EZH2

EZH2

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 Mutations of this residue and some of the less common hotspots lead to enhanced methylation by PRC2.^2,3 Pharmacologic inhibitors of this activity such as tazemetostat have shown benefit in FL.³ EZH2 mutations are one of the defining features of the EZB genetic subgroup of DLBCL. Although mutations in EZH2 have been described in some BL patients, they are extremely rare in most studies.⁴

History

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timeline
    title Publication timing
      2010-02-02 : Morin : DLBCL
      2012-12-01 : Love : BL
      2019-09-05 : Mottok : PMBL

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Relevance tier by entity

Entity	Tier	Description
	1	high-confidence MZL gene
	1	high-confidence PMBL/cHL/GZL gene
	1	high-confidence DLBCL gene
	1	high-confidence FL gene
	2	relevance in BL not firmly established

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
BL	GAMBL genomes+capture	3.46
BL	Thomas cohort	1.30
BL	Panea cohort	10.90
DLBCL	GAMBL genomes	13.77
DLBCL	Schmitz cohort	9.15
DLBCL	Reddy cohort	8.91
DLBCL	Chapuy cohort	5.56
FL	GAMBL genomes	24.94

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	No	No	4.992	0
DLBCL	No	Yes	19.753	0
FL	No	Yes	117.987	0

Note

First described in BL in 2012 by Love C. First described in DLBCL in 2010 by Morin RD. First described in FL in 2010 by Morin RD

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

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):181-5. doi: 10.1038/ng.518. Epub 2010 Jan 17. PMID: 20081860; PMCID: PMC2850970.
2. Yap DB, Chu J, Berg T, Schapira M, Cheng SW, Moradian A, Morin RD, Mungall AJ, Meissner B, Boyle M, Marquez VE, Marra MA, Gascoyne RD, Humphries RK, Arrowsmith CH, Morin GB, Aparicio SA. 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):2451-9. doi: 10.1182/blood-2010-11-321208. Epub 2010 Dec 29. PMID: 21190999; PMCID: PMC3062411.
3. Morin RD, Arthur SE, Assouline S. Treating lymphoma is now a bit EZ-er. Blood Adv. 2021 Apr 27;5(8):2256-2263. doi: 10.1182/bloodadvances.2020002773. PMID: 33904892; PMCID: PMC8095133.
4. 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. doi: 10.1182/blood.2022016534. PMID: 36201743; PMCID: PMC10023728.