Oncotarget

Clinical Research Papers:

Immunohistochemical and genomic profiles of diffuse large B-cell lymphomas: Implications for targeted EZH2 inhibitor therapy?

Sydney Dubois _, Sylvain Mareschal, Jean-Michel Picquenot, Pierre-Julien Viailly, Elodie Bohers, Marie Cornic, Philippe Bertrand, Elena Liana Veresezan, Philippe Ruminy, Catherine Maingonnat, Vinciane Marchand, Hélène Lanic, Dominique Penther, Christian Bastard, Hervé Tilly and Fabrice Jardin

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Oncotarget. 2015; 6:16712-16724. https://doi.org/10.18632/oncotarget.3154

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Abstract

Sydney Dubois1, Sylvain Mareschal1, Jean-Michel Picquenot1,2, Pierre-Julien Viailly1, Elodie Bohers1, Marie Cornic2, Philippe Bertrand1, Elena Liana Veresezan1,2, Philippe Ruminy1, Catherine Maingonnat1, Vinciane Marchand1, Hélène Lanic1,3, Dominique Penther1, Christian Bastard1, Hervé Tilly1,3, Fabrice Jardin1,3

1INSERM U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France

2Department of Pathology, Centre Henri Becquerel, Rouen, France

3Department of Clinical Hematology, Centre Henri Becquerel, Rouen, France

Correspondence to:

Fabrice Jardin, e-mail: fabrice.jardin@chb.unicancer.fr

Keywords: DLBCL, EZH2, Methylation, Immunohistochemistry, NGS

Received: October 20, 2014     Accepted: January 15, 2015     Published: February 05, 2015

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.


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