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

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% 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
PMBL 1 high-confidence PMBL/cHL/GZL gene1
MZL 1 high-confidence MZL generossiCodingGenomeSplenic2012c?
BL 3 Retired, Failed QC2
DLBCL 1 aSHM target and high-confidence DLBCL gene3,schmitzGeneticsPathogenesisDiffuse2018a?,chapuyMolecularSubtypesDiffuse2018b?
FL 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*

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

DTX1 Expression

Representative Mutations

BL2

Rating ★ ☆ ☆ ☆ ☆

DLBCLschmitzGeneticsPathogenesisDiffuse2018a?

Rating ★ ★ ★ ★ ☆

All Mutations

BL

1059 323 742

References

1.
Gomez F, Fisk B, McMichael JF, Mosior M, Foltz JA, Skidmore ZL, Duncavage EJ, Miller CA, Abel H, Li YS, Russler-Germain DA, Krysiak K, Watkins MP, Ramirez CA, Schmidt A, Martins Rodrigues F, Trani L, Khanna A, Wagner JA, Fulton RS, Fronick CC, O’Laughlin MD, Schappe T, Cashen AF, Mehta-Shah N, Kahl BS, Walker J, Bartlett NL, Griffith M, Fehniger TA, Griffith OL. Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma. Cancer Res Commun. 2023 Nov 15;3(11):2312–2330. PMCID: PMC10648575
2.
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
3.
Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA, Dunphy C, Choi W, Au WY, Srivastava G, Lugar PL, Rizzieri DA, Lagoo AS, Bernal-Mizrachi L, Mann KP, Flowers C, Naresh K, Evens A, Gordon LI, Czader M, Gill JI, Hsi ED, Liu Q, Fan A, Walsh K, Jima D, Smith LL, Johnson AJ, Byrd JC, Luftig MA, Ni T, Zhu J, Chadburn A, Levy S, Dunson D, Dave SS. Genetic heterogeneity of diffuse large B-cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:1398–1403. PMCID: PMC3557051

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