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

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

doi:10.18632/oncotarget.3154

Sydney Dubois, Sylvain Mareschal + Show 14 more

Open Access

https://doi.org/10.18632/oncotarget.3154

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Journal: Oncotarget	Publication Date: Feb 5, 2015
Citations: 31	License type: cc-by

Affiliation: University of Rouen, Inserm, Centre Virchow-Villermé

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.

Highlights

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy, accounting for 30– 40% of all Non Hodgkin Lymphomas (NHL) [1]
One Enhancer of Zeste Homolog 2 (EZH2) mutant patient in our 100-patient cohort was of the Activated B-Cell like (ABC) subtype, examples of which have been reported in the literature [19]
IHC-usable WT EZH2 patients were quite evenly split between ABC (n = 37/70) and Germinal Center B-cell like (GCB) (n = 30/70) subtype, while all IHC-usable EZH2 mutant patients were of the GCB subtype (n = 12/12), as is most frequent [18, 20]

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy, accounting for 30– 40% of all Non Hodgkin Lymphomas (NHL) [1]. Multiple studies have shown cell lines with EZH2 mutations to be dependent on the higher catalytic activity of mutant EZH2 Y641 www.impactjournals.com/oncotarget for proliferation, leading to the development of novel EZH2 inhibitors for therapeutic use, capable of reversing malignant phenotype [8,9,10,11]. We used Generation Sequencing (NGS) analysis to further detail patients’ genomic profiles and to determine whether associated mutations could justify EZH2 inhibitor treatment for patients otherwise not considered. We propose that these methods, used in conjunction, could serve to better determine candidates most likely to respond to EZH2 inhibitor treatment

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Conclusion