title: Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P-Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases.
abstract: Purpose:MYD88mutations, notably the recurrent gain-of-function L265P variant, are a distinguishing feature of activated B-cell like (ABC) diffuse large B-cell lymphoma (DLBCL), leading to constitutive NFκB pathway activation. The aim of this study was to examine the distinct genomic profiles ofMYD88-mutant DLBCL, notably according to the presence of the L265P or other non-L265P MYD88 variants.Experimental Design:A cohort of 361 DLBCL cases (94MYD88mutant and 267MYD88wild-type) was submitted to next-generation sequencing (NGS) focusing on 34 genes to analyze associated mutations and copy number variations, as well as gene expression profiling, and clinical and prognostic analyses.Results:Importantly, we highlighted different genomic profiles for MYD88 L265P and MYD88 non-L265P-mutant DLBCL, shedding light on their divergent backgrounds. Clustering analysis also segregated subgroups according to associated genetic alterations among patients with the sameMYD88mutation. We showed that associatedCD79Band MYD88 L265P mutations act synergistically to increase NFκB pathway activation, although the majority of MYD88 L265P-mutant cases harbors downstream NFκB alterations, which can predict BTK inhibitor resistance. Finally, although the MYD88 L265P variant was not an independent prognostic factor in ABC DLBCL, associatedCD79Bmutations significantly improved the survival of MYD88 L265P-mutant ABC DLBCL in our cohort.Conclusions:This study highlights the relative heterogeneity ofMYD88-mutant DLBCL, adding to the field's knowledge of the theranostic importance ofMYD88mutations, but also of associated alterations, emphasizing the usefulness of genomic profiling to best stratify patients for targeted therapy.Clin Cancer Res; 23(9); 2232-44. ©2016 AACR.
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Sydney
authors.initials: S
authors.lastname: Dubois
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.|LITIS EA 4108, Normandie Université, Rouen, France.
authors.forename: Pierre-Julien
authors.initials: PJ
authors.lastname: Viailly
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Bohers
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertrand
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruminy
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Vinciane
authors.initials: V
authors.lastname: Marchand
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Maingonnat
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Mareschal
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Picquenot
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Penther
authors.affiliation: Inserm UMRS 872, AP-HP Hôpital Necker, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Jais
authors.affiliation: Institut Carnot CALYM, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Tesson
authors.affiliation: Université de Lille 2, Lille, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Peyrouze
authors.affiliation: Université de Lille 2, Lille, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Figeac
authors.affiliation: Inserm U917, CHU Pontchaillou, Rennes, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Desmots
authors.affiliation: Inserm U917, CHU Pontchaillou, Rennes, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fest
authors.affiliation: Unité Hémopathies Lymphoïdes, AP-HP Hôpital Henri Mondor, Créteil, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Haioun
authors.affiliation: Inserm U917, CHU Pontchaillou, Rennes, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lamy
authors.affiliation: IMRB - Inserm U955, AP-HP Hôpital Henri Mondor, Créteil, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Copie-Bergman
authors.affiliation: Laboratoire de Pathologie, AP-HP Hôpital Saint Antoine, Paris, France.
authors.forename: Bettina
authors.initials: B
authors.lastname: Fabiani
authors.affiliation: Department of Hematology, AP-HP Hôpital Necker, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Delarue
authors.affiliation: Department of Hematology, Lacassagne Center, Nice, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Peyrade
authors.affiliation: CHU Dinant Godinne, UcL Namur, Yvoir, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: André
authors.affiliation: Center of Oncology, Clinique Bois-Cerf, Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ketterer
authors.affiliation: Inserm U955 Team 09, AP-HP Hôpital Henri Mondor, Créteil, France.
authors.forename: Karen
authors.initials: K
authors.lastname: Leroy
authors.affiliation: CNRS UMR5239, Hospices Civils de Lyon, Lyon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.affiliation: Pathology, AP-HP Hôpital Necker, Université Paris Descartes, Paris, France.
authors.forename: Thierry J
authors.initials: TJ
authors.lastname: Molina
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.affiliation: Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France. fabrice.jardin@chb.unicancer.fr.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jardin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D015894:Genome, Human; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B