CREBBP - morinlab/LLMPP GitHub Wiki

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CREBBP

Overview

CREBBP mutations are highly prevalent in both DLBCL and FL.[@pasqualucciInactivatingMutationsAcetyltransferase2011a] 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.[@drevalGeneticSubdivisionsFollicular2023]

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.[@pasqualucciInactivatingMutationsAcetyltransferase2011a] In a transgenic mouse model, CREBBP loss cooperated with BCL2 overexpression to promote B-cell lymphomagenesis.[@garcia-ramirezCrebbpLossCooperates2017] Mutations in CREBBP and EP300 affect a common pathway and have been described as mutually exclusive due to some functional redundancy.[@pasqualucciInactivatingMutationsAcetyltransferase2011a; @veazeyCARM1InhibitionReduces2020b] 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.[@nieGenomewideCRISPRScreens2021b]

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%%
timeline
    title Publication timing
      2011-03-10 : Pasqualucci : DLBCL
      2012-12-01 : Love : BL
      2013-12-13 : Parry : MZL
      2021-07-15 : Duns : PMBL

Relevance tier by entity

Entity	Tier	Description
	2	relevance in MZL not firmly established[@parryWholeExomeSequencing2013]
	1	high-confidence PMBL/cHL/GZL gene[@dunsCharacterizationDLBCLPMBL2021b]
	1-EE	high-confidence DLBCL gene supported by functional data[@pasqualucciInactivatingMutationsAcetyltransferase2011a]
	1-EE	high-confidence FL gene supported by functional data[@pasqualucciInactivatingMutationsAcetyltransferase2011a]
	2	association with BL is tenuous[@loveGeneticLandscapeMutations2012]

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
DLBCL	GAMBL genomes	25.81
DLBCL	Schmitz cohort	17.87
DLBCL	Reddy cohort	12.11
DLBCL	Chapuy cohort	16.67
FL	GAMBL genomes	65.13
BL	GAMBL genomes+capture	6.00
BL	Thomas cohort	3.00
BL	Panea cohort	12.90

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	No	No	1.357	3.999
DLBCL	No	Yes	13.231	65.302
FL	No	Yes	43.869	112.938

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