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

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignancy assumed to originate from plasmacytoid dendritic cells (pDCs), which mostly affects the skin, bone marrow, lymph nodes and sequentially other organ systems. RNA-, targeted- and exome sequencing studies have identified molecular characteristics, associated with BPDCN-pathogenesis, yet an integrative molecular assessment of BPDCN remains pending. Here, we combined paired WES/RNA-Seq with genome-wide copy-number analysis to characterize 47 BPDCN patients for mutational drivers, cytogenetic aberrations and gene-expression profiles. We identified alterations in epigenetic regulators (TET2, EP300, DNMT3A, SF3B1, EZH2) and a mutational disruption of RTK-RAS signaling (NF1, NRAS, EGFR) as drivers of BPDCN alongside deletions of tumor suppressors (CDKN2A, RB1, TP53), amplifications of oncogenes (IDH2, MET, EZH2) and recurrent fusions (MYB, ALK). The mutational landscape further provides evidence for frequent induction of PDGF signaling and extracellular matrix interactions as well as a gender specificity and a subset of MSIhigh patients. Many genes affected in BPDCN are shared with chronic myelomonocytic leukemia (CMML), emphasizing a close relationship between these entities and to a lesser extent with acute myeloid leukemia (AML). Ontological assessment of RNA-Seq data revealed two BPDCN subtypes, a typical pDC-derived subtype (C1) and a (common) cDC-enriched subtype (C2), which were then shown to exhibit distinct mutational (EP300, ARID2, NF1 mutations in typical pDC vs. DNMT3A, SRSF2 mutations in the cDC-enriched subtype) and clinical features. In summary, our hitherto most comprehensive characterization of BPDCN reveals molecular hallmarks alongside actionable vulnerabilities and highlights two novel subtypes that are molecularly and clinically distinct.

Molecular profiling of primary renal diffuse large B-cell lymphoma unravels a proclivity for immune-privileged organ-tropism

“…Patients provided written informed consent regarding routine diagnostic and academic assessment, including genomic studies. Histopathological work-up was performed as described and diagnosis was confirmed following the 5 th edition WHO classification of hematopoietic and lymphoid tumors and the ICC criteria and yielded 34 cases of PR-DLBCL for which sufficient formalin-fixed paraffinembedded (FFPE) tissue samples were available for subsequent molecular analysis 1,13,14 .…”

“…Alterations employing the OncoScan CNV array (ThermoFisher was performed as described, and Raw fastq files have been added to the European Genome-phenome archive (EGA) under the previous accession number EGA50000000386 13,15 . OncoScan Array data has been deposited in Gene Expression Omnibus (GEO) under accession number GSE270422.…”