title: Targetable activating mutations are very frequent in GCB and ABC diffuse large B-cell lymphoma.
abstract: Diffuse large B cell lymphoma (DLBCL) is an aggressive and heterogeneous malignancy that can be divided in two major subgroups, germinal center B-cell-like (GCB) and activated B-cell-like (ABC). Activating mutations of genes involved in the BCR and NF-κB pathways (CD79A, CD79B, MYD88, and CARD11) or in epigenetic regulation (EZH2) have been recently reported, preferentially in one of the two DLBCL subtypes. We analyzed the mutational status of these five recurrently mutated genes in a cohort of 161 untreated de novo DLBCL. Overall, 93 mutations were detected, in 61 (38%) of the patients. The L265P MYD88 mutation was the most frequent MYD88 variant (n = 18), observed exclusively in the ABC subtype. CD79A/CD79B ITAM domains were targeted in ABC DLBCL (12/77; 16%), whereas CARD11 mutations were equally distributed in the two subtypes. The EZH2 Y641 substitution was found almost exclusively in the GCB subgroup (15/62; 24%). Twenty cases (12%) displayed two activating mutations, including the most frequent CD79/MYD88 variants combination (n = 8) which is observed exclusively in the ABC subtype. When considering only ABC DLBCL patients treated by rituximab plus chemotherapy, the presence of an activating NF-κB mutation was associated with an unfavorable outcome (3-years OS 26% for mutated cases versus 67% for the cases without mutations, P = 0.0337). Our study demonstrates that activating and targetable mutations are observed at a very high frequency in DLBCL at the time of diagnosis, indicating that sequencing of a limited number of genes could help tailor an optimal treatment strategy in DLBCL.
authors: Inserm U918, Centre Henri Becquerel, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors: Elodie
authors: E
authors: Bohers
authors: Sylvain
authors: S
authors: Mareschal
authors: Abdelilah
authors: A
authors: Bouzelfen
authors: Vinciane
authors: V
authors: Marchand
authors: Philippe
authors: P
authors: Ruminy
authors: Catherine
authors: C
authors: Maingonnat
authors: Anne-Lise
authors: AL
authors: Ménard
authors: Pascaline
authors: P
authors: Etancelin
authors: Philippe
authors: P
authors: Bertrand
authors: Sydney
authors: S
authors: Dubois
authors: Marion
authors: M
authors: Alcantara
authors: Christian
authors: C
authors: Bastard
authors: Hervé
authors: H
authors: Tilly
authors: Fabrice
authors: F
authors: Jardin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D005260:Female; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000069283:Rituximab; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab