Oncotarget

Research Papers:

An epigenetic regulator-related score (EpiScore) predicts survival in patients with diffuse large B cell lymphoma and identifies patients who may benefit from epigenetic therapy

Vanessa Szablewski, Caroline Bret, Alboukadel Kassambara, Julie Devin, Guillaume Cartron, Valérie Costes-Martineau and Jérôme Moreaux _

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Oncotarget. 2018; 9:19079-19099. https://doi.org/10.18632/oncotarget.24901

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Abstract

Vanessa Szablewski3,4, Caroline Bret1,2,3, Alboukadel Kassambara1,2, Julie Devin2, Guillaume Cartron3,5,6, Valérie Costes-Martineau3,4 and Jérôme Moreaux1,2,3

1Department of Biological Hematology, CHU Montpellier, Montpellier, France

2Institute of Human Genetics, CNRS-UM UMR 9002, Montpellier, France

3University of Montpellier, UFR de Médecine, Montpellier, France

4Department of Biopathology, CHU Montpellier, Montpellier, France

5CHU Montpellier, Department of Clinical Hematology, Montpellier, France

6Montpellier University, UMR CNRS 5235, Montpellier, France

Correspondence to:

Jérôme Moreaux, email: jerome.moreaux@igh.cnrs.fr

Keywords: epigenetics; Diffuse large B cells lymphoma; prognostic value; gene expression profiling; targeted treatment

Received: May 30, 2017     Accepted: March 01, 2018     Published: April 10, 2018

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma and shows considerable clinical and biological heterogeneity. Much research is currently focused on the identification of prognostic markers for more specific patients’ risk stratification and on the development of therapeutic approaches to improve the long-term outcome. Epigenetic alterations are involved in various cancers, including lymphoma. Interestingly, epigenetic alterations are reversible and drugs to target some of them have been developed. In this study, we demonstrated that the gene expression profile of epigenetic regulators has a prognostic value in DLBCL and identified pathways that could be involved in DLBCL poor outcome. We then designed a new risk score (EpiScore) based on the gene expression level of the epigenetic regulators DNMT3A, DOT1L, SETD8. EpiScore was predictive of overall survival in DLBCL and allowed splitting patients with DLBCL from two independent cohorts (n = 414 and n = 69) in three groups (high, intermediate and low risk). EpiScore was an independent predictor of survival when compared with previously described prognostic factors, such as the International Prognostic Index (IPI), germinal center B cell and activated B cell molecular subgroups, gene expression-based risk score (GERS) and DNA repair score. Immunohistochemistry analysis of DNMT3A in 31 DLBCL samples showed that DNMT3A overexpression (>42% of positive tumor cells) correlated with reduced overall and event-free survival. Finally, an HDAC gene signature was significantly enriched in the DLBCL samples included in the EpiScore high-risk group. We conclude that EpiScore identifies high-risk patients with DLBCL who could benefit from epigenetic therapy.


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