Clinical and genomic impact of TP53 and BCL2 co-alterations in diffuse large B-cell lymphoma

Abstract Background Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with both clinical and genetic variability. Mutations in TP53 and BCL2 have each been independently linked to worse outcomes, but limited large-scale data exist evaluating the combined effect of these alterations. Although it may be expected that dual alterations would result in more aggressive disease, this association has not been thoroughly examined in a large patient cohort. This study utilizes publicly available genomic data from cBioPortal to evaluate the clinical characteristics, survival outcomes, and genomic features of DLBCL patients with TP53 and/or BCL2 mutations, aiming to identify high-risk subgroups who may benefit from closer monitoring or alternative therapeutic approaches. Methods: We analyzed 1,638 DLBCL cases from five published studies using data from cBioPortal. Patients were grouped by TP53 and BCL2 mutation status: TP53 altered versus unaltered, BCL2 altered versus unaltered, and both TP53 and BCL2 altered versus unaltered. We compared clinical and genomic features across these groups, including tumor mutational burden (TMB), mutation count, fraction of genome altered, number of driver SCNAs, prognostic risk classification, and overall survival. We also examined the frequency of co-occurring gene mutations to identify patterns that might contribute to differences in disease behavior. Results: Patients with concurrent TP53 and BCL2 alterations presented at an older age compared to those without either mutation (mean 68.4 vs. 60.7 years, p = 0.0309). All altered groups had higher tumor mutational burden (TMB) relative to unaltered cases, with the dual-altered group showing the highest burden (1.1 vs. 0.8, p < 10⁻¹⁰). This group also had elevated mutation counts (32.9 vs. 24.6, p = 1.318e-4) and a greater fraction of genome altered (0.22 vs. 0.14, p = 1.318e-4). The number of driver SCNAs was significantly higher in TP53-altered (16.3 vs. 8.3, p = 9.46e-7) and dual-altered cases (17.1 vs. 7.5, p = 6.66e-4). Prognostic modeling classified more dual-altered patients as high risk compared to unaltered cases (80% vs. 37.6%, p = 0.0159). In survival analysis, TP53-altered patients had significantly shorter overall survival than unaltered patients (median 63.5 vs. 109.9 months, p = 2.15e-4). BCL2 alteration alone was not associated with a significant difference in survival (p = 0.279), while dual-altered patients had worse survival than unaltered cases (log-rank p = 0.0392). Gene mutation profiling revealed enrichment of KMT2D (40.2%) and CREBBP (25.7%) mutations in TP53-altered cases, with similar enrichment in BCL2-altered tumors. Dual-altered cases had the highest frequencies of both KMT2D (57.6%) and CREBBP (50.0%) mutations and were also enriched for TNFRSF14 mutations (30.3%). Conclusion This study demonstrates that patients with concurrent TP53 and BCL2 mutations exhibit significantly worse overall survival and more aggressive genomic profiles compared to those with single or no alterations. While this association may be anticipated, our analysis confirms it in a large dataset and identifies additional co-occurring mutations, particularly KMT2D, CREBBP, and TNFRSF14, that may contribute to disease progression. These findings suggest that tumor suppressor loss and epigenetic dysregulation could work together to drive more aggressive disease. Our results support the clinical utility of molecular profiling in DLBCL to guide risk stratification, identify patients who may benefit from closer follow-up, and inform decisions about enrollment in clinical trials exploring targeted or novel therapies.