Table of Contents

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

Relevance tier by entity

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

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 98 0.0900 [0.073,0.107]
DLBCL GAMBL with Reddy 2,088 169 0.0809 [0.0692,0.0926]
DLBCL BC 231 23 0.0996 [0.061,0.1382]
DLBCL Dana-Farber 303 24 0.0792 [0.0488,0.1096]
DLBCL NCI 470 46 0.0979 [0.071,0.1247]
DLBCL Reddy 999 71 0.0711 [0.0551,0.087]
DLBCL DLBCL_ICGC 85 5 0.0588 [0.0088,0.1088]

FL

pathology Collection N mutated Incidence CI
FL GAMBL without Crouch 642 69 0.1075 [0.0835,0.1314]
FL GAMBL with Crouch 1,189 153 0.1287 [0.1096,0.1477]
FL BC 379 43 0.1135 [0.0815,0.1454]
FL Kalmbach 164 17 0.1037 [0.057,0.1503]
FL Crouch 547 84 0.1536 [0.1234,0.1838]
FL FL_ICGC 99 9 0.0909 [0.0343,0.1475]

Mutation pattern and selective pressure estimates

Entity Missense dN/dS Nonsense dN/dS Q value
BL 2.2441 2.2971 1.0000
FL 4.9599 3.4753 0.0001
DLBCL 1.3472 2.2117 0.0202

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

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Expression

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

References

1.
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
2.
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
3.
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
4.
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

Citing

If you use the information or data from this site, please cite

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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