Genetic and phenotypic attributes of splenic marginal zone lymphoma
Authors: Bonfiglio Ferdinando , Bruscaggin Alessio , Guidetti Francesca , Terzi di Bergamo Lodovico , Faderl Martin , Spina Valeria , Condoluci Adalgisa , Bonomini Luisella , Forestieri Gabriela , Koch Ricardo , Piffaretti Deborah , Pini Katia , Pirosa Maria Cristina , Cittone Micol Giulia , Arribas Alberto , Lucioni Marco , Ghilardi Guido , Wu Wei , Arcaini Luca , Baptista Maria Joao , Bastidas Gabriela , Bea Silvia , Boldorini Renzo , Broccoli Alessandro , Buehler Marco Matteo , Canzonieri Vincenzo , Cascione Luciano , Ceriani Luca , Cogliatti Sergio , Corradini Paolo , Derenzini Enrico , Devizzi Liliana , Dietrich Sascha , Elia Angela Rita , Facchetti Fabio , Gaidano Gianluca , Garcia Juan Fernando , Gerber Bernhard , Ghia Paolo , Gomes da Silva Maria , Gritti Giuseppe , Guidetti Anna , Hitz Felicitas , Inghirami Giorgio , Ladetto Marco , Lopez-Guillermo Armando , Lucchini Elisa , Maiorana Antonino , Marasca Roberto , Matutes Estella , Meignin Veronique , Merli Michele , Moccia Alden , Mollejo Manuela , Montalban Carlos , Novak Urban , Oscier David Graham , Passamonti Francesco , Piazza Francesco , Pizzolitto Stefano , Rambaldi Alessandro , Sabattini Elena , Salles Gilles , Santambrogio Elisa , Scarfò Lydia , Stathis Anastasios , Stüssi Georg , Geyer Julia T. , Tapia Gustavo , Tarella Corrado , Thieblemont Catherine , Tousseyn Thomas , Tucci Alessandra , Vanini Giorgio , Visco Carlo , Vitolo Umberto , Walewska Renata , Zaja Francesco , Zenz Thorsten , Zinzani Pier Luigi , Khiabanian Hossein , Calcinotto Arianna , Bertoni Francesco , Bhagat Govind , Campo Elias , De Leval Laurence , Dirnhofer Stefan , Pileri Stefano A. , Piris Miguel A. , Traverse-Glehen Alexandra , Tzankov Alexander , Paulli Marco , Ponzoni Maurilio , Mazzucchelli Luca , Cavalli Franco , Zucca Emanuele , Rossi Davide 
Published: October 2021

Abstract
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.