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

• Published in: Blood advances 2022-01, Vol.6 (2), p.637-651
• Main Authors: Witte, Hanno M., Künstner, Axel, Hertel, Nadine, Bernd, Heinz-Wolfram, Bernard, Veronica, Stölting, Stephanie, Merz, Hartmut, von Bubnoff, Nikolas, Busch, Hauke, Feller, Alfred C., Gebauer, Niklas
• Format: Article
• Language: English
• Subjects: Epstein-Barr Virus Infections - complications; Epstein-Barr Virus Infections - genetics; Genomics; Herpesvirus 4, Human - genetics; Humans; Lymphoid Neoplasia; Plasmablastic Lymphoma - complications; Plasmablastic Lymphoma - diagnosis; Plasmablastic Lymphoma - genetics; Proto-Oncogene Proteins c-myc - genetics; Signal Transduction; Transcriptome
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2021005486

Plasmablastic lymphoma (PBL) represents a clinically heterogeneous subtype of aggressive B-cell non-Hodgkin lymphoma. Targeted-sequencing studies and a single-center whole-exome sequencing (WES) study in HIV-positive patients recently revealed several genes associated with PBL pathogenesis; however, 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-positive and HIV-negative PBL, we performed WES and transcriptome sequencing (RNA-sequencing) of 33 PBL tumors. Integrative analysis of somatic mutations and gene expression profiles was performed to acquire insights into the divergent genotype–phenotype correlation in Epstein-Barr virus–positive (EBV+) and EBV– PBL. We describe a significant accumulation of mutations in the JAK signal transducer and transcription activator (OSMR, STAT3, PIM1, and SOCS1), as well as receptor tyrosine-kinase RAS (ERBB3, NRAS, PDGFRB, and NTRK) pathways. We provide further evidence of frequent perturbances of NF-κB signaling (NFKB2 and BTK). Induced pathways, identified by RNA-sequencing, closely resemble the mutational profile regarding alterations accentuated in interleukin-6/JAK/STAT signaling, NF-κB activity, and MYC signaling. Moreover, class I major histocompatibility complex–mediated antigen processing and cell cycle regulation were significantly affected by EBV status. An almost exclusive upregulation of phosphatidylinositol 3-kinase/AKT/mTOR signaling in EBV+ PBL and a significantly induced expression of NTRK3 in concert with recurrent oncogenic mutations in EBV– PBL hint at a specific therapeutically targetable mechanism in PBL subgroups. Our characterization of a mutational and transcriptomic landscape in PBL, distinct from that of diffuse large B-cell lymphoma and multiple myeloma, substantiates the pathobiological independence of PBL in the spectrum of B-cell malignancies and thereby refines the taxonomy for aggressive lymphomas. •WES coupled with RNA-sequencing of a large PBL cohort reveals genetic drivers of oncogenesis in RTK-RAS, NF-kB, and JAK/STAT signaling.•The mutational landscape and SCNV data emphasize the distinctness of EBV+/EBV– PBL from both DLBCL and multiple myeloma. [Display omitted]