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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]

Introduction: Formalin-fixed paraffin-embedded (FFPE) tumor biopsy is the current mainstay of genotyping, but is limited by its invasiveness and tumor heterogeneity. Plasma cell-free DNA (cfDNA) constitutes a minimally invasive alternative that may better capture tumor-derived profiles from circulating tumor DNA (ctDNA). This study compares the performance and genomic concordance of cfDNA and FFPE tumor DNA in aggressive non-Hodgkin large B-cell lymphoma., Methods: Paired diagnostic FFPE tissue and plasma samples from 15 patients were sequenced with a custom 53-gene panel., Results: Detection thresholds were empirically guided at 1% variant allele frequency (VAF) for cfDNA and 10% for unpaired FFPE DNA. The median number of cfDNA variants was 6 (interquartile range (IQR): 2-11) versus 63 (IQR: 15-250) in FFPE DNA at 1% VAF. Collectively, 102 somatic variants were shared between cfDNA and FFPE DNA with a median of 5 (range: 0-23). cfDNA showed a five-fold lower median VAF for shared variants than FFPE DNA (7% vs. 36%, p < 0.0001). Eighty percent of patients harbored at least one cfDNA variant. A maximum cfDNA recall rate of 83% was observed at FFPE DNA VAF > 50%. COSMIC database overlap was twice as high for cfDNA compared to FFPE DNA (22% vs. 11%) at 10% VAF., Conclusion: cfDNA has superior specificity for somatic mutation detection but lower sensitivity than FFPE DNA. Modest concordance was demonstrated between the two compartments. Our results support a complementary role of ctDNA in mutational profiling at a 1% VAF threshold in a pragmatic and clinically applicable setup., (© 2025 The Author(s). International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)