Genetic and phenotypic attributes of splenic marginal zone lymphoma
Bonfiglio, Ferdinando (Institute of Oncology Research, Bellinzona, Switzerland)
Bruscaggin, Alessio (Institute of Oncology Research, Bellinzona, Switzerland)
Guidetti, Francesca (Institute of Oncology Research, Bellinzona, Switzerland)
Terzi di Bergamo, Lodovico (Institute of Oncology Research, Bellinzona, Switzerland)
Faderl, Martin (Institute of Oncology Research, Bellinzona, Switzerland)
Spina, Valeria (Institute of Oncology Research, Bellinzona, Switzerland)
Condoluci, Adalgisa (Institute of Oncology Research, Bellinzona, Switzerland)
Bonomini, Luisella (International Extranodal Lymphoma Study Group, Bellinzona, Switzerland)
Forestieri, Gabriela (Institute of Oncology Research, Bellinzona, Switzerland)
Koch, Ricardo (Institute of Oncology Research, Bellinzona, Switzerland)
Piffaretti, Deborah (Institute of Oncology Research, Bellinzona, Switzerland)
Pini, Katia (Institute of Oncology Research, Bellinzona, Switzerland)
Pirosa, Maria Cristina (Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland)
Cittone, Micol Giulia (Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland)
Arribas, Alberto (Lymphoma Genomics, Institute of Oncology Research, Bellinzona, Switzerland)
Lucioni, Marco (Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, Pavia, Italy)
Ghilardi, Guido (Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.)
Wu, Wei (Institute of Oncology Research, Bellinzona, Switzerland)
Arcaini, Luca (University of Pavia, Pavia, Italy.)
Baptista, Maria Joao (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Bastidas-Mora, Gabriela (Hospital Clínic i Provincial de Barcelona)
Bea, Sílvia (Hospital Clínic i Provincial de Barcelona)
Boldorini, Renzo (University of Eastern Piedmont, Novara, Italy)
Broccoli, Alessandro (IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia Seràgnoli, Bologna, Italy.)
Buehler, Marco Matteo (University Hospital Zurich, Switzerland)
Canzonieri, Vincenzo (Pathology Unit, CRO Aviano National Cancer Institute, Aviano, Italy)
Cascione, Luciano (Institute of Oncology Research, Bellinzona, Switzerland)
Ceriani, Luca (Clinic of Nuclear Medicine and PET-CT Centre, Imaging Institute of Southern Switzerland, Bellinzona, Switzerland)
Cogliatti, Sergio (Institute of Pathology, Kantonsspital St Gallen, St Gallen, Switzerland)
Corradini, Paolo (Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy)
Derenzini, Enrico (European Institute of Oncology (IEO) IRCCS, Milan, Italy)
Devizzi, Liliana (Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy)
Dietrich, Sascha (University Hospital Heidelberg, Germany)
Elia, Angela Rita (Institute of Oncology Research, Bellinzona, Switzerland)
Facchetti, Fabio (Pathology Unit, Spedali Civili, Brescia, Italy)
Gaidano, Gianluca (University of Eastern Piedmont, Novara, Italy)
Garcia, Juan Fernando (MD Anderson Cancer Center, Madrid)
Gerber, Bernhard (Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland)
Ghia, Paolo (IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy)
Gomes da Silva, Maria (Instituto Português de Oncologia de Lisboa, Portugal)
Gritti, Giuseppe (Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy)
Guidetti, Anna (Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy)
Hitz, Felicitas (Kantonsspital St Gallen, St Gallen, Switzerland)
Inghirami, Giorgio (Weill Cornell Medical College, New York)
Ladetto, Marco (Azienda Ospedaliera SS Antonio e Biagio, Alessandria, Italy)
Lopez-Guillermo, Armando (Hospital Clínic i Provincial de Barcelona)
Lucchini, Elisa (Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy)
Maiorana, Antonino (Universitá degli Studi di Modena e Reggio Emilia, Modena, Italy)
Marasca, Roberto (University of Modena and Reggio Emilia, Modena, Italy)
Matutes, Estella (Hospital Clínic i Provincial de Barcelona)
Meignin, Veronique (Saint Louis Hospital, Paris, France)
Merli, Michele (University of Insubria and ASST Sette Laghi, Ospedale di Circolo of Varese, Varese, Italy)
Moccia, Alden (Oncology Institute of Southern Switzerland, Bellinzona, Switzerland)
Mollejo, Manuela (Hospital Virgen de la Salud (Toledo))
Montalban, Carlos (MD Anderson Cancer Center, Madrid)
Novak, Urban (University of Bern, Bern, Switzerland)
Oscier, David Graham (University Hospitals Dorset, Bournemouth, United Kingdom)
Passamonti, Francesco (University of Insubria)
Piazza, Francesco (Ospedale Universitario di Padova, Italy)
Pizzolitto, Stefano (General Hospital S Maria della Misericordia, Udine, Italy)
Rambaldi, Alessandro (Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy)
Sabattini, Elena (University of Bologna, Italy)
Salles, Gilles (Université de Lyon, France)
Santambrogio, Elisa (Candiolo Cancer Institute (FPO-IRCCS), Candiolo, Turin, Italy)
Scarfò, Lydia (IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy)
Stathis, Anastasios (Oncology Institute of Southern Switzerland, Bellinzona, Switzerland)
Stüssi, Georg (Oncology Institute of Southern Switzerland, Bellinzona, Switzerland)
Geyer, Julia T. (Weill Cornell Medical College, New York)
Tapia, G. (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Tarella, Corrado (European Institute of Oncology (IEO) IRCCS, Milan, Italy)
Thieblemont, Catherine (Université de Paris, France)
Tousseyn, Thomas (University Hospitals Leuven, Belgium)
Tucci, Alessandra (Spedali Civili, Brescia, Italy.)
Vanini, Giorgio (University of Bern, Switzerland)
Visco, Carlo (University of Verona, Italy)
Vitolo, Umberto (Candiolo Cancer Institute (FPO-IRCCS), Candiolo, Turin, Italy)
Walewska, Renata (University Hospitals Dorset, Bournemouth, United Kingdom)
Zaja, Francesco (Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy)
Zenz, Thorsten (University Hospital Zurich, Switzerland)
Zinzani, Pier Luigi (Università di Bologna, Italy)
Khiabanian, Hossein (Rutgers University, New Brunswick)
Calcinotto, Arianna (Institute of Oncology Research, Bellinzona, Switzerland)
Bertoni, Francesco (Institute of Oncology Research, Bellinzona, Switzerland)
Bhagat, Govind (Columbia University, New York, USA)
Campo, Elias (Hospital Clínic i Provincial de Barcelona)
de Leval, Laurence (Institut Universitaire de Pathologie, Lausanne, Switzerland)
Dirnhofer, Stefan (University Hospital Basel (Basilea, Suïssa))
Pileri, Stefano A. (European Institute of Oncology IRCCS, Milan, Italy)
Piris, Miguel Angel (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) Madrid)
Traverse-Glehen, Alexandra (Centre Hospitalier Lyon Sud, Lyon, France)
Tzankov, Alexander (University Hospital Basel (Basilea, Suïssa))
Paulli, Marco (Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, Italy)
Ponzoni, Maurilio (Ateneo Vita-Salute San Raffaele University and Pathology Unit San Raffaele Scientific Institute, Milan, Italy)
Mazzucchelli, Luca (antonal Institute of Pathology, Locarno, Switzerland)
Cavalli, Franco (Institute of Oncology Research, Bellinzona, Switzerland; and.)
Zucca, Emanuele (International Extranodal Lymphoma Study Group, Bellinzona, Switzerland)
Rossi, Davide (Oncology Institute of Southern Switzerland, Bellinzona, Switzerland)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	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 in genetically modified mouse models, 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.
Ajuts:	European Commission. Horizon 2020 772051
Nota:	Altres ajuts: Swiss Cancer Research, ID 3746, 4395, 4660, and 4705; Swiss National Science Foundation, ID
Drets:	Tots els drets reservats.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Blood, Vol. 139 Núm. 5 (february 2022) , p. 732-747, ISSN 1528-0020

DOI: 10.1182/blood.2021012386

16 p, 3.8 MB

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