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. Missense mutations are predominantly found in male patients and rarely in females, hence showing a sex-specific pattern.²

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2012-10-04 : Schmitz : BL 2017-10-10 : Reddy : DLBCL 2018-04-12 : Schmitz : DLBCL 2018-10-01 : Arthur : DLBCL 2019-09-05 : Mottok : PMBL

Relevance tier by entity

Entity	Tier	Description
	1	high-confidence PMBL/cHL/GZL gene³
	1	high-confidence BL gene⁴
	1	high-confidence DLBCL gene^5–7
	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

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

DDX3X Expression

References

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. PMCID: PMC6804880

Gong C, Krupka JA, Gao J, Grigoropoulos NF, Giotopoulos G, Asby R, Screen M, Usheva Z, Cucco F, Barrans S, Painter D, Zaini NBM, Haupl B, Bornelöv S, Ruiz De Los Mozos I, Meng W, Zhou P, Blain AE, Forde S, Matthews J, Khim Tan MG, Burke GAA, Sze SK, Beer P, Burton C, Campbell P, Rand V, Turner SD, Ule J, Roman E, Tooze R, Oellerich T, Huntly BJ, Turner M, Du MQ, Samarajiwa SA, Hodson DJ. Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis. Molecular Cell. 2021;

Mottok A, Hung SS, Chavez EA, Woolcock B, Telenius A, Chong LC, Meissner B, Nakamura H, Rushton C, Viganò E, Sarkozy C, Gascoyne RD, Connors JM, Ben-Neriah S, Mungall A, Marra MA, Siebert R, Scott DW, Savage KJ, Steidl C. Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma. Blood. 2019 Sep 5;134(10):802–813.

Schmitz R, Young RM, Ceribelli M, Jhavar S, Xiao W, Zhang M, Wright G, Shaffer AL, Hodson DJ, Buras E, Liu X, Powell J, Yang Y, Xu W, Zhao H, Kohlhammer H, Rosenwald A, Kluin P, Müller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Ogwang MD, Reynolds SJ, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pittaluga S, Wilson W, Waldmann TA, Rowe M, Mbulaiteye SM, Rickinson AB, Staudt LM. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. 2012 Oct 4;490(7418):116–120. PMCID: PMC3609867

Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, Leppa S, Pasanen A, Meriranta L, Karjalainen-Lindsberg ML, Nørgaard P, Pedersen M, Gang AO, Høgdall E, Heavican TB, Lone W, Iqbal J, Qin Q, Li G, Kim SY, Healy J, Richards KL, Fedoriw Y, Bernal-Mizrachi L, Koff JL, Staton AD, Flowers CR, Paltiel O, Goldschmidt N, Calaminici M, Clear A, Gribben J, Nguyen E, Czader MB, Ondrejka SL, Collie A, Hsi ED, Tse E, Au-Yeung RKH, Kwong YL, Srivastava G, Choi WWL, Evens AM, Pilichowska M, Sengar M, Reddy N, Li S, Chadburn A, Gordon LI, Jaffe ES, Levy S, Rempel R, Tzeng T, Happ LE, Dave T, Rajagopalan D, Datta J, Dunson DB, Dave SS. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell. 2017 Oct;171(2):481–494.e15. PMCID: PMC5659841

Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, Roulland S, Kasbekar M, Young RM, Shaffer AL, Hodson DJ, Xiao W, Yu X, Yang Y, Zhao H, Xu W, Liu X, Zhou B, Du W, Chan WC, Jaffe ES, Gascoyne RD, Connors JM, Campo E, Lopez-Guillermo A, Rosenwald A, Ott G, Delabie J, Rimsza LM, Tay Kuang Wei K, Zelenetz AD, Leonard JP, Bartlett NL, Tran B, Shetty J, Zhao Y, Soppet DR, Pittaluga S, Wilson WH, Staudt LM. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med. 2018 Apr 12;378(15):1396–1407. PMCID: PMC6010183

Arthur SE, Jiang A, Grande BM, Alcaide M, Cojocaru R, Rushton CK, Mottok A, Hilton LK, Lat PK, Zhao EY, Culibrk L, Ennishi D, Jessa S, Chong L, Thomas N, Pararajalingam P, Meissner B, Boyle M, Davidson J, Bushell KR, Lai D, Farinha P, Slack GW, Morin GB, Shah S, Sen D, Jones SJM, Mungall AJ, Gascoyne RD, Audas TE, Unrau P, Marra MA, Connors JM, Steidl C, Scott DW, Morin RD. Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. Nat Commun. 2018 Oct 1;9(1):4001. PMCID: PMC6167379