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Integrated genomics with refined cell-of-origin subtyping distinguishes subtype-specific mechanisms of treatment resistance and relapse in diffuse large B-cell lymphoma
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Integrated genomics with refined cell-of-origin subtyping distinguishes subtype-specific mechanisms of treatment resistance and relapse in diffuse large B-cell lymphoma
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Journal Article
Integrated genomics with refined cell-of-origin subtyping distinguishes subtype-specific mechanisms of treatment resistance and relapse in diffuse large B-cell lymphoma
2025
Overview
Up to 40% of diffuse large B-cell lymphoma (DLBCL) patients do not experience a durable response to frontline immunochemotherapy, and prospective identification of high-risk cases that may benefit from personalized therapeutic management remains an unmet need. Molecular phenotyping techniques have established a landscape of genomic variants in diagnostic DLBCL; however, these have not yet been applied in large-scale studies of relapsed/refractory DLBCL, resulting in incomplete characterization of mechanisms driving tumor progression and treatment resistance. Here, we performed an integrated multiomic analysis on 228 relapsed/refractory DLBCL samples, including 24 with serial biopsies. Refined cell-of-origin subtyping identified patients harboring GCB and DZsig+ relapsed/refractory tumors in cases with primary refractory disease with remarkably poor outcomes, and comparative analysis of genomic features between relapsed and diagnostic samples identified subtype-specific mechanisms of therapeutic resistance driven by frequent alteration to
MYC
,
BCL2
,
BCL6
, and
TP53
among additional strong lymphoma driver genes. Tumor evolution dynamics suggest innate mechanisms of chemoresistance are present in many DLBCL tumors at diagnosis, and that relapsed/refractory tumors are primarily comprised of a homogenous clonal expansion with reduced tumor microenvironment activity. Adaptation of personalized therapeutic strategies targeting DLBCL subtype-specific resistance mechanisms should be considered to benefit these high-risk populations.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 38/23
/ 45
/ 45/91
/ Adult
/ Aged
/ Biology
/ Biomarkers, Tumor - genetics
/ Biomedical and Life Sciences
/ Drug Resistance, Neoplasm - genetics
/ Female
/ Humans
/ Lymphoma
/ Lymphoma, Large B-Cell, Diffuse - drug therapy
/ Lymphoma, Large B-Cell, Diffuse - genetics
/ Lymphoma, Large B-Cell, Diffuse - pathology
/ Male
/ Mutation
/ Neoplasm Recurrence, Local - genetics
/ Neoplasm Recurrence, Local - pathology
/ Oncology
/ Patients
/ Tumors
