Table of Contents

Overview

CXCR4 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. No notable hot spots have been described in this gene in the context of the cancers listed below. The mutation pattern in DLBCL implies the preferential accumulation of inactivating mutations.

Mutations in this gene were first described in DLBCL in 20121 in FL in 20212 and in BL in 2019.3

Experimental Evidence

Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).4

Relevance tier by entity

Entity Tier Description
BL 2 Role of CXCR4 mutations in BL requires confirmation
DLBCL 1 High-confidence DLBCL gene
FL 2 Role of CXCR4 mutations in FL requires confirmation
MZL 1 High-confidence MZL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 24 0.0220 [0.0133,0.0308]
DLBCL GAMBL with Reddy 2,088 39 0.0187 [0.0129,0.0245]
DLBCL BC 231 5 0.0216 [0.0029,0.0404]
DLBCL Dana-Farber 303 6 0.0198 [0.0041,0.0355]
DLBCL NCI 470 12 0.0255 [0.0113,0.0398]
DLBCL Reddy 999 15 0.0150 [0.0075,0.0226]
DLBCL DLBCL_ICGC 85 1 0.0118 [0,0.0347]

FL

pathology Collection N mutated Incidence CI
FL GAMBL without Crouch 642 19 0.0296 [0.0165,0.0427]
FL GAMBL with Crouch 1,189 33 0.0278 [0.0184,0.0371]
FL BC 379 11 0.0290 [0.0121,0.0459]
FL Kalmbach 164 5 0.0305 [0.0042,0.0568]
FL Crouch 547 14 0.0256 [0.0124,0.0388]
FL FL_ICGC 99 3 0.0303 [0,0.0641]

Mutation pattern and selective pressure estimates

Entity Missense dN/dS Nonsense dN/dS Q value
BL 3.4904 82.8268 0.0057
FL 4.6911 30.4325 0.0007
DLBCL 1.6582 11.0942 0.0000

aSHM regions

chr_name hg19_start hg19_end region regulatory_comment
chr2 136874728 136875461 intron weak_promoter

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Expression

Representative Mutations

BL

Rating ★ ★ ★ ★ ★

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2012-11-12 : Khodabakhshi : DLBCL 2017-01-26 : Krysiak : FL 2017-10-10 : Reddy : DLBCL 2018-05-01 : Chapuy : DLBCL 2019-09-26 : Panea : BL 2021-05-05 : Hubschmann : DLBCL

References

1.
Khodabakhshi AH, Morin RD, Fejes AP, Mungall AJ, Mungall KL, Bolger-Munro M, Johnson NA, Connors JM, Gascoyne RD, Marra MA, Birol I, Jones SJM. Recurrent targets of aberrant somatic hypermutation in lymphoma. Oncotarget. 2012;3(11):1308–1319. PMCID: PMC3717795
2.
Hübschmann D, Kleinheinz K, Wagener R, Bernhart SH, López C, Toprak UH, Sungalee S, Ishaque N, Kretzmer H, Kreuz M, Waszak SM, Paramasivam N, Ammerpohl O, Aukema SM, Beekman R, Bergmann AK, Bieg M, Binder H, Borkhardt A, Borst C, Brors B, Bruns P, Carrillo de Santa Pau E, Claviez A, Doose G, Haake A, Karsch D, Haas S, Hansmann ML, Hoell JI, Hovestadt V, Huang B, Hummel M, Jäger-Schmidt C, Kerssemakers JNA, Korbel JO, Kube D, Lawerenz C, Lenze D, Martens JHA, Ott G, Radlwimmer B, Reisinger E, Richter J, Rico D, Rosenstiel P, Rosenwald A, Schillhabel M, Stilgenbauer S, Stadler PF, Martín-Subero JI, Szczepanowski M, Warsow G, Weniger MA, Zapatka M, Valencia A, Stunnenberg HG, Lichter P, Möller P, Loeffler M, Eils R, Klapper W, Hoffmann S, Trümper L, ICGC MMML-Seq consortium, ICGC DE-Mining consortium, BLUEPRINT consortium, Küppers R, Schlesner M, Siebert R. Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas. Leukemia. 2021 Jul;35(7):2002–2016. PMCID: PMC8257491
3.
Panea R, Love C, Shingleton JR, Reddy A, Bailey J, Moormann A, Otieno J, Ong’echa J, Oduor C, Schroêder K, Masalu N, Chao N, Agajanian M, Major M, Fedoriw Y, Richards K, Rymkiewicz G, Miles R, Alobeid B, Bhagat G, Flowers C, Ondrejka S, Hsi E, Choi W, Au-Yeung R, Hartmann W, Lenz G, Meyerson H, Lin YY, Zhuang Y, Luftig M, Waldrop A, Dave T, Thakkar D, Sahay H, Li G, Palus B, Seshadri V, Kim S, Gascoyne R, Levy S, Mukhopadhyay M, Dunson D, Dave S. The whole genome landscape of Burkitt lymphoma subtypes. Blood. 2019;
4.
Zmajkovicova K, Pawar S, Maier-Munsa S, Maierhofer B, Wiest I, Skerlj R, Taveras AG, Badarau A. Genotype-phenotype correlations in WHIM syndrome: A systematic characterization of CXCR4WHIM variants. Genes Immun. 2022 Sep;23(6):196–204. PMCID: PMC9519442
5.
Krysiak K, Gomez F, White BS, Matlock M, Miller CA, Trani L, Fronick CC, Fulton RS, Kreisel F, Cashen AF, Carson KR, Berrien-Elliott MM, Bartlett NL, Griffith M, Griffith OL, Fehniger TA. Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma. Blood. 2017 Jan 26;129(4):473–483. PMCID: PMC5270390

Citing

If you use the information or data from this site, please cite

Krysta Coyle, Kostiantyn Dreval, Daniel Hodson and Ryan D. Morin. Audit of B-cell cancer genes. Blood Adv (2025) 9 (8): 2019–2031.

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