Frequent mutated B2M, EZH2, IRF8, and TNFRSF14 in primary bone diffuse large B-cell lymphoma reflect a GCB phenotype

Ruben Al de Groen, Ronald van Eijk, Stefan Boehringer, Tom van Wezel, Richard Raghoo, Dina Ruano, Patty M Jansen, Inge Briaire-de Bruijn, Fleur A de Groot, Karin Kleiverda, Liane Te Boome, Valeska Terpstra, Henriette Levenga, Alina Nicolae-Cristea, Eduardus Franciscus Posthuma, Isabelle Focke-Snieders, Lizan Hardi, Wietske C E den Hartog, Lara H Bohmer, Pancras C W HogendoornAnke van den Berg, Arjan Diepstra, Marcel Nijland, Pieternella J Lugtenburg, Marie José Kersten, Steven T Pals, Hendrik Veelken, Judith V M G Bovee, Arjen Cleven, Joost S P Vermaat*

*Corresponding author for this work

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Abstract

Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal lymphoma subtype. This retrospective study elucidates the currently unknown genetic background of a large clinically well-annotated cohort of DLBCL with osseous localizations (O-DLBCL), including PB-DLBCL. 103 O-DLBCL patients were included and compared with 63 (extra)nodal non-osseous (NO)-DLBCLs with germinal center B-cell phenotype (NO-DLBCL-GCB). Cell-of-origin (COO) was determined by immunohistochemistry and gene-expression-profiling (GEP) using (extended)-NanoString/Lymph2Cx. Mutational profiles were identified with targeted next-generation deep-sequencing, including 52 B-cell lymphoma-relevant genes. O-DLBCLs, including 34 PB-DLBCL, were predominantly classified as GCB-phenotype based on immunohistochemistry (74%) and NanoString analysis (88%). Unsupervised hierarchical clustering of an extended-NanoString/Lymph2Cx demonstrated significantly different GEP-clusters for PB-DLBCL as opposed to NO-DLBCL-GCB (P<0.001). Expression levels of 23 genes of two different targeted GEP-panels, indicated a centrocyte-like phenotype for PB-DLBCL, whereas NO-DLBCL-GCB showed a centroblast-like constitution. PB-DLBCL had significantly more frequent mutations in four GCB-associated genes, i.e. B2M, EZH2, IRF8, and TNFRSF14, compared to NO-DLBCL-GCB (P=0.031, P=0.010, P=0.047, and P=0.003). PB-DLBCL with its corresponding specific mutational profile were significantly associated with a superior overall survival compared to equivalent Ann Arbor limited-stage I/II NO-DLBCL-GCB (P=0.011). This study is the first to demonstrate that PB-DLBCL is characterized by a GCB-phenotype, with a centrocyte-like GEP-pattern and a GCB-associated mutational profile (both involved in immune surveillance) and a favorable prognosis. These novel biology-associated features provide evidence that PB-DLBCL represents a distinct extranodal DLBCL entity and its specific mutational landscape holds potential for targeted therapies (e.g. EZH2-inhibitors).

Original languageEnglish
Article number2021005215
Number of pages32
JournalBlood Advances
Early online date3-Sep-2021
DOIs
Publication statusPublished - 3-Sep-2021

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