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ABSTRACT Introduction Methods Results Conclusion Diffuse large B‐cell lymphoma (DLBCL) exhibits striking clinical and biological heterogeneity. Recent studies have identified new subgroups within germinal center B‐cell like (GCB) DLBCL, associated with inferior prognosis, irrespective of MYC and BCL2 translocations. We explored the existence of such a DLBCL high‐risk subgroup, based on multilevel aberrations, especially focusing on MYC and BCL2.Tissue samples from 111 DLBCL patients were sequenced with a 90‐gene lymphoma panel, followed by integrative analyses combining sequencing data, immunohistochemistry, fluorescent in situ hybridization, and clinical data.We identified a high‐risk subgroup in DLBCL defined by: dual immunohistochemical MYC and BCL2 expression (DEL), concurrent MYC and BCL2 translocations (DHL‐BCL2), mutations in MYC, CXCR4, or both, and/or BCL2 amplification. The high‐risk subgroup constituted 41% of the cohort and included DHL‐BCL2, DEL, a GCB subgroup likely representing the recently described GCB subgroups, and a subset of non‐GCB patients. In multivariate analysis, high‐risk features provided independent predictive value from age and IPI. The 5‐year overall survival was 36% in high‐risk patients, compared to 76% in non‐high‐risk patients.We identified a distinct high‐risk DLBCL subgroup, characterized by MYC and BCL2 aberrations, beyond conventional DHL‐BCL2 and DEL, and irrespective of cell‐of‐origin, thereby expanding the poor‐prognosis group. [ABSTRACT FROM AUTHOR]