Table of Contents

Overview

EZH2 encodes a histone methyltransferase that is a component of the polycomb repressive complex 2 (PRC2). This gene is recurrently mutated in both FL and DLBCL and has a common mutation hot spot (Y646) that affects the SET domain.1 EZH2 mutations are one of the defining features of the EZB genetic subgroup of DLBCL.2 Although mutations in EZH2 have been described in some BL patients, they are extremely rare in most BL cohorts that have been sequenced.3,4

Experimental Evidence

Mutations at the main hotspot and some less common hotspots lead to enhanced methylation by PRC2.5 A number of small molecule/pharmacologic inhibitors of EZH2 activity have been described.6,7 At least one of these, tazemetostat, has shown benefit in FL.8 Combination therapies including EZH2 inhibitors are also under exploration for DLBCL patients with mutant EZH2.9

Relevance tier by entity

Entity Tier Description
MZL 1 high-confidence MZL gene
PMBL 1 high-confidence PMBL/cHL/GZL gene10
DLBCL 1 high-confidence DLBCL gene supported by functional data1
FL 1 high-confidence FL gene supported by functional data1
BL 2 relevance in BL not firmly established3

Mutation incidence in large patient cohorts (GAMBL reanalysis)

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Mutation pattern and selective pressure estimates

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EZH2 Hotspots

Chromosome Coordinate (hg19) ref>alt HGVSp
chr7 148508745 T>C N640S
chr7 148508740 A>G F642L
chr7 148508728 A>T Y646N
chr7 148508728 A>G Y646H
chr7 148508727 T>G Y646S
chr7 148508727 T>C Y646C
chr7 148508727 T>A Y646F
chr7 148506466 TG>GC A682G
chr7 148506467 G>C A682G
chr7 148506437 GC>AA A692L
chr7 148506437 G>A A692V

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

EZH2 Expression

Representative Mutations

BL5

Rating ★ ★ ★ ★ ★

All Mutations

BL

1092 671 672 675

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References

1.
Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F, Yap D, Humphries RK, Griffith OL, Shah S, Zhu H, Kimbara M, Shashkin P, Charlot JF, Tcherpakov M, Corbett R, Tam A, Varhol R, Smailus D, Moksa M, Zhao Y, Delaney A, Qian H, Birol I, Schein J, Moore R, Holt R, Horsman DE, Connors JM, Jones S, Aparicio S, Hirst M, Gascoyne RD, Marra MA. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010 Feb;42(2):181–185. PMCID: PMC2850970
2.
Wright GW, Huang DW, Phelan JD, Coulibaly ZA, Roulland S, Young RM, Wang JQ, Schmitz R, Morin RD, Tang J, Jiang A, Bagaev A, Plotnikova O, Kotlov N, Johnson CA, Wilson WH, Scott DW, Staudt LM. A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications. Cancer Cell. 2020 Apr 13;37(4):551–568.e14.
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Love C, Sun Z, Jima D, Li G, Zhang J, Miles R, Richards KL, Dunphy CH, Choi WWL, Srivastava G, Lugar PL, Rizzieri DA, Lagoo AS, Bernal-Mizrachi L, Mann KP, Flowers CR, Naresh KN, Evens AM, Chadburn A, Gordon LI, Czader MB, Gill JI, Hsi ED, Greenough A, Moffitt AB, McKinney M, Banerjee A, Grubor V, Levy S, Dunson DB, Dave SS. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet. 2012 Dec;44(12):1321–1325. PMCID: PMC3674561
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Thomas N, Dreval K, Gerhard DS, Hilton LK, Abramson JS, Ambinder RF, Barta S, Bartlett NL, Bethony J, Bhatia K, Bowen J, Bryan AC, Cesarman E, Casper C, Chadburn A, Cruz M, Dittmer DP, Dyer MA, Farinha P, Gastier-Foster JM, Gerrie AS, Grande BM, Greiner T, Griner NB, Gross TG, Harris NL, Irvin JD, Jaffe ES, Henry D, Huppi R, Leal FE, Lee MS, Martin JP, Martin MR, Mbulaiteye SM, Mitsuyasu R, Morris V, Mullighan CG, Mungall AJ, Mungall K, Mutyaba I, Nokta M, Namirembe C, Noy A, Ogwang MD, Omoding A, Orem J, Ott G, Petrello H, Pittaluga S, Phelan JD, Ramos JC, Ratner L, Reynolds SJ, Rubinstein PG, Sissolak G, Slack G, Soudi S, Swerdlow SH, Traverse-Glehen A, Wilson WH, Wong J, Yarchoan R, ZenKlusen JC, Marra MA, Staudt LM, Scott DW, Morin RD. Genetic subgroups inform on pathobiology in adult and pediatric Burkitt lymphoma. Blood. 2023 Feb 23;141(8):904–916. PMCID: PMC10023728
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Yap DB, Chu J, Berg T, Schapira M, Cheng S-WG, Moradian A, Morin RD, Mungall AJ, Meissner B, Boyle M, Marquez VE, Marra MA, Gascoyne RD, Humphries RK, Arrowsmith CH, Morin GB, Aparicio SAJR. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2011 Feb 24;117(8):2451–2459. PMCID: PMC3062411
6.
Garapaty-Rao S, Nasveschuk C, Gagnon A, Chan EY, Sandy P, Busby J, Balasubramanian S, Campbell R, Zhao F, Bergeron L, Audia JE, Albrecht BK, Harmange JC, Cummings R, Trojer P. Identification of EZH2 and EZH1 Small Molecule Inhibitors with Selective Impact on Diffuse Large B Cell Lymphoma Cell Growth. Chemistry & Biology. 2013 Nov;20(11):1329–1339.
7.
Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, Kadowaki T, Uesugi M, Kuznetsov G, Kumar N, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Waters NJ, Smith JJ, Porter-Scott M, Chesworth R, Moyer MP, Copeland RA, Richon VM, Uenaka T, Pollock RM, Kuntz KW, Yokoi A, Keilhack H. Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma. Molecular Cancer Therapeutics [Internet]. 2014;13(4):842–854. Available from: http://dx.doi.org/10.1158/1535-7163.mct-13-0773
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Morin RD, Arthur SE, Assouline S. Treating lymphoma is now a bit EZ-er. Blood Adv. 2021 Apr 27;5(8):2256–2263. PMCID: PMC8095133
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Scholze H, Stephenson RE, Reynolds R, Shah SB, Puri R, Butler SD, Trujillo-Alonso V, Teater M, Besien H van, Gibbs-Curtis D, Ueno H, Parvin S, Letai A, Mathew S, Singh A, Cesarman E, Melnick A, Giulino‐Roth L. Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes. Blood advances. 2020;4 20:5226–5231.
10.
Mottok A, Hung SS, Chavez EA, Woolcock B, Telenius A, Chong LC, Meissner B, Nakamura H, Rushton C, Viganò E, Sarkozy C, Gascoyne RD, Connors JM, Ben-Neriah S, Mungall A, Marra MA, Siebert R, Scott DW, Savage KJ, Steidl C. Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma. Blood. 2019 Sep 5;134(10):802–813.

Citing

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Krysta Coyle, Kostiantyn Dreval, Daniel Hodson and Ryan D. Morin. Audit of B-cell cancer genes. Blood Adv (2025) 9 (8): 2019–2031.

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