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

Clinical relevance

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 Tazemetostat (TAZVERIK) has FDA approval for adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least 2 prior systemic therapies, and for adult patients with R/R FL who have no satisfactory alternative treatment options. Combination therapies including EZH2 inhibitors are also under exploration for DLBCL patients with mutant EZH2.9

Relevance tier by entity

Entity Tier Description
BL 1 High-confidence BL gene
DLBCL 1 High-confidence DLBCL gene
FL 1 High-confidence FL gene
MZL 1 High-confidence MZL gene
PMBL 1 High-confidence PMBL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 102 0.0937 [0.0764,0.111]
DLBCL GAMBL with Reddy 2,088 191 0.0915 [0.0791,0.1038]
DLBCL BC 231 32 0.1385 [0.094,0.1831]
DLBCL Dana-Farber 303 19 0.0627 [0.0354,0.09]
DLBCL NCI 470 43 0.0915 [0.0654,0.1176]
DLBCL Reddy 999 89 0.0891 [0.0714,0.1068]
DLBCL DLBCL_ICGC 85 8 0.0941 [0.032,0.1562]

FL

pathology Collection N mutated Incidence CI
FL GAMBL without Crouch 642 143 0.2227 [0.1906,0.2549]
FL GAMBL with Crouch 1,189 291 0.2447 [0.2203,0.2692]
FL BC 379 83 0.2190 [0.1774,0.2606]
FL Kalmbach 164 36 0.2195 [0.1562,0.2829]
FL Crouch 547 148 0.2706 [0.2333,0.3078]
FL FL_ICGC 99 24 0.2424 [0.158,0.3268]

BL

pathology Collection N mutated Incidence CI
BL GAMBL without Panea 309 4 0.0128 [3e-04,0.0254]
BL GAMBL without ICGC/Zhou 320 14 0.0194 [0.0045,0.0344]
BL GAMBL with Panea 410 15 0.0168 [0.0045,0.029]
BL BLGSP 219 3 0.0137 [0,0.0291]
BL Zhou/ICGC 90 1 0.0111 [0,0.0328]
BL Panea 101 11 0.1089 [0.0482,0.1697]

Mutation pattern and selective pressure estimates

Entity Missense dN/dS Nonsense dN/dS Q value
BL 3.5147 0.0000 1
FL 18.8751 0.0000 0
DLBCL 5.6322 0.3606 0

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
EZH2 3D structure with HotMAPS hotspots

Visualizations

Protein

View coding variants in ProteinPaint hg19 or hg38

Genome

View all variants in GenomePaint hg19 or hg38

Expression

Representative Mutations

BL

Rating ★ ★ ★ ★ ★

All Mutations

BL

3

1092 671 672 675

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2010-02-02 : Morin : DLBCL 2012-03-06 : Lohr : DLBCL 2012-12-01 : Love : BL 2013-01-01 : Zhang : DLBCL 2013-08-15 : Morin : DLBCL 2019-09-05 : Mottok : PMBL

References

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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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