Universität zu Köln

Gebauer, Niklas, Kuenstner, Axel, Ketzer, Julius, Witte, Hanno M., Rausch, Tobias ORCID: 0000-0001-5773-5620, Benes, Vladimir ORCID: 0000-0002-0352-2547, Zimmermann, Juergen, Gebauer, Judith, Merz, Hartmut, Bernard, Veronica, Harder, Lana, Ratjen, Katharina, Gesk, Stefan, Peter, Wolfgang, Busch, Yannik, Trojok, Peter, von Bubnoff, Nikolas, Biersack, Harald, Busch, Hauke and Feller, Alfred C. (2021). Genomic insights into the pathogenesis of Epstein-Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing. Blood Cancer J., 11 (5). LONDON: SPRINGERNATURE. ISSN 2044-5385

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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 kappa B (NF kappa B) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gebauer, Niklas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuenstner, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Ketzer, Julius UNSPECIFIED UNSPECIFIED UNSPECIFIED Witte, Hanno M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rausch, Tobias UNSPECIFIED orcid.org/0000-0001-5773-5620 UNSPECIFIED Benes, Vladimir UNSPECIFIED orcid.org/0000-0002-0352-2547 UNSPECIFIED Zimmermann, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Gebauer, Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Merz, Hartmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Bernard, Veronica UNSPECIFIED UNSPECIFIED UNSPECIFIED Harder, Lana UNSPECIFIED UNSPECIFIED UNSPECIFIED Ratjen, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Gesk, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Peter, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Busch, Yannik UNSPECIFIED UNSPECIFIED UNSPECIFIED Trojok, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED von Bubnoff, Nikolas UNSPECIFIED UNSPECIFIED UNSPECIFIED Biersack, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Busch, Hauke UNSPECIFIED UNSPECIFIED UNSPECIFIED Feller, Alfred C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-595826
DOI:	10.1038/s41408-021-00493-5
Journal or Publication Title:	Blood Cancer J.
Volume:	11
Number:	5
Date:	2021
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	2044-5385
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LYMPHOPROLIFERATIVE DISORDERS; CANCER; AGE; CONTRIBUTES; PREVALENCE; MUTATIONS; SURVIVAL Multiple languages Oncology; Hematology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59582