TY - JOUR
T1 - Frequent mutated B2M, EZH2, IRF8, and TNFRSF14 in primary bone diffuse large B-cell lymphoma reflect a GCB phenotype
AU - de Groen, Ruben Al
AU - van Eijk, Ronald
AU - Boehringer, Stefan
AU - van Wezel, Tom
AU - Raghoo, Richard
AU - Ruano, Dina
AU - Jansen, Patty M
AU - Briaire-de Bruijn, Inge
AU - de Groot, Fleur A
AU - Kleiverda, Karin
AU - Te Boome, Liane
AU - Terpstra, Valeska
AU - Levenga, Henriette
AU - Nicolae-Cristea, Alina
AU - Posthuma, Eduardus Franciscus
AU - Focke-Snieders, Isabelle
AU - Hardi, Lizan
AU - den Hartog, Wietske C E
AU - Bohmer, Lara H
AU - Hogendoorn, Pancras C W
AU - van den Berg, Anke
AU - Diepstra, Arjan
AU - Nijland, Marcel
AU - Lugtenburg, Pieternella J
AU - Kersten, Marie José
AU - Pals, Steven T
AU - Veelken, Hendrik
AU - Bovee, Judith V M G
AU - Cleven, Arjen
AU - Vermaat, Joost S P
N1 - Copyright © 2021 American Society of Hematology.
PY - 2021/10/12
Y1 - 2021/10/12
N2 - 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).
AB - 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).
KW - PARAFFIN-EMBEDDED TISSUE
KW - GENE-EXPRESSION
KW - GERMINAL-CENTER
KW - MOLECULAR CLASSIFICATION
KW - PROGNOSIS
KW - SYSTEM
KW - PATHOGENESIS
KW - SUBTYPES
KW - MYC
U2 - 10.1182/bloodadvances.2021005215
DO - 10.1182/bloodadvances.2021005215
M3 - Article
C2 - 34478526
SN - 0000-0000
VL - 5
SP - 3760
EP - 3775
JO - -
JF - -
IS - 19
M1 - 2021005215
ER -