Genomic insights into the pathogenesis of Epstein–Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing

Autor: Niklas Gebauer, Axel Künstner, Julius Ketzer, Hanno M. Witte, Tobias Rausch, Vladimir Benes, Jürgen Zimmermann, Judith Gebauer, Hartmut Merz, Veronica Bernard, Lana Harder, Katharina Ratjen, Stefan Gesk, Wolfgang Peter, Yannik Busch, Peter Trojok, Nikolas von Bubnoff, Harald Biersack, Hauke Busch, Alfred C. Feller
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Blood Cancer Journal, Vol 11, Iss 5, Pp 1-12 (2021)
Druh dokumentu: article
ISSN: 2044-5385
DOI: 10.1038/s41408-021-00493-5
Popis: Abstract Epstein–Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitute a distinct clinicopathological entity in the current World Health Organization (WHO) classification. However, its genomic features remain sparsely characterized. Here, we combine whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS), and fluorescence in situ hybridization (FISH) from 47 EBV + DLBCL (NOS) cases to delineate the genomic landscape of this rare disease. Integrated WGS and tNGS analysis clearly distinguished this tumor type from EBV-negative DLBCL due to frequent mutations in ARID1A (45%), KMT2A/KMT2D (32/30%), ANKRD11 (32%), or NOTCH2 (32%). WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Expanding on previous reports, we identified recurrent alterations in CCR6 (15%), DAPK1 (15%), TNFRSF21 (13%), CCR7 (11%), and YY1 (6%). Lastly, functional annotation of the mutational landscape by sequential gene set enrichment and network propagation predicted an effect on the nuclear factor κB (NFκB) pathway (CSNK2A2, CARD10), IL6/JAK/STAT (SOCS1/3, STAT3), and WNT signaling (FRAT1, SFRP5) alongside aberrations in immunological processes, such as interferon response. This first comprehensive description of EBV + DLBCL (NOS) tumors substantiates the evidence of its pathobiological independence and helps stratify the molecular taxonomy of aggressive lymphomas in the effort for future therapeutic strategies.
Databáze: Directory of Open Access Journals
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