KLHL14

Overview

KLHL14 (Kelch-like family member 14) is a gene that has been identified as playing a role in B-cell lymphomas, particularly diffuse large B-cell lymphoma (DLBCL).¹ KLHL14 has been identified as a recurrent target of somatic mutations in ABC DLBCLs. These mutations are a feature of the MCD genetic subgroup of DLBCL. The gene encodes a protein involved in the ubiquitin-proteasome system, and its inactivation leads to increased cell proliferation and survival, suggesting its role as a tumor suppressor.² KLHL14 loss has been shown to BCR-dependent NF-κB activation and cell survival in DLBCL.² This gene has some mutation hotspots but the patter of mutation overall is consistent with its role as a tumor suppressor gene.

Relevance tier by entity

Entity	Tier	Description
DLBCL	1	high-confidence DLBCL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
DLBCL	GAMBL genomes	4.59
DLBCL	Schmitz cohort	6.60
DLBCL	Reddy cohort	4.60
DLBCL	Chapuy cohort	7.26

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	No	No	0.000	0.000
DLBCL	No	No	3.154	2.846
FL	No	No	12.248	24.944

[!NOTE] First described in DLBCL in 2013 by Zhang J

## KLHL14 Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr18	30349909	G>A	L216F
chr18	30349905	T>G	N217T
chr18	30349902	A>C	F218C
chr18	30349882	G>C	L225V

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

References

1. 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. Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1398-403. doi: 10.1073/pnas.1205299110. Epub 2013 Jan 4. PMID: 23292937; PMCID: PMC3557051.
2. Choi J, Phelan JD, Wright GW, Häupl B, Huang DW, Shaffer AL 3rd, Young RM, Wang Z, Zhao H, Yu X, Oellerich T, Staudt LM. Regulation of B cell receptor-dependent NF-κB signaling by the tumor suppressor KLHL14. Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):6092-6102. doi: 10.1073/pnas.1921187117. Epub 2020 Mar 3. PMID: 32127472; PMCID: PMC7084139.

KLHL14 Expression