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - A Chiappella
- Department of Pathology and Center for Experimental Research and Medical Studies, University of Turin, Turin
| | - L Baldini
- Hematology/Bone Marrow Transplantation Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, University of Milan, Milan
| | - M Ponzoni
- Pathology Unit and Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan
| | - A J M Ferreri
- Pathology Unit and Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan
| | - S Franceschetti
- Division of Hematology, Department of Clinical and Experimental Medicine & Centro di Biotecnologie per la Ricerca Medica Applicata, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
| | - G Gaidano
- Division of Hematology, Department of Clinical and Experimental Medicine & Centro di Biotecnologie per la Ricerca Medica Applicata, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
| | - S Montes-Moreno
- Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - M A Piris
- Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - F Facchetti
- Department of Pathology, University of Brescia, I Servizio di Anatomia Patologica, Spedali Civili di Brescia, Brescia; Division of Hematology, Spedali Civili di Brescia, Brescia, Italy
| | - A Tucci
- Department of Pathology, University of Brescia, I Servizio di Anatomia Patologica, Spedali Civili di Brescia, Brescia; Division of Hematology, Spedali Civili di Brescia, Brescia, Italy
| | - J Fr Nomdedeu
- Department of Hematology and Laboratori d'Hematologia, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - T Lazure
- Departments of Internal Medicine and Pathology, University Hospital of Bicêtre, AP/HP, Le Kremlin Bicêtre, France
| | - S Uccella
- Anatomic Pathology Unit, University of Insubria, Ospedale di Circolo, Varese, Italy
| | - M G Tibiletti
- Anatomic Pathology Unit, University of Insubria, Ospedale di Circolo, Varese, Italy
| | - E Zucca
- Laboratory of Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - I Kwee
- Laboratory of Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland
| | - F Bertoni
- Laboratory of Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
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34
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Kwee I, Rinaldi A, Rancoita P, Rossi D, Capello D, Forconi F, Giuliani N, Piva R, Inghirami G, Gaidano G, Zucca E, Bertoni F. Integrated DNA copy number and methylation profiling of lymphoid neoplasms using a single array. Br J Haematol 2011; 156:354-7. [PMID: 22118580 DOI: 10.1111/j.1365-2141.2011.08946.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Changes in DNA copy number (CN) and DNA methylation represent important aberrations for lymphomas and other cancers. Here, for the first time, we show that the Illumina Infinium Methylation (IIM) assay, although not originally designed for CN profiling, is able to estimate CN changes. We compared the IIM CN profiles to those obtained with a standard technique in a series of diffuse large B-cell lymphomas: the profiles showed a high degree of consensus. The demonstration of CN profiling as an additional function of the IIM assay may impact the choice of platform for methylation profiling of haematological and solid tumours.
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Affiliation(s)
- Ivo Kwee
- Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland.
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35
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Kwee I, Capello D, Rinaldi A, Rancoita PMV, Bhagat G, Greiner TC, Spina M, Gloghini A, Chan WC, Paulli M, Zucca E, Tirelli U, Carbone A, Gaidano G, Bertoni F. Genomic aberrations affecting the outcome of immunodeficiency-related diffuse large B-cell lymphoma. Leuk Lymphoma 2011; 53:71-6. [DOI: 10.3109/10428194.2011.607729] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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36
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Kamdar KY, Rooney CM, Heslop HE. Posttransplant lymphoproliferative disease following liver transplantation. Curr Opin Organ Transplant 2011; 16:274-80. [PMID: 21467936 PMCID: PMC3167800 DOI: 10.1097/mot.0b013e3283465715] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Despite contemporary immunosuppressive regimens, posttransplant lymphoproliferative disease (PTLD) remains a major complication after liver transplantation. This review highlights advances in the understanding of the pathophysiology, diagnosis, and management of PTLD in liver transplant recipients. RECENT FINDINGS The spectrum of PTLD after liver transplant ranges from polymorphic lymphoproliferation to high-grade monoclonal lymphoma and is usually related to outgrowth of lymphocytes infected with Epstein-Barr virus (EBV). Risk factors for PTLD include EBV-seronegativity of the recipient, young age, intensity of immunosuppression, and the first year posttransplant. Measurement of EBV load by quantitative polymerase chain reaction assays is an important aid in the surveillance and diagnosis of PTLD although the specificity for PTLD is only about 50% (specificity for EBV is ∼100%). In patients diagnosed with PTLD, management options include reduction of immunosuppression, rituximab, combination chemotherapy, and adoptive immunotherapy. Outcomes have improved because rituximab has been incorporated into treatment regimens, and immunotherapy approaches show promise. SUMMARY PTLD is a significant complication after liver transplantation, particularly in children. Advances in early detection approaches have aided in the diagnosis and management of PTLD, but further research to identify better predictive biomarkers is needed to improve risk-based treatment strategies.
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Affiliation(s)
- Kala Y Kamdar
- Department of Pediatrics, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas, USA.
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37
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38
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Nourse JP, Jones K, Gandhi MK. Epstein-Barr Virus-related post-transplant lymphoproliferative disorders: pathogenetic insights for targeted therapy. Am J Transplant 2011; 11:888-95. [PMID: 21521464 DOI: 10.1111/j.1600-6143.2011.03499.x] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is a spectrum of major, life-threatening lymphoproliferative diseases occurring in the post-transplant setting. The majority of PTLD is of B-cell origin and is associated with several risk factors, the most significant being Epstein-Barr virus (EBV) infection. EBV's in vitro transforming abilities, distinctive latency, clonality within the malignant cells and response to targeted therapies implicate a critical role in the biology of PTLD. This minireview focuses on EBV-related PTLD pathogenesis, in particular the interplay between aspects of the EBV life cycle and latency with nonviral factors resulting in the wide spectrum of histology and clinical presentations encountered in PTLD. With the increased prevalence of transplantation a rise in the incidence of PTLD may be expected. Therefore the importance of laboratory and animal models in the understanding of PTLD and the development of novel therapeutic approaches is discussed.
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Affiliation(s)
- J P Nourse
- Clinical Immunohaematology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia
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39
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Chigrinova E, Mian M, Scandurra M, Greiner TC, Chan WC, Vose JM, Inghirami G, Chiappella A, Baldini L, Ponzoni M, Ferreri AJ, Franceschetti S, Gaidano G, Tucci A, Facchetti F, Lazure T, Lambotte O, Montes-Moreno S, Piris MA, Nomdedeu JF, Uccella S, Rancoita PM, Kwee I, Zucca E, Bertoni F. Diffuse large B-cell lymphoma with concordant bone marrow involvement has peculiar genomic profile and poor clinical outcome. Hematol Oncol 2011; 29:38-41. [DOI: 10.1002/hon.953] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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40
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Evens AM, Roy R, Sterrenberg D, Moll MZ, Chadburn A, Gordon LI. Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy. Curr Oncol Rep 2011; 12:383-94. [PMID: 20963522 DOI: 10.1007/s11912-010-0132-1] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Post-transplantation lymphoproliferative disorders (PTLD) are a heterogenous group of abnormal lymphoid proliferations that occur after solid organ transplant (SOT) or hematopoietic transplantation. PTLDs consist of a disease spectrum ranging from hyperplasia to aggressive lymphomas with 60-70% being Epstein-Barr virus positive. The majority of cases are B-cell, although 10-15% are of T-cell origin or rarely Hodgkin lymphoma. Recent SOT series suggest PTLD occurs at a median of 36-40 months after transplant. Clinically, extra-nodal disease is common (up to 75-85%) including CNS involvement, which is seen in 10-15% of all cases. Since the first report over 40 years ago, PTLD has remained one of the most morbid complications associated with SOT. However, recent data suggests improved survival in the modern era, especially with the integration of early rituximab-based therapy. These studies utilized first line rituximab (+/- chemotherapy) together with reduced immune suppression (RI) for monomorphic and polymorphic PTLD. It will be critical in future studies to determine which PTLDs are most amenable to initial therapy with RI alone, versus RI/rituximab, versus RI/rituximab/chemotherapy. Additionally, novel therapeutics, such as adoptive immunotherapy, should continue to be explored.
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Affiliation(s)
- Andrew M Evens
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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41
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Capello D, Gloghini A, Martini M, Spina M, Tirelli U, Bertoni F, Rinaldi A, Morra E, Rambaldi A, Sinigaglia F, Larocca LM, Carbone A. Mutations of CD79A, CD79B and EZH2 genes in immunodeficiency-related non-Hodgkin lymphomas. Br J Haematol 2011; 152:777-80. [PMID: 21275949 DOI: 10.1111/j.1365-2141.2010.08445.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Genome-wide DNA profiling of marginal zone lymphomas identifies subtype-specific lesions with an impact on the clinical outcome. Blood 2010; 117:1595-604. [PMID: 21115979 DOI: 10.1182/blood-2010-01-264275] [Citation(s) in RCA: 132] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Marginal zone B-cell lymphomas (MZLs) have been divided into 3 distinct subtypes (extranodal MZLs of mucosa-associated lymphoid tissue [MALT] type, nodal MZLs, and splenic MZLs). Nevertheless, the relationship between the subtypes is still unclear. We performed a comprehensive analysis of genomic DNA copy number changes in a very large series of MZL cases with the aim of addressing this question. Samples from 218 MZL patients (25 nodal, 57 MALT, 134 splenic, and 2 not better specified MZLs) were analyzed with the Affymetrix Human Mapping 250K SNP arrays, and the data combined with matched gene expression in 33 of 218 cases. MALT lymphoma presented significantly more frequently gains at 3p, 6p, 18p, and del(6q23) (TNFAIP3/A20), whereas splenic MZLs was associated with del(7q31), del(8p). Nodal MZLs did not show statistically significant differences compared with MALT lymphoma while lacking the splenic MZLs-related 7q losses. Gains of 3q and 18q were common to all 3 subtypes. del(8p) was often present together with del(17p) (TP53). Although del(17p) did not determine a worse outcome and del(8p) was only of borderline significance, the presence of both deletions had a highly significant negative impact on the outcome of splenic MZLs.
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43
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Scandurra M, Mian M, Greiner TC, Rancoita PMV, De Campos CP, Chan WC, Vose JM, Chigrinova E, Inghirami G, Chiappella A, Baldini L, Ponzoni M, Ferreri AJM, Franceschetti S, Gaidano G, Montes-Moreno S, Piris MA, Facchetti F, Tucci A, Nomdedeu JF, Lazure T, Lambotte O, Uccella S, Pinotti G, Pruneri G, Martinelli G, Young KH, Tibiletti MG, Rinaldi A, Zucca E, Kwee I, Bertoni F. Genomic lesions associated with a different clinical outcome in diffuse large B-Cell lymphoma treated with R-CHOP-21. Br J Haematol 2010; 151:221-231. [PMID: 20813005 DOI: 10.1111/j.1365-2141.2010.08326.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Despite recent therapeutic improvements, the clinical course of diffuse large B-cell lymphoma (DLBCL) still differs considerably among patients. We conducted this retrospective multi-centre study to evaluate the impact of genomic aberrations detected using a high-density genome wide-single nucleotide polymorphism-based array on clinical outcome in a population of DLBCL patients treated with R-CHOP-21 (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 d). 166 DNA samples were analysed using the GeneChip Human Mapping 250K NspI. Genomic anomalies were analysed regarding their impact on the clinical course of 124 patients treated with R-CHOP-21. Unsupervised clustering was performed to identify genetically related subgroups of patients with different clinical outcomes. Twenty recurrent genetic lesions showed an impact on the clinical course. Loss of genomic material at 8p23.1 showed the strongest statistical significance and was associated with additional aberrations, such as 17p- and 15q-. Unsupervised clustering identified five DLBCL clusters with distinct genetic profiles, clinical characteristics and outcomes. Genetic features and clusters, associated with a different outcome in patients treated with R-CHOP, have been identified by arrayCGH.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal, Murine-Derived/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Chromosome Aberrations
- Chromosome Deletion
- Chromosomes, Human, Pair 8/genetics
- Comparative Genomic Hybridization
- Cyclophosphamide/administration & dosage
- Doxorubicin/administration & dosage
- Epidemiologic Methods
- Female
- Humans
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/genetics
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Prednisone/administration & dosage
- Rituximab
- Signal Transduction/genetics
- Treatment Outcome
- Vincristine/administration & dosage
- Young Adult
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Affiliation(s)
- Marta Scandurra
- Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
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