• WES coupled with RNA-seq of a large PBL cohort reveals genetic drivers of oncogenesis in RTK-RAS, NFκB and JAK/STAT signaling

  • Both the mutational landscape and SCNV data emphasize the distinctness of EBV+/EBV- PBL from both DLBCL and multiple myeloma

Plasmablastic-lymphoma (PBL) represents a clinically heterogeneous subtype of aggressive-B-cell-non-Hodgkin-lymphoma. Although targeted-sequencing-studies and a single-center whole-exome-sequencing (WES) study in HIV+ patients recently revealed several genes, associated with PBL-pathogenesis, the global mutational-landscape and transcriptional-profile of PBL remain elusive. To inform on disease-associated mutational-drivers, mutational-patterns and perturbed pathways in HIV+ and HIV-PBL we performed WES and transcriptome sequencing (RNA-seq) of 33 PBL-tumors. Integrative analysis of somatic-mutations and gene-expression-profiles were performed to acquire insights into the divergent genotype-phenotype-correlation in EBV+ and EBV-PBL. We describe a significant accumulation of mutations in the Janus-kinase-signal-transducer and transcription-activator (OSMR, STAT3, PIM1, SOCS1) as well as receptor tyrosine-kinase RAS-pathways (ERBB3, NRAS, PDGFRB, NTRK). We provide further evidence of frequent perturbance of nuclear-factor κB (NFκB) signaling (NFKB2, BTK). Induced pathways, identified by RNA-seq closely resemble the mutational-profile regarding alterations accentuated in IL-6/JAK/STAT-signaling, NFκB-activity and MYC-signaling. Moreover, class I-MHC mediated antigen-processing and cell-cycle-regulation were significantly impacted by the EBV-status. An almost exclusive upregulation of PI3K/AKT/MTOR-signaling in EBV+ PBL and a significantly induced expression of NTRK3 in concert with recurrent oncogenic-mutations in EBV- PBL, hints at specific therapeutically targetable-mechanism in PBL-subgroups. Our characterization of a mutational and transcriptomic-landscape in PBL, distinct from DLBCL and MM substantiates the pathobiological-independence of PBL in the spectrum of B-cell-malignancies and thereby refines the taxonomy for aggressive-lymphomas.

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