IL4R

Overview

Mutations in IL4R have been identified in various types of B-cell lymphomas, particularly primary mediastinal large B-cell lymphoma (PMBCL) and DLBCL. IL4R 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. IL4R mutations are found in approximately 24.2% of primary PMBCL cases. These mutations are commonly single nucleotide variants in exon 8, resulting in the I242N amino acid change. This leads to constitutive activation of the JAK-STAT signaling pathway and upregulation of downstream cytokine expression profiles and B cell-specific antigens.^1,2 In DLBCL, IL4R mutations are more rare and tend to occur within the GCB subgroup.²

Relevance tier by entity

Entity	Tier	Description
DLBCL	1-a	aSHM target and high-confidence DLBCL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
DLBCL	GAMBL genomes	2.68
DLBCL	Schmitz cohort	2.13
DLBCL	Reddy cohort	2.50
DLBCL	Chapuy cohort	3.85

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	Yes	No	3.355	0
DLBCL	Yes	No	9.640	0
FL	Yes	No	0.000	0

aSHM regions

chr_name	hg19_start	hg19_end	region	regulatory_comment
chr16	27322895	27329423	TSS	active_promoter

[!NOTE] First described in DLBCL in 2021 by Duns G

## IL4R Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr16	27367183	T>A	I242N

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

References

1. Gunawardana, J., Tol, T., Mak, K., Twa, D., Chavez, E., Woolcock, B., Kridel, R., Mottok, A., Healy, S., Telenius, A., Boyle, M., Ben-Neriah, S., Hung, S., Hother, C., Gascoyne, R., & Steidl, C. (2015). Abstract 3941: Recurrent IL4R mutations in primary mediastinal large B cell lymphoma. Cancer Research, 75, 3941-3941. https://doi.org/10.1158/1538-7445.AM2015-3941.
2. Viganò E, Gunawardana J, Mottok A, Van Tol T, Mak K, Chan FC, Chong L, Chavez E, Woolcock B, Takata K, Twa D, Shulha HP, Telenius A, Kutovaya O, Hung SS, Healy S, Ben-Neriah S, Leroy K, Gaulard P, Diepstra A, Kridel R, Savage KJ, Rimsza L, Gascoyne R, Steidl C. Somatic IL4R mutations in primary mediastinal large B-cell lymphoma lead to constitutive JAK-STAT signaling activation. Blood. 2018 May 3;131(18):2036-2046. doi: 10.1182/blood-2017-09-808907. Epub 2018 Feb 21. PMID: 29467182.