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

Oncotarget
Sydney DuboisFabrice Jardin

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 ...Continue Reading

References

Aug 6, 2003·Proceedings of the National Academy of Sciences of the United States of America·George WrightLouis M Staudt
Dec 17, 2005·Nature·Emmanuelle ViréFrançois Fuks
Jun 22, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·C Alexander TurnerMark M Davis
Jul 6, 2010·Nucleic Acids Research·Kai WangHakon Hakonarson
Nov 17, 2010·Proceedings of the National Academy of Sciences of the United States of America·Christopher J SneeringerRobert A Copeland
Jan 15, 2011·Leukemia·C BödörJ Fitzgibbon
Jan 21, 2011·Nature·Raphaël Margueron, Danny Reinberg
Jan 13, 2012·Blood·Wolfram KlapperUNKNOWN Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe
Feb 22, 2012·Proceedings of the National Academy of Sciences of the United States of America·Jens G LohrTodd R Golub
Jul 7, 2012·Molecular Oncology·Karolina HolmMarkus Ringnér
Dec 14, 2012·Proceedings of the National Academy of Sciences of the United States of America·Wei QiEn Li
Dec 12, 2013·Genes, Chromosomes & Cancer·Elodie BohersFabrice Jardin
Mar 19, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Shuangping GuoWing C Chan

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Citations

Oct 27, 2015·Oncotarget·Laurie HerviouJérôme Moreaux
Nov 12, 2017·Paediatric Drugs·Christine Mauz-KörholzDieter Körholz
Feb 8, 2019·British Journal of Haematology·Monika L Metzger, Christine Mauz-Körholz
Nov 9, 2019·Pharmacogenomics·Vincent Camus, Fabrice Jardin
Apr 4, 2019·Current Oncology Reports·Rachel HuBrian T Hill
Sep 14, 2018·The American Journal of Surgical Pathology·Bo-Jung ChenLeticia Quintanilla-Martinez
Oct 29, 2018·Annals of Hematology·Fang-Tian WuJian-Yong Li
Dec 8, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sydney DuboisFabrice Jardin
Jan 29, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sydney DuboisFabrice Jardin
Aug 3, 2021·Critical Reviews in Oncology/hematology·Maria Lopez-SantillanIdoia Martin-Guerrero
Oct 28, 2019·EBioMedicine·Sydney DuboisUNKNOWN Lymphoma Study Association (LYSA) investigators

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Methods Mentioned

BETA
PCR
Chips
Fusion Translocation

Clinical Trials Mentioned

NCT01897571
NCT02082977

Software Mentioned

ANNOVAR
Torrent [UNK]
Variant Caller
Medcalc
R
COSMIC
PyroMark

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