DDX3X

Overview

Mutations in the DDX3X gene, which encodes an RNA helicase involved in various aspects of RNA metabolism, have significant implications in B-cell lymphomas, including BL, DLBCL, and other related malignancies and are particularly enriched within MYC-translocated tumors and those expressing the dark zone signature (DZsig).¹ These mutations are predominantly loss-of-function (LOF) mutations, affecting the helicase domain of the protein.² Missense mutations are predominantly found in male patients and rarely in females, hence showing a sex-specific pattern.³

Relevance tier by entity

Entity	Tier	Description
BL	1	high-confidence BL gene
DLBCL	1	high-confidence DLBCL gene
FL	2	Although recurrent, the relevance of mutations in FL is tenuous

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
BL	GAMBL genomes+capture	44.34
BL	Thomas cohort	48.70
BL	Panea cohort	39.60
DLBCL	GAMBL genomes	8.80
DLBCL	Schmitz cohort	4.68
DLBCL	Reddy cohort	4.50
DLBCL	Chapuy cohort	5.56
FL	GAMBL genomes	2.54

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	Yes	Yes	19.270	125.826
DLBCL	Yes	No	3.193	8.744
FL	Yes	No	11.136	21.489

aSHM regions

chr_name	hg19_start	hg19_end	region	regulatory_comment
chrX	42800580	42804184	intergenic	NA

[!NOTE] First described in BL in 2012 by Schmitz R. First described in DLBCL in 2018 by Schmitz R. First described in FL in 2023 by Dreval K

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

References

1. Ennishi D, Jiang A, Boyle M, Collinge B, Grande BM, Ben-Neriah S, Rushton C, Tang J, Thomas N, Slack GW, Farinha P, Takata K, Miyata-Takata T, Craig J, Mottok A, Meissner B, Saberi S, Bashashati A, Villa D, Savage KJ, Sehn LH, Kridel R, Mungall AJ, Marra MA, Shah SP, Steidl C, Connors JM, Gascoyne RD, Morin RD, Scott DW. Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583. Epub 2018 Dec 3. PMID: 30523716; PMCID: PMC6804880.
2. Lacroix, M., Beauchemin, H., & Möröy, T. (2022). DDX3: a relevant therapeutic target for lymphoma?. Expert Opinion on Therapeutic Targets, 26, 1037 - 1040. https://doi.org/10.1080/14728222.2022.2166830.
3. Gong, C., Krupka, J., Gao, J., Grigoropoulos, N., Giotopoulos, G., Asby, R., Screen, M., Usheva, Z., Cucco, F., Barrans, S., Painter, D., Zaini, N., Haupl, B., Bornelöv, S., Mozos, I., Meng, W., Zhou, P., Blain, A., Forde, S., Matthews, J., Tan, M., Burke, G., Sze, S., Beer, P., Burton, C., Campbell, P., Rand, V., Turner, S., Ule, J., Roman, E., Tooze, R., Oellerich, T., Huntly, B., Turner, M., Du, M., Samarajiwa, S., & Hodson, D. (2021). Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis.. Molecular cell. https://doi.org/10.1016/j.molcel.2021.07.041.