Genetic and phenotypic attributes of splenic marginal zone lymphoma

  • Ferdinando Bonfiglio
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Alessio Bruscaggin
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Francesca Guidetti
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Lodovico Terzi di Bergamo
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Martin Faderl
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Valeria Spina
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Adalgisa Condoluci
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Luisella Bonomini
    International Extranodal Lymphoma Study Group, Bellinzona, Switzerland;
  • Gabriela Forestieri
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Ricardo Koch
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Deborah Piffaretti
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Katia Pini
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Maria Cristina Pirosa
    Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
  • Micol Giulia Cittone
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Alberto Arribas
    Lymphoma Genomics, Institute of Oncology Research, Bellinzona, Switzerland;
  • Marco Lucioni
    Unit of Anatomic Pathology, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, Pavia, Italy;
  • Guido Ghilardi
    Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
  • Wei Wu
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;
  • Luca Arcaini
    Division of Hematology, Fondazione IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy;
  • Maria Joao Baptista
    Lymphoid Neoplasms Group, Josep Carreras Leukaemia Research Institute, Badalona, Spain;
  • Gabriela Bastidas
    Division of Hematology, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain;
  • Silvia Bea
    Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS),
  • Renzo Boldorini
    Division of Pathology, University of Eastern Piedmont, Novara, Italy;
  • Alessandro Broccoli
    IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia Seràgnoli, Bologna, Italy;
  • Marco Matteo Buehler
    Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland;
  • Vincenzo Canzonieri
    Pathology Unit, CRO Aviano National Cancer Institute, Aviano, Italy;
  • Luciano Cascione
    Lymphoma Genomics, Institute of Oncology Research, Bellinzona, Switzerland;
  • Luca Ceriani
    Clinic of Nuclear Medicine and PET-CT Centre, Imaging Institute of Southern Switzerland, Bellinzona, Switzerland;
  • Sergio Cogliatti
    Institute of Pathology, Kantonsspital St Gallen, St Gallen, Switzerland;
  • Paolo Corradini
    Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy;
  • Enrico Derenzini
    Onco-hematology Division, European Institute of Oncology (IEO) IRCCS, Milan, Italy;
  • Liliana Devizzi
    Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy;
  • Sascha Dietrich
    Division of Hematology, University Hospital Heidelberg, Heidelberg, Germany;
  • Angela Rita Elia
    Cancer Immunotherapy, Institute of Oncology Research, Bellinzona, Switzerland;
  • Fabio Facchetti
    Department of Molecular and Translational Medicine, Pathology Unit, Spedali Civili, Brescia, Italy;
  • Gianluca Gaidano
    Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy;
  • Juan Fernando Garcia
    Division of Pathology, MD Anderson Cancer Center, Madrid, Spain;
  • Bernhard Gerber
    Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
  • Paolo Ghia
    Strategic Research Program on Chronic Lymphocytic Leukemia (CLL), IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy;
  • Maria Gomes da Silva
    Division of Hematology, Instituto Português de Oncologia de Lisboa, Lisbon, Portugal;
  • Giuseppe Gritti
    Division of Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy;
  • Anna Guidetti
    Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy;
  • Felicitas Hitz
    Division of Hematology, Kantonsspital St Gallen, St Gallen, Switzerland;
  • Giorgio Inghirami
    Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
  • Marco Ladetto
    Division of Hematology, Azienda Ospedaliera SS Antonio e Biagio, Alessandria, Italy;
  • Armando Lopez-Guillermo
    Division of Lymphoid Neoplasms, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain;
  • Elisa Lucchini
    Division of Hematology, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy;
  • Antonino Maiorana
    Division of Pathology, Universitá degli Studi di Modena e Reggio Emilia, Modena, Italy;
  • Roberto Marasca
    Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy;
  • Estella Matutes
    Haematopathology Unit, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain;
  • Veronique Meignin
    Division of Pathology, Saint Louis Hospital, Paris, France;
  • Michele Merli
    Division of Hematology, University of Insubria and ASST Sette Laghi, Ospedale di Circolo of Varese, Varese, Italy;
  • Alden Moccia
    Clinic of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
  • Manuela Mollejo
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) 28029, Madrid, Spain;
  • Carlos Montalban
    Division of Hematology, MD Anderson Cancer Center, Madrid, Spain;
  • Urban Novak
    Department of Medical Oncology and University Cancer Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland;
  • David Graham Oscier
    Division of Hematology, University Hospitals Dorset, Bournemouth, United Kingdom;
  • Francesco Passamonti
    Department of Medicine and Surgery, University of Insubria and ASST Sette Laghi, Ospedale di Circolo of Varese, Varese, Italy;
  • Francesco Piazza
    Division of Hematology, Ospedale Universitario di Padova, Padova, Italy;
  • Stefano Pizzolitto
    Division of Pathology, General Hospital S Maria della Misericordia, Udine, Italy;
  • Alessandro Rambaldi
    Division of Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy;
  • Elena Sabattini
    Haematopathology Unit, Department of Experimental Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy;
  • Gilles Salles
    Faculté de Médecine et de Maïeutique Lyon Sud, Université de Lyon, Lyon, France;
  • Elisa Santambrogio
    Candiolo Cancer Institute (FPO-IRCCS), Candiolo, Turin, Italy;
  • Lydia Scarfò
    Strategic Research Program on Chronic Lymphocytic Leukemia (CLL), IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy;
  • Anastasios Stathis
    Clinic of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
  • Georg Stüssi
    Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
  • Julia T. Geyer
    Division of Anatomic Pathology and Clinical Pathology, Weill Cornell Medical College, New York, NY;
  • Gustavo Tapia
    Division of Pathology, Hospital Germans Trias I Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain;
  • Corrado Tarella
    Onco-hematology Division, European Institute of Oncology (IEO) IRCCS, Milan, Italy;
  • Catherine Thieblemont
    Assistance Publique–Hôpitaux de Paris, Hopital Saint-Louis, Hemato-Oncology Unit; Université de Paris, Paris, France;
  • Thomas Tousseyn
    Department of Haematology, University Hospitals Leuven, Leuven, Belgium;
  • Alessandra Tucci
    Division of Hematology, Spedali Civili, Brescia, Italy;
  • Giorgio Vanini
    Department of Medical Oncology and University Cancer Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland;
  • Carlo Visco
    Department of Medicine, Section of Hematology, University of Verona, Italy;
  • Umberto Vitolo
    Candiolo Cancer Institute (FPO-IRCCS), Candiolo, Turin, Italy;
  • Renata Walewska
    Division of Hematology, University Hospitals Dorset, Bournemouth, United Kingdom;
  • Francesco Zaja
    Division of Hematology, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy;
  • Thorsten Zenz
    Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland;
  • Pier Luigi Zinzani
    IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia Seràgnoli, Bologna, Italy;
  • Hossein Khiabanian
    Center for Systems and Computational Biology, Rutgers University, New Brunswick, NJ;
  • Arianna Calcinotto
    Cancer Immunotherapy, Institute of Oncology Research, Bellinzona, Switzerland;
  • Francesco Bertoni
    Lymphoma Genomics, Institute of Oncology Research, Bellinzona, Switzerland;
  • Govind Bhagat
    Department of Pathology and Cell Biology, Columbia University, New York, NY;
  • Elias Campo
    Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS),
  • Laurence De Leval
    Division of Pathology, Institut Universitaire de Pathologie, Lausanne, Switzerland;
  • Stefan Dirnhofer
    Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland;
  • Stefano A. Pileri
    Haematopathology Division, European Institute of Oncology IRCCS, Milan, Italy;
  • Miguel A. Piris
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) 28029, Madrid, Spain;
  • Alexandra Traverse-Glehen
    Division of Pathology, Centre Hospitalier Lyon Sud, Lyon, France;
  • Alexander Tzankov
    Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland;
  • Marco Paulli
    Unit of Anatomic Pathology, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, Pavia, Italy;
  • Maurilio Ponzoni
    Ateneo Vita-Salute San Raffaele University and Pathology Unit San Raffaele Scientific Institute, Milan, Italy;
  • Luca Mazzucchelli
    Division of Pathology, Cantonal Institute of Pathology, Locarno, Switzerland;
  • Franco Cavalli
    Institute of Oncology Research, Bellinzona, Switzerland; and
  • Emanuele Zucca
    International Extranodal Lymphoma Study Group, Bellinzona, Switzerland;
  • Davide Rossi
    Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;

抄録

<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>

収録刊行物

  • Blood

    Blood 139 (5), 732-747, 2022-02-03

    American Society of Hematology

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