Integrative genomic and transcriptomic analysis in plasmablastic lymphoma identifies disruption of key regulatory pathways

Abstract

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.

Targeting CD38 with Daratumumab Plus Chemotherapy for Patients with Advanced-Stage Plasmablastoid Large B-Cell Lymphoma

“…Several recent studies performing whole-exome sequencings have identified the disruption of several key regulatory pathways including JAK-STAT3, RAS-MAPK and non-canonical NF-kB signaling in PBL [ 30 ]. Gain-of-function JAK/STAT signaling was found in 64% of PBL cases, while RTK-RAS signaling and NF-kB signaling were found in 76% and 58% of patients, respectively.…”

“…There also appears to be a difference in mutational landscape based on the EBV status of PBL patients, with EBV- patients having higher mutational and copy-number loads and more frequent TP53 , MYC and CARD11 mutations and EBV+ patients having more mutations that disrupt the JAK-STAT pathway [ 31 ]. MYC status had no correlation with OS or PFS and no bearing on the number of mutations [ 30 ]. Furthermore, there was no correlation between MYC rearrangement and EBV status [ 30 ].…”

“…MYC status had no correlation with OS or PFS and no bearing on the number of mutations [ 30 ]. Furthermore, there was no correlation between MYC rearrangement and EBV status [ 30 ]. Comparing the mutational signature of PBL with DLBCL, there were three common candidate drivers ( TP53 , PRDM1 and HIST1H1E ) and five common genes ( PIM1 , BTG1 , CD79B , ETS1 and STAT3 ).…”

“…Comparing the mutational signature of PBL with DLBCL, there were three common candidate drivers ( TP53 , PRDM1 and HIST1H1E ) and five common genes ( PIM1 , BTG1 , CD79B , ETS1 and STAT3 ). In addition, there is one common gene between PBL and MM ( NRAS ) [ 30 ].…”

Integrative molecular profiling identifies two molecularly and clinically distinct subtypes of blastic plasmacytoid dendritic cell neoplasm

“…Genomic DNA and RNA were extracted from three 5µm FFPE tissue sections of either tumor or normal tissue (where available; n = 3) employing Maxwell® RSC DNA FFPE kit and Maxwell® RSC RNA FFPE kit (both Promega). WES and RNA-Seq following library preparation using Agilent SureSelect Human All Exon V6 library preparation kit (Agilent Technologies) and NEBNext® UltraT Directional RNA Library Prep Kit (New England BioLabs), respectively were performed on a NovaSeq platform (Illumina) at Novogene (UK) Co. as described 21 . Tumor whole exome libraries were sequenced to a median depth of 119x (mean 129 ± 54 s.d.)…”