Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P-Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Sydney Dubois (1, 2) , Pierre-Julien Viailly (1, 3, 2) , Elodie Bohers (1, 2) , Philippe Bertrand (1, 2) , Philippe Ruminy (1, 2) , Vinciane Marchand (1, 2) , Catherine Maingonnat (1, 2) , Sylvain Mareschal (1, 2) , Jean-Michel Picquenot (1, 2) , Dominique Penther (1, 2) , Jean-Philippe Jais (4, 5) , Bruno Tesson (6, 7, 8) , Pauline Peyrouze (9) , Martin Figeac (10) , Fabienne Desmots (11, 12) , Thierry Fest (13, 14, 15, 12) , Corinne Haioun (16) , Thierry Lamy (17, 11, 12) , Christiane Copie-Bergman (18) , Bettina Fabiani (19) , Richard Delarue (20) , Frédéric Peyrade (21) , Marc André (22) , Nicolas Ketterer (23) , Karen Leroy (24) , Gilles Salles (25, 26) , Thierry J. Molina (27) , Hervé Tilly (1, 2) , Fabrice Jardin (1, 2)

1 GPL - Groupe d'étude des proliférations lymphoïdes
2 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
3 LITIS - Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes
4 CRC - Centre de Recherche des Cordeliers
5 CHU Necker - Enfants Malades [AP-HP]
6 Res Ctr
7 Institut Curie [Paris]
8 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
9 Faculté de Médecine Henri Warembourg - Université de Lille
10 Plateforme de génomique fonctionnelle et structurelle [Lille]
11 CHU Pontchaillou [Rennes]
12 MICMAC - Microenvironment, Cell Differentiation, Immunology and Cancer
13 EFS Bretagne - Etablissement français du sang [Rennes]
14 Biosit : Biologie - Santé - Innovation Technologique - Structure Fédérative de Recherche en Biologie et Santé de Rennes
15 Service d’immunologie, de thérapie cellulaire et d’hématopoïèse
16 Service d'hématologie clinique
17 CIC - Centre d'Investigation Clinique [Rennes]
18 Département de pathologie [Mondor]
19 Service de Pathologie [CHU Saint-Antoine]
20 Service d'immuno-hématologie pédiatrique [CHU Necker]
21 UNICANCER/CAL - Centre de Lutte contre le Cancer Antoine Lacassagne [Nice]
22 Cliniques Universitaires UCL Mont-Godinne
23 Department of Oncology, Lausanne Hospital
24 IMRB - Institut Mondor de Recherche Biomédicale
25 Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL]
26 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
27 Service d'anatomie pathologique [CHU Necker]

Purpose:MYD88 mutations, 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 of MYD88-mutant DLBCL, notably according to the presence of the L265P or other non-L265P MYD88 variants.Experimental Design: A cohort of 361 DLBCL cases (94 MYD88 mutant and 267 MYD88 wild-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 same MYD88 mutation. We showed that associated CD79B and 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, associated CD79B mutations significantly improved the survival of MYD88 L265P-mutant ABC DLBCL in our cohort.Conclusions: This study highlights the relative heterogeneity of MYD88-mutant DLBCL, adding to the field's knowledge of the theranostic importance of MYD88 mutations, 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

Domains: Life Sciences [q-bio]; Cancer

Sydney Dubois, Pierre-Julien Viailly, Elodie Bohers, Philippe Bertrand, Philippe Ruminy, et al.. Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P-Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases. Clinical Cancer Research, 2017, 23 (9), pp.2232-2244. ⟨10.1158/1078-0432.CCR-16-1922⟩. ⟨hal-01526582⟩