title: Immunohistochemical and genomic profiles of diffuse large B-cell lymphomas: implications for targeted EZH2 inhibitor therapy?
abstract: Enhancer of Zeste Homolog 2 (EZH2) plays an essential epigenetic role in Diffuse Large B Cell Lymphoma (DLBCL) development. Recurrent somatic heterozygous gain-of-function mutations of EZH2 have been identified in DLBCL, most notably affecting tyrosine 641 (Y641), inducing hyper-trimethylation of H3K27 (H3K27me3). Novel EZH2 inhibitors are being tested in phase 1 and 2 clinical trials but no study has examined which patients would most benefit from this treatment. We evaluated the immunohistochemical (IHC) methylation profiles of 82 patients with DLBCL, as well as the mutational profiles of 32 patients with DLBCL using NGS analysis of a panel of 34 genes involved in lymphomagenesis. A novel IHC score based on H3K27me2 and H3K27me3 expression was developed, capable of distinguishing patients with wild-type (WT) EZH2 and patients with EZH2 Y641 mutations (p = 10-5). NGS analysis revealed a subclonal EZH2 mutation pattern in EZH2 mutant patients with WT-like IHC methylation profiles, while associated mutations capable of upregulating EZH2 were detected in WT EZH2 patients with mutant-like IHC methylation profiles. IHC and mutational profiles highlight in vivo hyper-H3K27me3 and hypo-H3K27me2 status, pinpoint associated activating mutations and determine EZH2 mutation clonality, maximizing EZH2 inhibitor potential by identifying patients most likely to benefit from treatment.
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.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Mareschal
authors.affiliation: INSERM U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.|Department of Pathology, Centre Henri Becquerel, 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: 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: Department of Pathology, Centre Henri Becquerel, Rouen, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Cornic
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.|Department of Pathology, Centre Henri Becquerel, Rouen, France.
authors.forename: Elena Liana
authors.initials: EL
authors.lastname: Veresezan
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: Catherine
authors.initials: C
authors.lastname: Maingonnat
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.|Department of Clinical Hematology, Centre Henri Becquerel, Rouen, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Lanic
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 U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Bastard
authors.affiliation: INSERM U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.|Department of Clinical Hematology, Centre Henri Becquerel, Rouen, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.affiliation: INSERM U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.|Department of Clinical Hematology, Centre Henri Becquerel, Rouen, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jardin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004268:DNA-Binding Proteins / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D008297:Male; D008745:Methylation; D008875:Middle Aged; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: DLBCL; EZH2; NGS; immunohistochemistry; methylation