Mutational landscape of high-grade B-cell lymphoma with <i>MYC-</i>, <i>BCL2</i> and/or <i>BCL6</i> rearrangements characterized by whole-exome sequencing
Axel Künstner,
Hanno M. Witte,
Jörg Riedl,
Veronica Bernard,
Stephanie Stölting,
Hartmut Merz,
Vito Olschewski,
Wolfgang Peter,
Julius Ketzer,
Yannik Busch,
Peter Trojok,
Nikolas von Bubnoff,
Hauke Busch,
Alfred C. Feller,
Niklas Gebauer
Affiliations
Axel Künstner
Medical Systems Biology Group, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; Institute for Cardiogenetics, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; University Cancer Center Schleswig-Holstein, University Hospital of Schleswig- Holstein, Campus Lübeck, 23538 Lübeck
Hanno M. Witte
Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; Department of Hematology and Oncology, Federal Armed Forces Hospital Ulm, Oberer Eselsberg 40, 89081 Ulm
Jörg Riedl
Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; Hämatopathologie Lübeck, Reference Centre for Lymph Node Pathology and Hematopathology, Lübeck
Veronica Bernard
Hämatopathologie Lübeck, Reference Centre for Lymph Node Pathology and Hematopathology, Lübeck
Stephanie Stölting
Hämatopathologie Lübeck, Reference Centre for Lymph Node Pathology and Hematopathology, Lübeck
Hartmut Merz
Hämatopathologie Lübeck, Reference Centre for Lymph Node Pathology and Hematopathology, Lübeck
Vito Olschewski
Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck
Wolfgang Peter
HLA Typing Laboratory of the Stefan-Morsch-Foundation, 557565 Birkenfeld, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute for Transfusion Medicine, 50937 Cologne
Julius Ketzer
Department of Paediatrics, University Hospital of Schleswig-Holstein, Campus Luebeck, 23538 Luebeck
Yannik Busch
HLA Typing Laboratory of the Stefan-Morsch-Foundation, 557565 Birkenfeld
Peter Trojok
HLA Typing Laboratory of the Stefan-Morsch-Foundation, 557565 Birkenfeld
Nikolas von Bubnoff
University Cancer Center Schleswig-Holstein, University Hospital of Schleswig- Holstein, Campus Lübeck, 23538 Lübeck, Germany; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck
Hauke Busch
Medical Systems Biology Group, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; Institute for Cardiogenetics, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; University Cancer Center Schleswig-Holstein, University Hospital of Schleswig- Holstein, Campus Lübeck, 23538 Lübeck
Alfred C. Feller
Hämatopathologie Lübeck, Reference Centre for Lymph Node Pathology and Hematopathology, Lübeck
Niklas Gebauer
University Cancer Center Schleswig-Holstein, University Hospital of Schleswig- Holstein, Campus Lübeck, 23538 Lübeck, Germany; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck
High-grade B-cell lymphoma accompanied with double/triple-hit MYC and BCL2 and/or BCL6 rearrangements (HGBLDH/ TH) poses a cytogenetically-defined provisional entity among aggressive B-cell lymphomas that is traditionally associated with unfavorable prognosis. In order to better understand the mutational and molecular landscape of HGBLDH/ TH we here performed whole-exome sequencing and deep panel next-generation sequencing of 47 clinically annotated cases. Oncogenic drivers, mutational signatures and perturbed pathways were compared with data from follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We find an accumulation of oncogenic mutations in NOTCH, IL6/JAK/STAT and NFκB signaling pathways and delineate the mutational relationship within the continuum between FL/DLBCL, HGBL-DH/TH and BL. Further, we provide evidence of a molecular divergence between BCL2 and BCL6 rearranged HGBL-DH. Beyond a significant congruency with the C3/EZB DLBCL cluster in BCL2 rearranged cases on an exome-wide level, we observe an enrichment of the SBS6 mutation signature in BCL6 rearranged cases. Differential gene set enrichment and subsequent network propagation analysis according to cytogenetically defined subgroups revealed an impairment of TP53 and MYC pathway signaling in BCL2 rearranged cases, whereas BCL6 rearranged cases lacked this enrichment, but instead showed impairment of E2F targets. Intriguingly, HGBL-TH displayed intermediate mutational features considering all three aspects. This study elucidates a recurrent pattern of mutational events driving FL into MYC-driven BCL2-rearranged HGBL, unveiling the mutational pathogenesis of this provisional entity. Through this refinement of the molecular taxonomy for aggressive, germinal center-derived B-cell lymphomas, this calls into question the current World Health Organization classification system, especially regarding the status of MYC/BCL6- rearranged HGBL.
