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Cell of origin-specific genetic alterations and chromosomal instability have therapeutic and immunologic impact in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype worldwide, is a diverse disease with distinct molecular and clinical features in which ~40% of patients experience treatment failure. To understand the molecular distinctions and their therapeutic relevance specific to Cell-of-Origin (COO) in DLBCL, for the first time we performed an integrative genomic and transcriptomic analysis of biopsies from a large population registry-based cohort of uniformly treated patients with de novo DLBCL. We identified that NFATC1 amplification was significantly enriched in ABC-DLBCL with prognostic significance. Distinct impact of copy number alterations on PI3K-AKT signaling pathway gene expression was observed in GCB-DLBCL relative to ABC-DLBCL. Furthermore, deletions of INPP4B and PTEN (implicating disrupted PI3K-AKT signaling), as well as activated phosphorylation of AKT were indicators of poor prognosis in GCB-DLBCL, suggesting a potential therapeutic target in this subtype. Finally, genome-wide analysis revealed chromosomal instability stratifies clinically and genetically distinct subgroups in DLBCL, which were associated with distinct tumor immune microenvironments across COO subtypes.