EZH2.md
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## Overview
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EZH2 encodes a histone methyltransferase that is a component of the polycomb repressive complex 2 (PRC2).
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-This gene is recurrently mutated in both FL and DLBCL and has a common mutation hot spot (Y646) that affects the SET domain.<sup>1</sup> Mutations of this residue and some of the less common hotspots lead to enhanced methylation by PRC2.<sup>2,3</sup>
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-Pharmacologic inhibitors of this activity such as tazemetostat have shown benefit in FL.<sup>3</sup> EZH2 mutations are one of the defining features of the EZB genetic subgroup of DLBCL.
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-Although mutations in EZH2 have been described in some BL patients, they are extremely rare in most BL cohorts that have been sequenced.<sup>4,5</sup>
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+This gene is recurrently mutated in both FL and DLBCL and has a common mutation hot spot (Y646) that affects the SET domain.[@morinSomaticMutationsAltering2010a]
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+Mutations of this residue and some of the less common hotspots lead to enhanced methylation by PRC2.[@yapSomaticMutationsEZH22011b]
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+Pharmacologic inhibitors of this activity such as tazemetostat have shown benefit in FL.[@morinTreatingLymphomaNow2021]
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+EZH2 mutations are one of the defining features of the EZB genetic subgroup of DLBCL.[@wrightProbabilisticClassificationTool2020]
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+Although mutations in EZH2 have been described in some BL patients, they are extremely rare in most BL cohorts that have been sequenced.[@loveGeneticLandscapeMutations2012; @thomasGeneticSubgroupsInform2023]
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## History
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```mermaid
morinlab.bib
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+@article{yapSomaticMutationsEZH22011b,
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+ title = {Somatic Mutations at {{EZH2 Y641}} Act Dominantly through a Mechanism of Selectively Altered {{PRC2}} Catalytic Activity, to Increase {{H3K27}} Trimethylation},
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+ author = {Yap, Damian B. and Chu, Justin and Berg, Tobias and Schapira, Matthieu and Cheng, S.-W. Grace and Moradian, Annie and Morin, Ryan D. and Mungall, Andrew J. and Meissner, Barbara and Boyle, Merrill and Marquez, Victor E. and Marra, Marco A. and Gascoyne, Randy D. and Humphries, R. Keith and Arrowsmith, Cheryl H. and Morin, Gregg B. and Aparicio, Samuel A. J. R.},
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+ date = {2011-02-24},
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+ journaltitle = {Blood},
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+ shortjournal = {Blood},
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+ volume = {117},
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+ number = {8},
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+ eprint = {21190999},
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+ eprinttype = {pmid},
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+ pages = {2451--2459},
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+ issn = {1528-0020},
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+ doi = {10.1182/blood-2010-11-321208},
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+ abstract = {Next-generation sequencing of follicular lymphoma and diffuse-large B-cell lymphoma has revealed frequent somatic, heterozygous Y641 mutations in the histone methyltransferase EZH2. Heterozygosity and the presence of equal quantities of both mutant and wild-type mRNA and expressed protein suggest a dominant mode of action. Surprisingly, B-cell lymphoma cell lines and lymphoma samples harboring heterozygous EZH2(Y641) mutations have increased levels of histone H3 Lys-27-specific trimethylation (H3K27me3). Expression of EZH2(Y641F/N) mutants in cells with EZH2(WT) resulted in an increase of H3K27me3 levels in vivo. Structural modeling of EZH2(Y641) mutants suggests a "Tyr/Phe switch" model whereby structurally neutral, nontyrosine residues at position 641 would decrease affinity for unmethylated and monomethylated H3K27 substrates and potentially favor trimethylation. We demonstrate, using in vitro enzyme assays of reconstituted PRC2 complexes, that Y641 mutations result in a decrease in monomethylation and an increase in trimethylation activity of the enzyme relative to the wild-type enzyme. This represents the first example of a disease-associated gain-of-function mutation in a histone methyltransferase, whereby somatic EZH2 Y641 mutations in lymphoma act dominantly to increase, rather than decrease, histone methylation. The dominant mode of action suggests that allele-specific EZH2 inhibitors should be a future therapeutic strategy for this disease.},
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+ langid = {english},
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+ pmcid = {PMC3062411},
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+ keywords = {Biopsy,Catalysis,Cell Line Tumor,DNA-Binding Proteins,Enhancer of Zeste Homolog 2 Protein,Histone-Lysine N-Methyltransferase,Histones,Humans,Lymphoma,Lymphoma Large B-Cell Diffuse,Methylation,Models Molecular,Mutation Missense,Polycomb Repressive Complex 2,Substrate Specificity,Transcription Factors},
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+ file = {/Users/rmorin/Zotero/storage/H9XFJ83A/Yap et al. - 2011 - Somatic mutations at EZH2 Y641 act dominantly thro.pdf}
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+}
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+
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@article{hartmannHighlyRecurrentMutations2016b,
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title = {Highly Recurrent Mutations of {{SGK1}}, {{DUSP2}} and {{JUNB}} in Nodular Lymphocyte Predominant {{Hodgkin}} Lymphoma},
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author = {Hartmann, S. and Schuhmacher, B. and Rausch, T. and Fuller, L. and Döring, C. and Weniger, M. and Lollies, A. and Weiser, C. and Thurner, L. and Rengstl, B. and Brunnberg, U. and Vornanen, M. and Pfreundschuh, M. and Benes, V. and Küppers, R. and Newrzela, S. and Hansmann, M.-L.},