EZH2 - morinlab/LLMPP GitHub Wiki

bibliography: 'morinlab.bib' csl: 'NLM.csl' link-citations: true nocite: | @mottokIntegrativeGenomicAnalysis2019, @morinSomaticMutationsAltering2010, @loveGeneticLandscapeMutations2012

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.[@morinSomaticMutationsAltering2010] 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.[@yapSomaticMutationsEZH22011] 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.[@scholzeCombinedEZH2Bcl22020]

Relevance tier by entity

include:tables/table1_EZH2

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Mutation pattern and selective pressure estimates

include:tables/dnds_EZH2.md

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