KLHL6

Overview

KLHL6 mutations appear to be relatively common in DLBCL, FL and possibly BL.¹ KLHL6 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. KLHL6 mutations lead to the loss of its function as part of a cullin-RING ubiquitin ligase complex. KLHL6 is considered a tumor suppressor gene in DLBCL with mutations tending to disrupt its interaction with cullin3, leading to the loss of its ligase activity.²

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2011-07-27 : Morin : FL 2016-05-27 : Ganapathi : MZL

Relevance tier by entity

Entity	Tier	Description
	1	high-confidence MZL gene
	1-a	aSHM target and high-confidence DLBCL gene
	1-a	aSHM target and high-confidence FL gene
	2-a	aSHM target; Although recurrent, the relevance of mutations in BL is tenuous

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
DLBCL	GAMBL genomes	5.35
DLBCL	Schmitz cohort	9.15
DLBCL	Reddy cohort	6.41
DLBCL	Chapuy cohort	8.97
FL	GAMBL genomes	7.16
BL	GAMBL genomes+capture	3.93
BL	Thomas cohort	3.00
BL	Panea cohort	6.90

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	Yes	No	4.630	0.000
DLBCL	Yes	No	7.379	6.684
FL	Yes	Yes	20.169	55.914

aSHM regions

chr_name	hg19_start	hg19_end	region	regulatory_comment
chr3	183269360	183274139	TSS	active_promoter-strong_enhancer

## KLHL6 Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr3	183273284	C>A	G53V
chr3	183273275	A>T	L56*
chr3	183273274	T>G	L56F
chr3	183273248	A>T	L65Q
chr3	183273248	A>G	L65P
chr3	183273235	G>C	N69K
chr3	183273234	C>G	A70P
chr3	183273224	T>G	D73A
chr3	183273223	A>C	D73E
chr3	183273218	A>C	I75S
chr3	183273204	T>C	I80V
chr3	183273198	C>G	E82Q
chr3	183273195	A>G	F83L
chr3	183273179	A>T	V88E
chr3	183273174	G>A	L90F
chr3	183273162	T>C	S94G
chr3	183273162	T>A	S94C
chr3	183273161	C>T	S94N
chr3	183273161	C>G	S94T
chr3	183273161	C>A	S94I
chr3	183273155	T>A	Y96F
chr3	183273153	A>G	F97L

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

KLHL6 Expression

References

Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJ, Connors JM, Hirst M, Gascoyne RD, Marra MA. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011 Jul 27;476(7360):298-303. doi: 10.1038/nature10351. PMID: 21796119; PMCID: PMC3210554.
Choi, J., Zhou, N., & Busino, L. (2019). KLHL6 is a tumor suppressor gene in diffuse large B-cell lymphoma. Cell Cycle, 18, 249 - 256. https://doi.org/10.1080/15384101.2019.1568765.