DTX1 - morinlab/LLMPP GitHub Wiki

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DTX1

Overview

Mutations in the DTX1 gene, which encodes the E3 ubiquitin ligase Deltex 1, have been identified in various B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). DTX1 is one of a number of genes affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. These mutations are associated with the BN2 genetic subgroup of DLBCL. There are numerous mutation hotspots in this gene with some leading to a truncated protein. DTX1 functions as a negative regulator of the Notch signaling pathway. Some DTX1 mutations impair its function, thereby dysregulating Notch signaling, which is crucial for normal B-cell development and function. Due to minimal support in the original primary data and very few mutations reported in subsequent BL studies, this gene is very unlikely to be relevant in BL.

History

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timeline
    title Publication timing
      2012-08-27 : Rossi : MZL
      2012-12-01 : Love : BL
      2013-01-01 : Zhang : DLBCL
      2018-04-12 : Schmitz : DLBCL
      2018-05-01 : Chapuy : DLBCL
      2023-11-15 : Gomez : PMBL

Relevance tier by entity

Entity	Tier	Description
	1	high-confidence PMBL/cHL/GZL gene[@gomezUltraDeepSequencingReveals2023]
	1	high-confidence MZL gene[@rossiCodingGenomeSplenic2012c]
	3	Retired, Failed QC[@loveGeneticLandscapeMutations2012]
	1	aSHM target and high-confidence DLBCL gene [@zhangGeneticHeterogeneityDiffuse2013; @schmitzGeneticsPathogenesisDiffuse2018a; @chapuyMolecularSubtypesDiffuse2018b]
	1	aSHM target and high-confidence FL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
DLBCL	GAMBL genomes	10.71
DLBCL	Schmitz cohort	13.62
DLBCL	Reddy cohort	5.91
DLBCL	Chapuy cohort	11.54
FL	GAMBL genomes	5.54
BL	GAMBL genomes+capture	5.54
BL	Thomas cohort	5.90
BL	Panea cohort	8.90

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
DLBCL	Yes	Yes	2.228	4.244
FL	Yes	No	6.305	0.000
BL	Yes	No	5.556	14.253

aSHM regions

chr_name	hg19_start	hg19_end	region	regulatory_comment
chr12	113492311	113497546	TSS	NA

DTX1 Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr12	113496076	G>A	V27M
chr12	113496081	G>A	W28*
chr12	113496082	G>A	E29K
chr12	113496083	A>G	E29G
chr12	113496085	T>G	W30G
chr12	113496087	G>A	W30*
chr12	113496089	T>A	L31Q
chr12	113496089	T>C	L31P
chr12	113496096	G>C	E33D
chr12	113496097	C>T	H34Y
chr12	113496112	C>T	P39S
chr12	113496115	T>C	Y40H
chr12	113496116	A>C	Y40S
chr12	113496116	A>G	Y40C
chr12	113496117	C>G	Y40*
chr12	113496121	G>C	A42P
chr12	113496130	T>A	C45S
chr12	113496132	C>A	C45*
chr12	113496133	C>T	H46Y
chr12	113496135	C>A	H46Q
chr12	113496139	A>T	I48F
chr12	113496140	T>A	I48N
chr12	113496141	T>G	I48M
chr12	113496148	G>A	V51M
chr12	113496155	A>T	K53M
chr12	113496156	G>C	K53N
chr12	113496159	G>C	E54D
chr12	113496162	CG>AA	DA55ET
chr12	113496170	G>A	G58D
chr12	113496173	C>A	S59Y
chr12	113496173	C>T	S59F
chr12	113496175	G>A	V60M
chr12	113496191	T>C	V65A
chr12	113496191	T>G	V65G
chr12	113496196	G>A	A67T
chr12	113496197	C>T	A67V
chr12	113496201	G>C	Q68H
chr12	113496202	C>T	L69F
chr12	113496205	G>C	V70L
chr12	113496208	C>G	P71A
chr12	113496208	C>T	P71S
chr12	113496210	CT>TC	Y72H
chr12	113496212	A>G	Y72C
chr12	113496213	C>A	Y72*