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Pathogenesis of Diffuse Large B-cell Lymphoma Proteogenotypes

ABSTRACT: The clinical and molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) is incompletely understood. By integrating proteomic, transcriptomic and genomic data from 478 DLBCL tumors, we identify seven DLBCL proteogenotypes (PGs) reflecting specific pathophysiological features and spanning cell-of-origin (COO) as well as genetic subtypes. PG4 is associated with poor outcome, independent of known risk factors including COO, genetic features or the international prognostic index. PG4 is enriched for subsets of activated B-cell-like DLBCL, germinal-center-B-cell-like tumors and genetically unclassified cases. It shares a dark-zone related B-cell phenotype and an enrichment of BTG1 and TBL1XR1 mutations. Single-cell sequencing and spatial transcriptomics further reveals enhanced MYC and TCF3/4 transcriptional activity while MYC translocations were absent, as well as exhausted CD8 T cells as common driver mechanisms in PG4. Our proteogenomic framework identifies heretofore unknown biological heterogeneity among DLBCL tumors, including high-risk proteogenomic features that provide a basis for innovative diagnostic and therapeutic approaches.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324977 | GEO | 2026/03/31

REPOSITORIES: GEO

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Project description:Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal lymphoma subtype. This retrospective study elucidates the currently unknown genetic background of a large clinically well-annotated cohort of DLBCL with osseous localizations (O-DLBCL), including PB-DLBCL. 103 O-DLBCL patients were included and compared with 63 (extra)nodal non-osseous (NO)-DLBCLs with germinal center B-cell phenotype (NO-DLBCL-GCB). Cell-of-origin (COO) was determined by immunohistochemistry and gene-expression-profiling (GEP) using (extended)-NanoString/Lymph2Cx. Mutational profiles were identified with targeted next-generation deep-sequencing, including 52 B-cell lymphoma-relevant genes. O-DLBCLs, including 34 PB-DLBCL, were predominantly classified as GCB-phenotype based on immunohistochemistry (74%) and NanoString analysis (88%). Unsupervised hierarchical clustering of an extended-NanoString/Lymph2Cx demonstrated significantly different GEP-clusters for PB-DLBCL as opposed to NO-DLBCL-GCB (P<0.001). Expression levels of 23 genes of two different targeted GEP-panels, indicated a centrocyte–like phenotype for PB-DLBCL, whereas NO-DLBCL-GCB showed a centroblast-like constitution. PB-DLBCL had significantly more frequent mutations in four GCB-associated genes, i.e. B2M, EZH2, IRF8, and TNFRSF14, compared to NO-DLBCL-GCB (P=0.031, P=0.010, P=0.047, and P=0.003). PB-DLBCL with its corresponding specific mutational profile were significantly associated with a superior overall survival compared to equivalent Ann Arbor limited-stage I/II NO-DLBCL-GCB (P=0.011). This study is the first to demonstrate that PB-DLBCL is characterized by a GCB-phenotype, with a centrocyte-like GEP-pattern and a GCB-associated mutational profile (both involved in immune surveillance) and a favorable prognosis. These novel biology-associated features provide evidence that PB-DLBCL represents a distinct extranodal DLBCL entity and its specific mutational landscape holds potential for targeted therapies (e.g. EZH2-inhibitors). The NanoString analsyis consisted out of 219 probes for Lymph2Cx classifier (COO), MYC-activity GEP score, CNV-associated GEP signature, consensus clustering, and immune-ratio signature. This custome probeset was used to differentiate GEPs between osseous and non-osseos DLBCL of the GCB-phenotype.

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Pathogenesis of Diffuse Large B-cell Lymphoma Proteogenotypes

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