Genetic and phenotypic attributes of splenic marginal zone lymphoma
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- Ferdinando Bonfiglio
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Alessio Bruscaggin
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Francesca Guidetti
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Lodovico Terzi di Bergamo
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Martin Faderl
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Valeria Spina
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Adalgisa Condoluci
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Luisella Bonomini
- International Extranodal Lymphoma Study Group, Bellinzona, Switzerland;
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- Gabriela Forestieri
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Ricardo Koch
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Deborah Piffaretti
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Katia Pini
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Maria Cristina Pirosa
- Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
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- Micol Giulia Cittone
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Alberto Arribas
- Lymphoma Genomics, Institute of Oncology Research, Bellinzona, Switzerland;
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- Marco Lucioni
- Unit of Anatomic Pathology, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, Pavia, Italy;
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- Guido Ghilardi
- Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
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- Wei Wu
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
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- Luca Arcaini
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy;
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- Maria Joao Baptista
- Lymphoid Neoplasms Group, Josep Carreras Leukaemia Research Institute, Badalona, Spain;
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- Gabriela Bastidas
- Division of Hematology, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain;
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- Silvia Bea
- Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS),
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- Renzo Boldorini
- Division of Pathology, University of Eastern Piedmont, Novara, Italy;
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- Alessandro Broccoli
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia Seràgnoli, Bologna, Italy;
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- Marco Matteo Buehler
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland;
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- Vincenzo Canzonieri
- Pathology Unit, CRO Aviano National Cancer Institute, Aviano, Italy;
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- Luciano Cascione
- Lymphoma Genomics, Institute of Oncology Research, Bellinzona, Switzerland;
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- Luca Ceriani
- Clinic of Nuclear Medicine and PET-CT Centre, Imaging Institute of Southern Switzerland, Bellinzona, Switzerland;
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- Sergio Cogliatti
- Institute of Pathology, Kantonsspital St Gallen, St Gallen, Switzerland;
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- Paolo Corradini
- Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy;
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- Enrico Derenzini
- Onco-hematology Division, European Institute of Oncology (IEO) IRCCS, Milan, Italy;
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- Liliana Devizzi
- Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy;
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- Sascha Dietrich
- Division of Hematology, University Hospital Heidelberg, Heidelberg, Germany;
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- Angela Rita Elia
- Cancer Immunotherapy, Institute of Oncology Research, Bellinzona, Switzerland;
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- Fabio Facchetti
- Department of Molecular and Translational Medicine, Pathology Unit, Spedali Civili, Brescia, Italy;
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- Gianluca Gaidano
- Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy;
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- Juan Fernando Garcia
- Division of Pathology, MD Anderson Cancer Center, Madrid, Spain;
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- Bernhard Gerber
- Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
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- Paolo Ghia
- Strategic Research Program on Chronic Lymphocytic Leukemia (CLL), IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy;
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- Maria Gomes da Silva
- Division of Hematology, Instituto Português de Oncologia de Lisboa, Lisbon, Portugal;
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- Giuseppe Gritti
- Division of Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy;
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- Anna Guidetti
- Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy;
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- Felicitas Hitz
- Division of Hematology, Kantonsspital St Gallen, St Gallen, Switzerland;
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- Giorgio Inghirami
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
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- Marco Ladetto
- Division of Hematology, Azienda Ospedaliera SS Antonio e Biagio, Alessandria, Italy;
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- Armando Lopez-Guillermo
- Division of Lymphoid Neoplasms, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain;
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- Elisa Lucchini
- Division of Hematology, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy;
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- Antonino Maiorana
- Division of Pathology, Universitá degli Studi di Modena e Reggio Emilia, Modena, Italy;
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- Roberto Marasca
- Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy;
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- Estella Matutes
- Haematopathology Unit, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain;
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- Veronique Meignin
- Division of Pathology, Saint Louis Hospital, Paris, France;
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- Michele Merli
- Division of Hematology, University of Insubria and ASST Sette Laghi, Ospedale di Circolo of Varese, Varese, Italy;
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- Alden Moccia
- Clinic of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
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- Manuela Mollejo
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) 28029, Madrid, Spain;
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- Carlos Montalban
- Division of Hematology, MD Anderson Cancer Center, Madrid, Spain;
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- Urban Novak
- Department of Medical Oncology and University Cancer Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland;
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- David Graham Oscier
- Division of Hematology, University Hospitals Dorset, Bournemouth, United Kingdom;
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- Francesco Passamonti
- Department of Medicine and Surgery, University of Insubria and ASST Sette Laghi, Ospedale di Circolo of Varese, Varese, Italy;
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- Francesco Piazza
- Division of Hematology, Ospedale Universitario di Padova, Padova, Italy;
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- Stefano Pizzolitto
- Division of Pathology, General Hospital S Maria della Misericordia, Udine, Italy;
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- Alessandro Rambaldi
- Division of Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy;
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- Elena Sabattini
- Haematopathology Unit, Department of Experimental Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy;
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- Gilles Salles
- Faculté de Médecine et de Maïeutique Lyon Sud, Université de Lyon, Lyon, France;
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- Elisa Santambrogio
- Candiolo Cancer Institute (FPO-IRCCS), Candiolo, Turin, Italy;
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- Lydia Scarfò
- Strategic Research Program on Chronic Lymphocytic Leukemia (CLL), IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy;
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- Anastasios Stathis
- Clinic of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
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- Georg Stüssi
- Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
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- Julia T. Geyer
- Division of Anatomic Pathology and Clinical Pathology, Weill Cornell Medical College, New York, NY;
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- Gustavo Tapia
- Division of Pathology, Hospital Germans Trias I Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain;
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- Corrado Tarella
- Onco-hematology Division, European Institute of Oncology (IEO) IRCCS, Milan, Italy;
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- Catherine Thieblemont
- Assistance Publique–Hôpitaux de Paris, Hopital Saint-Louis, Hemato-Oncology Unit; Université de Paris, Paris, France;
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- Thomas Tousseyn
- Department of Haematology, University Hospitals Leuven, Leuven, Belgium;
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- Alessandra Tucci
- Division of Hematology, Spedali Civili, Brescia, Italy;
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- Giorgio Vanini
- Department of Medical Oncology and University Cancer Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland;
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- Carlo Visco
- Department of Medicine, Section of Hematology, University of Verona, Italy;
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- Umberto Vitolo
- Candiolo Cancer Institute (FPO-IRCCS), Candiolo, Turin, Italy;
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- Renata Walewska
- Division of Hematology, University Hospitals Dorset, Bournemouth, United Kingdom;
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- Francesco Zaja
- Division of Hematology, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy;
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- Thorsten Zenz
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland;
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- Pier Luigi Zinzani
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia Seràgnoli, Bologna, Italy;
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- Hossein Khiabanian
- Center for Systems and Computational Biology, Rutgers University, New Brunswick, NJ;
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- Arianna Calcinotto
- Cancer Immunotherapy, Institute of Oncology Research, Bellinzona, Switzerland;
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- Francesco Bertoni
- Lymphoma Genomics, Institute of Oncology Research, Bellinzona, Switzerland;
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- Govind Bhagat
- Department of Pathology and Cell Biology, Columbia University, New York, NY;
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- Elias Campo
- Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS),
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- Laurence De Leval
- Division of Pathology, Institut Universitaire de Pathologie, Lausanne, Switzerland;
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- Stefan Dirnhofer
- Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland;
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- Stefano A. Pileri
- Haematopathology Division, European Institute of Oncology IRCCS, Milan, Italy;
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- Miguel A. Piris
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) 28029, Madrid, Spain;
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- Alexandra Traverse-Glehen
- Division of Pathology, Centre Hospitalier Lyon Sud, Lyon, France;
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- Alexander Tzankov
- Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland;
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- Marco Paulli
- Unit of Anatomic Pathology, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, Pavia, Italy;
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- Maurilio Ponzoni
- Ateneo Vita-Salute San Raffaele University and Pathology Unit San Raffaele Scientific Institute, Milan, Italy;
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- Luca Mazzucchelli
- Division of Pathology, Cantonal Institute of Pathology, Locarno, Switzerland;
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- Franco Cavalli
- Institute of Oncology Research, Bellinzona, Switzerland; and
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- Emanuele Zucca
- International Extranodal Lymphoma Study Group, Bellinzona, Switzerland;
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- Davide Rossi
- Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
Abstract
<jats:title>Abstract</jats:title> <jats:p>Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.</jats:p>
Journal
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- Blood
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Blood 139 (5), 732-747, 2022-02-03
American Society of Hematology
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Details 詳細情報について
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- CRID
- 1360017286988748672
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- ISSN
- 15280020
- 00064971
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- Data Source
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- Crossref