Table of Contents

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

Experimental Evidence

Driver mutations affecting this gene in DLBCL/FL have been experimentally demonstrated to cause a reduction or loss of function (LOF).2

Relevance tier by entity

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Mutation incidence in large patient cohorts (GAMBL reanalysis)

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Mutation pattern and selective pressure estimates

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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

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Expression

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References

1.
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 SJM, 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. PMCID: PMC3210554
2.
Choi J, Lee K, Ingvarsdottir K, Bonasio R, Saraf A, Florens L, Washburn MP, Tadros S, Green MR, Busino L. Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor Roquin2. Nat Cell Biol. 2018 May;20(5):586–596. PMCID: PMC5926793
3.
Ganapathi KA, Jobanputra V, Iwamoto F, Jain P, Chen J, Cascione L, Nahum O, Levy B, Xie Y, Khattar P, Hoehn D, Bertoni F, Murty VV, Pittaluga S, Jaffe ES, Alobeid B, Mansukhani MM, Bhagat G. The genetic landscape of dural marginal zone lymphomas. Oncotarget. Impact Journals; 2016 May 27;7(28):43052–43061.

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