PMID- 34039950 OWN - NLM STAT- MEDLINE DCOM- 20220110 LR - 20220110 IS - 2044-5385 (Electronic) IS - 2044-5385 (Linking) VI - 11 IP - 5 DP - 2021 May 26 TI - Genomic insights into the pathogenesis of Epstein-Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing. PG - 102 LID - 10.1038/s41408-021-00493-5 [doi] LID - 102 AB - 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 kappaB (NFkappaB) 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. FAU - Gebauer, Niklas AU - Gebauer N AUID- ORCID: 0000-0003-0566-4554 AD - Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. Niklas.Gebauer@uksh.de. AD - University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. Niklas.Gebauer@uksh.de. FAU - Kunstner, Axel AU - Kunstner A AUID- ORCID: 0000-0003-0692-2105 AD - University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. AD - Medical Systems Biology Group, University of Lubeck, Ratzeburger Allee 160, 23538, Lubeck, Germany. AD - Institute for Cardiogenetics, University of Lubeck, Ratzeburger Allee 160, 23538, Lubeck, Germany. FAU - Ketzer, Julius AU - Ketzer J AD - Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. AD - University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. AD - Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. FAU - Witte, Hanno M AU - Witte HM AUID- ORCID: 0000-0001-5767-7125 AD - Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. AD - University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. AD - Department of Hematology and Oncology, Federal Armed Hospital Ulm, Oberer Eselsberg 40, 89081, Ulm, Germany. FAU - Rausch, Tobias AU - Rausch T AUID- ORCID: 0000-0001-5773-5620 AD - EMBL, European Molecular Biology Laboratory, Genomics Core Facility, Meyerhofstrasse 1, 69117, Heidelberg, Germany. FAU - Benes, Vladimir AU - Benes V AUID- ORCID: 0000-0002-0352-2547 AD - EMBL, European Molecular Biology Laboratory, Genomics Core Facility, Meyerhofstrasse 1, 69117, Heidelberg, Germany. FAU - Zimmermann, Jurgen AU - Zimmermann J AD - EMBL, European Molecular Biology Laboratory, Genomics Core Facility, Meyerhofstrasse 1, 69117, Heidelberg, Germany. FAU - Gebauer, Judith AU - Gebauer J AD - University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. AD - Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. FAU - Merz, Hartmut AU - Merz H AD - Hamatopathologie Lubeck, Reference Centre for Lymph Node Pathology and Haematopathology, Lubeck, Germany. FAU - Bernard, Veronica AU - Bernard V AD - Hamatopathologie Lubeck, Reference Centre for Lymph Node Pathology and Haematopathology, Lubeck, Germany. FAU - Harder, Lana AU - Harder L AD - Institut fur Tumorgenetik Nord, Steenbeker Weg 23, 24106, Kiel, Germany. FAU - Ratjen, Katharina AU - Ratjen K AD - Institut fur Tumorgenetik Nord, Steenbeker Weg 23, 24106, Kiel, Germany. FAU - Gesk, Stefan AU - Gesk S AD - Institut fur Tumorgenetik Nord, Steenbeker Weg 23, 24106, Kiel, Germany. FAU - Peter, Wolfgang AU - Peter W AD - HLA Typing Laboratory of the Stefan-Morsch-Foundation, 557565, Birkenfeld, Germany. AD - Institut fur Tranfusionsmedizin, Universitatsklinikum Koln. Kerpenerstr. 62, 50937, Koln, Germany. FAU - Busch, Yannik AU - Busch Y AD - HLA Typing Laboratory of the Stefan-Morsch-Foundation, 557565, Birkenfeld, Germany. FAU - Trojok, Peter AU - Trojok P AD - HLA Typing Laboratory of the Stefan-Morsch-Foundation, 557565, Birkenfeld, Germany. FAU - von Bubnoff, Nikolas AU - von Bubnoff N AUID- ORCID: 0000-0001-9593-8947 AD - Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. AD - University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. FAU - Biersack, Harald AU - Biersack H AD - Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. AD - University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. FAU - Busch, Hauke AU - Busch H AD - University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lubeck, 23538, Lubeck, Germany. AD - Medical Systems Biology Group, University of Lubeck, Ratzeburger Allee 160, 23538, Lubeck, Germany. AD - Institute for Cardiogenetics, University of Lubeck, Ratzeburger Allee 160, 23538, Lubeck, Germany. FAU - Feller, Alfred C AU - Feller AC AD - Hamatopathologie Lubeck, Reference Centre for Lymph Node Pathology and Haematopathology, Lubeck, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210526 PL - United States TA - Blood Cancer J JT - Blood cancer journal JID - 101568469 SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Chromosome Aberrations MH - Epstein-Barr Virus Infections/*complications MH - Female MH - Gene Regulatory Networks MH - Herpesvirus 4, Human/isolation & purification MH - High-Throughput Nucleotide Sequencing MH - Humans MH - In Situ Hybridization, Fluorescence MH - Lymphoma, Large B-Cell, Diffuse/*genetics/*virology MH - Male MH - Middle Aged MH - Mutation MH - Whole Genome Sequencing MH - Young Adult PMC - PMC8155002 COIS- The authors declare no competing interests. EDAT- 2021/05/28 06:00 MHDA- 2022/01/11 06:00 PMCR- 2021/05/26 CRDT- 2021/05/27 05:55 PHST- 2021/02/28 00:00 [received] PHST- 2021/04/27 00:00 [accepted] PHST- 2021/04/12 00:00 [revised] PHST- 2021/05/27 05:55 [entrez] PHST- 2021/05/28 06:00 [pubmed] PHST- 2022/01/11 06:00 [medline] PHST- 2021/05/26 00:00 [pmc-release] AID - 10.1038/s41408-021-00493-5 [pii] AID - 493 [pii] AID - 10.1038/s41408-021-00493-5 [doi] PST - epublish SO - Blood Cancer J. 2021 May 26;11(5):102. doi: 10.1038/s41408-021-00493-5.