Table of Contents

Overview

CREBBP mutations are highly prevalent in both DLBCL and FL.1 This gene has some recurrent sites of mutations (hotspots), mostly in the HAT domain. The pattern of mutations in DLBCL is distinct from FL with the latter having more HAT domain mutations relative to truncating mutations.2

Experimental Evidence

CREBBP missense mutations often affect the histone acetyltransferase (HAT) domain, crucial for regulating gene expression through chromatin modification, or generate a truncated protein.1 In a transgenic mouse model, CREBBP loss cooperated with BCL2 overexpression to promote B-cell lymphomagenesis.3 Mutations in CREBBP and EP300 affect a common pathway and have been described as mutually exclusive due to some functional redundancy.1,4 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.5

Relevance tier by entity

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Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 207 0.1901 [0.1668,0.2134]
DLBCL GAMBL with Reddy 2,088 328 0.1571 [0.1415,0.1727]
DLBCL BC 231 52 0.2251 [0.1712,0.279]
DLBCL Dana-Farber 303 55 0.1815 [0.1381,0.2249]
DLBCL NCI 470 84 0.1787 [0.1441,0.2134]
DLBCL Reddy 999 121 0.1211 [0.1009,0.1414]
DLBCL DLBCL_ICGC 85 16 0.1882 [0.1051,0.2713]

FL

pathology Collection N mutated Incidence CI
FL GAMBL without Crouch 642 375 0.5841 [0.546,0.6222]
FL GAMBL with Crouch 1,189 738 0.6207 [0.5931,0.6483]
FL BC 379 229 0.6042 [0.555,0.6535]
FL Kalmbach 164 88 0.5366 [0.4603,0.6129]
FL Crouch 547 363 0.6636 [0.624,0.7032]
FL FL_ICGC 99 58 0.5859 [0.4888,0.6829]

BL

pathology Collection N mutated Incidence CI
BL GAMBL without Panea 309 11 0.0238 [0.0069,0.0407]
BL GAMBL without ICGC/Zhou 320 17 0.0258 [0.0087,0.043]
BL GAMBL with Panea 410 24 0.0304 [0.014,0.0467]
BL BLGSP 219 4 0.0183 [5e-04,0.036]
BL Zhou/ICGC 90 7 0.0778 [0.0224,0.1331]
BL Panea 101 13 0.1287 [0.0634,0.194]

Mutation pattern and selective pressure estimates

Entity Missense dN/dS Nonsense dN/dS Q value
BL 1.7791 5.2296 1
FL 22.2889 75.5630 0
DLBCL 3.1980 16.7955 0

CREBBP Hotspots

Chromosome Coordinate (hg19) ref>alt HGVSp
chr16 3788618 G>A R1446C
chr16 3788617 C>T R1446H
chr16 3788617 C>A R1446L
chr16 3788606 A>T Y1450N
chr16 3788606 A>C Y1450D
chr16 3788605 T>G Y1450S
chr16 3788605 T>C Y1450C
chr16 3788596 A>G I1453T
chr16 3788594 G>T L1454I
chr16 3788593 A>C L1454R
chr16 3786715 A>T L1499Q
chr16 3786715 A>G L1499P
chr16 3786715 A>C L1499R
chr16 3786710 C>A E1501*
chr16 3786707 A>T W1502R
chr16 3786707 A>G W1502R
chr16 3786705 C>T W1502*
chr16 3786705 C>G W1502C
chr16 3786705 C>A W1502C
chr16 3786704 A>T Y1503N
chr16 3786704 A>G Y1503H
chr16 3786704 A>C Y1503D
chr16 3786703 T>G Y1503S
chr16 3786703 T>A Y1503F
chr16 3786691 A>G L1507P

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Expression

Representative Mutations

BL

Source6

Rating ★ ★ ★ ★ ☆

All Mutations

BL

1093 322 324 515 677 745 851

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References

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Dreval K, Hilton LK, Cruz M, Shaalan H, Ben-Neriah S, Boyle M, Collinge B, Coyle KM, Duns G, Farinha P, Grande BM, Meissner B, Pararajalingam P, Rushton CK, Slack GW, Wong J, Mungall AJ, Marra MA, Connors JM, Steidl C, Scott DW, Morin RD. Genetic subdivisions of follicular lymphoma defined by distinct coding and noncoding mutation patterns. Blood. 2023 Aug 10;142(6):561–573. PMCID: PMC10644066
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García-Ramírez I, Tadros S, González-Herrero I, Martín-Lorenzo A, Rodríguez-Hernández G, Moore D, Ruiz-Roca L, Blanco O, Alonso-López D, Rivas JDL, Hartert K, Duval R, Klinkebiel D, Bast M, Vose J, Lunning M, Fu K, Greiner T, Rodrigues-Lima F, Jiménez R, Criado FJG, Cenador MBG, Brindle P, Vicente-Dueñas C, Alizadeh A, Sánchez-García I, Green MR. Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice. Blood. 2017 May 11;129(19):2645–2656. PMCID: PMC5428458
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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
5.
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
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Love C, Sun Z, Jima D, Li G, Zhang J, Miles R, Richards KL, Dunphy CH, Choi WWL, Srivastava G, Lugar PL, Rizzieri DA, Lagoo AS, Bernal-Mizrachi L, Mann KP, Flowers CR, Naresh KN, Evens AM, Chadburn A, Gordon LI, Czader MB, Gill JI, Hsi ED, Greenough A, Moffitt AB, McKinney M, Banerjee A, Grubor V, Levy S, Dunson DB, Dave SS. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet. 2012 Dec;44(12):1321–1325. PMCID: PMC3674561
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Duns G, Viganò E, Ennishi D, Sarkozy C, Hung SS, Chavez E, Takata K, Rushton C, Jiang A, Ben-Neriah S, Woolcock BW, Slack GW, Hsi ED, Craig JW, Hilton LK, Shah SP, Farinha P, Mottok A, Gascoyne RD, Morin RD, Savage KJ, Scott DW, Steidl C. Characterization of DLBCL with a PMBL gene expression signature. Blood. 2021 Jul 15;138(2):136–148.
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Parry M, Rose-Zerilli MJJ, Gibson J, Ennis S, Walewska R, Forster J, Parker H, Davis Z, Gardiner A, Collins A, Oscier DG, Strefford JC. Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma. PLoS One. 2013;8(12):e83244. PMCID: PMC3862727

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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