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• W3177381657 abstract "Introduction: Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous entity. The clinical course is variable, mutated genes are multiple with no unifying mechanism, essential regulatory pathways and surrounding microenvironments are diverse. We sought to provide a unifying view of SMZL by resolving its heterogeneity in subgroups sharing genomic abnormalities, pathway signatures and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. Methods: We studied 303 pathologically confirmed SMZL spleen samples collected through the IELSG46 multicenter, international study (NCT02945319). The study cohort was representative of SMZL in terms of demographics, clinical features and outcome. We carried out a genetic and phenotypic analysis, defined self-organized signatures, validated them in independent primary tumors meta-data and in genetically modified mouse models, and correlated them with outcome data. Results: We identified and validated two prominent and self-aggregating genetic clusters in SMZL, termed NNK (58% of cases, from NF-kB, NOTCH and KLF2 modules) and DMT (32% of cases, from DNA-damage response, MAPK and TLR modules). NNK-SMZLs were dominated by mutations of NF-κB (e.g., TNFAIP3, TRAF3, BIRC3), NOTCH (e.g., NOTCH2, NOTCH1, SPEN) and KLF2. DMT-SMZLs were characterized by mutations in DNA damage response pathway genes (e.g., TP53, ATM). Mutations in MAPK (e.g., BRAF) and TLR genes (e.g., MYD88, all involving positions other than p.L265) were also enriched in DMT-SMZLs (Figure A and B). These genetic clusters have distinct underpinning biology. NNK-SMZLs were enriched of IGHV1-2*04 allele usage and of 7q deletion, while conversely DMT-SMZLs were depleted of both of them (Figure C). NNK-SMZL expressed significantly higher levels of genes belonging to NOTCH2 pathway and of genes that are activated by non-canonical NF-κB transcription factors. Conversely, DMT-SMZL had a signature of TP53 and apoptosis impairment (Figure D). Digital cytometry and in situ profiling segregated two basic types of SMZL immune microenvironment termed inflamed SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and non-inflamed SMZL (50% of cases) (Figure E and F). The combination of molecular and phenotypic profiling allowed to sort out a high risk clinical subset of patients whose tumor was characterized by having both NNK genotype and ‘’inflamed’’ microenvironment (Figure G). The research was funded by: Swiss Cancer League, ID 3746, 4395 4660, and 4705, Bern, Switzerland; Research Advisory Board of the Ente Ospedaliero Cantonale, ABREOC 2019-22514, Bellinzona, Switzerland; European Research Council (ERC) Consolidator Grant CLLCLONE, ID: 772051; Swiss National Science Foundation, ID 320030_169670/1, 310030_192439, 320036_179318, Berne, Switzerland; Fondazione Ticinese Contro il Cancro; Fondazione Fidinam, Lugano, Switzerland; Nelia & Amadeo Barletta Foundation, Lausanne, Switzerland; Fond’Action, Lausanne, Switzerland; The Leukemia & Lymphoma Society, Translational Research Program, ID 6594-20, New York; AFRI, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Fondazione Dr. Ettore Balli. Keywords: Diagnostic and Prognostic Biomarkers, Indolent non-Hodgkin lymphoma, Pathology and Classification of Lymphomas Conflicts of interests pertinent to the abstract P. Ghia Honoraria: AbbVie, ArQule/MSD, AstraZeneca, Beigene, Celgene/Juno(BMS, Gilead, Janssen, Loxo/Lilly, Roche Research funding: AbbVie, AstraZeneca, Gilead, Janssen, Sunesis G. Gritti Consultant or advisory role: Takeda, IQvia, Gilead Sciences Research funding: Gilead Sciences Educational grants: Roche, Abbvie, Gilead Sciences, Abbvie A. Moccia Consultant or advisory role: Roche, Janssen and Takeda L. Scarfó Honoraria: AbbVie, AstraZeneca and Janssen D. Rossi Honoraria: AbbVie, AstraZeneca, Janssen Research funding: AbbVie, AstraZeneca, Janssen" @default.
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• W3177381657 date "2021-06-01" @default.
• W3177381657 modified "2023-10-18" @default.
• W3177381657 title "GENETIC AND PHENOTYPIC ATTRIBUTES OF SPLENIC MARGINAL ZONE LYMPHOMA" @default.
• W3177381657 doi "https://doi.org/10.1002/hon.43_2879" @default.
• W3177381657 hasPublicationYear "2021" @default.
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