EZH2 - morinlab/LLMPP GitHub Wiki


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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.[@morinSomaticMutationsAltering2010a] EZH2 mutations are one of the defining features of the EZB genetic subgroup of DLBCL.[@wrightProbabilisticClassificationTool2020] 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]

Experimental Evidence

Mutations at the main hotspot and some less common hotspots lead to enhanced methylation by PRC2.[@yapSomaticMutationsEZH22011b] A number of small molecule/pharmacologic inhibitors of EZH2 activity have been described.[@garapaty-raoIdentificationEZH2EZH12013; @knutsonSelectiveInhibitionEZH22014] At least one of these, tazemetostat, has shown benefit in FL.[@morinTreatingLymphomaNow2021] Combination therapies including EZH2 inhibitors are also under exploration for DLBCL patients with mutant EZH2.[@scholzeCombinedEZH2Bcl22020b]

History

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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
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Relevance tier by entity

Entity Tier Description
MZL 1 high-confidence MZL gene
PMBL 1 high-confidence PMBL/cHL/GZL gene[@mottokIntegrativeGenomicAnalysis2019b]
DLBCL 1-EE high-confidence DLBCL gene supported by functional data [@morinSomaticMutationsAltering2010a]
FL 1-EE high-confidence FL gene supported by functional data [@morinSomaticMutationsAltering2010a]
BL 2 relevance in BL not firmly established[@loveGeneticLandscapeMutations2012]

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

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

References

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