EP300

Overview

Mutations in EP300 are significant contributors to the pathogenesis and progression of B-cell lymphomas such as DLBCL and FL.¹ This gene has some recurrent sites of mutations (hot spots), which typically impact its HAT domain, a region crucial for acetylating histones and non-histone proteins.¹

Experimental Evidence

EP300 mutations impair histone acetylation, disrupt epigenetic gene regulation. Mutations in CREBBP and EP300 affect a common pathway and have been described as mutually exclusive due to some functional redundancy.^1,2 Studies using genome-wide CRISPR-Cas9 screens have identified synthetic lethal interactions between CREBBP and EP300, suggesting that targeting one may affect the viability of cells with mutations in the other.³

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2011-03-10 : Pasqualucci : FL 2012-08-27 : Rossi : MZL 2017-10-10 : Reddy : DLBCL 2018-04-12 : Schmitz : DLBCL 2018-05-01 : Chapuy : DLBCL 2018-10-01 : Arthur : DLBCL

Relevance tier by entity

Entity	Tier	Description
	1	high-confidence MZL gene⁴
	1	high-confidence DLBCL gene supported by functional data¹
	1	high-confidence FL gene supported by functional data¹

Mutation incidence in large patient cohorts (GAMBL reanalysis)

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Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	No	No	2.769	3.550
DLBCL	No	No	3.344	7.980
FL	No	Yes	15.586	7.719

EP300 Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr22	41566459	T>C	Y1446H
chr22	41566460	A>G	Y1446C
chr22	41566460	A>C	Y1446S
chr22	41566462	A>T	I1447F
chr22	41566466	T>G	F1448C
chr22	41566474	C>T	H1451Y
chr22	41566476	T>G	H1451Q
chr22	41566478	C>T	P1452L
chr22	41566486	C>G	Q1455E
chr22	41566487	A>G	Q1455R
chr22	41566488	G>T	Q1455H
chr22	41566495	C>T	P1458S
chr22	41566495	C>A	P1458T
chr22	41566496	C>T	P1458L
chr22	41566511	T>C	L1463P
chr22	41566511	T>G	L1463R
chr22	41566519	T>G	W1466G
chr22	41566519	T>A	W1466R
chr22	41566519	T>C	W1466R
chr22	41566520	G>T	W1466L
chr22	41566521	G>C	W1466C
chr22	41566522	T>A	Y1467N
chr22	41566522	T>C	Y1467H
chr22	41566522	T>G	Y1467D
chr22	41566523	A>G	Y1467C
chr22	41566523	A>T	Y1467F

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

EP300 Expression

References

Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, Kasper LH, Lerach S, Tang H, Ma J, Rossi D, Chadburn A, Murty VV, Mullighan CG, Gaidano G, Rabadan R, Brindle PK, Dalla-Favera R. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011 Mar 10;471(7337):189–195. PMCID: PMC3271441

Veazey KJ, Cheng D, Lin K, Villarreal OD, Gao G, Perez-Oquendo M, Van HT, Stratton SA, Green M, Xu H, Lu Y, Bedford MT, Santos MA. CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas. Leukemia. 2020 Dec;34(12):3269–3285. PMCID: PMC7688486

Nie M, Du L, Ren W, Joung J, Ye X, Shi X, Ciftci S, Liu D, Wu K, Zhang F, Pan-Hammarström Q. Genome-wide CRISPR screens reveal synthetic lethal interaction between CREBBP and EP300 in diffuse large B-cell lymphoma. Cell Death Dis. 2021 Apr 28;12(5):419. PMCID: PMC8080727

Rossi D, Trifonov V, Fangazio M, Bruscaggin A, Rasi S, Spina V, Monti S, Vaisitti T, Arruga F, Famà R, Ciardullo C, Greco M, Cresta S, Piranda D, Holmes A, Fabbri G, Messina M, Rinaldi A, Wang J, Agostinelli C, Piccaluga PP, Lucioni M, Tabbò F, Serra R, Franceschetti S, Deambrogi C, Daniele G, Gattei V, Marasca R, Facchetti F, Arcaini L, Inghirami G, Bertoni F, Pileri SA, Deaglio S, Foà R, Dalla-Favera R, Pasqualucci L, Rabadan R, Gaidano G. The coding genome of splenic marginal zone lymphoma: Activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med. 2012 Aug 27;209(9):1537–1551. PMCID: PMC3428941