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 voor dit werk

OnderzoeksoutputAcademicpeer review

19 Citaten (Scopus)
97 Downloads (Pure)

Samenvatting

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 DLBCLwith osseous localizations (O-DLBCL), including PB-DLBCL. A total of 103 patients with O-DLBCL were included and compared with 63 (extra)nodal non-osseous (NO)-DLBCLs with germinal center B-cell phenotype (NO-DLBCL-GCB). Cell-of-origin was determined by immunohistochemistry and gene-expression profiling (GEP) using (extended)-Nano-String/Lymph2Cx analysis. Mutational profileswere identifiedwith targeted next-generation deep sequencing, including 52 B-cell lymphoma-relevant genes. O-DLBCLs, including 34 PB-DLBCLs, were predominantly classified as GCB phenotype based on immunohistochemistry (74%) and NanoString analysis (88%). Unsupervised hierarchical clustering of an extended-NanoString/Lymph2Cx revealed significantly different GEP clusters for PB-DLBCL as opposed to NO-DLBCL-GCB (P < .001). Expression levels of 23 genes of 2 different targeted GEP panels indicated a centrocyte-like phenotype for PB-DLBCL, whereas NO-DLBCL-GCB exhibited a centroblast-like constitution. PB-DLBCL had significantly more frequent mutations in four GCB-associated genes (ie, B2M, EZH2, IRF8, TNFRSF14) comparedwithNO-DLBCL-GCB (P = .031, P = .010, P = .047, and P = .003, respectively). PB-DLBCL, with its corresponding specific mutational profile, was significantly associated with a superior survival compared with equivalent Ann Arbor limited-stage I/II NO-DLBCL-GCB (P = .016). This study is the first to show 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 offers potential for targeted therapies (eg, EZH2 inhibitors).

Originele taal-2English
Artikelnummer2021005215
Pagina's (van-tot)3760-3775
Aantal pagina's16
Tijdschrift-
Volume5
Nummer van het tijdschrift19
Vroegere onlinedatum3-sep.-2021
DOI's
StatusPublished - 12-okt.-2021

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