KMT2D

Overview

KMT2D (also known as MLL2) encodes a histone H3K4 methyltransferase, playing a crucial role in germinal center B cell development and function. Mutations in KMT2D are among the most common mutations in FL and are also common in DLBCL.¹ KMT2D mutations are recurrent but less common in BL and MCL and many other B-cell neoplasms. Mutations typically cause loss of KMT2D function, leading to diminished H3K4 methylation, impacting gene expression that favours lymphomagenesis. KMT2D mutations are associated with poor prognosis in DLBCL.^2,3

Relevance tier by entity

Entity	Tier	Description
BL	1	high-confidence BL gene
DLBCL	1	high-confidence DLBCL gene
FL	1	high-confidence FL gene
MCL	1	high-confidence MCL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
BL	GAMBL genomes+capture	11.32
BL	Thomas cohort	14.00
BL	Panea cohort	15.80
DLBCL	GAMBL genomes	33.46
DLBCL	Schmitz cohort	34.47
DLBCL	Reddy cohort	22.32
DLBCL	Chapuy cohort	26.07
FL	GAMBL genomes	67.67
MCL	GAMBL genomes	16.59

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	No	Yes	0.689	13.459
DLBCL	No	Yes	3.731	104.190
FL	No	Yes	20.755	1353.812

[!NOTE] First described in BL in 2019 by Grande BM. First described in DLBCL in 2011 by Morin RD. First described in FL in 2011 by Morin RD. First described in MCL in 2013 by Beà S

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

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 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.
2. You, H., Xu-Monette, Z., Wei, L., Nunns, H., Nagy, M., Bhagat, G., Fang, X., Zhu, F., Visco, C., Tzankov, A., Dybkaer, K., Chiu, A., Tam, W., Zu, Y., Hsi, E., Hagemeister, F., Huh, J., Ponzoni, M., Ferreri, A., Møller, M., Parsons, B., Krieken, J., Piris, M., Winter, J., Li, Y., Au, Q., Xu, B., Albitar, M., & Young, K. (2021). Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma. Oncoimmunology, 10. https://doi.org/10.1080/2162402X.2021.1928365.
3. Rushton CK, Arthur SE, Alcaide M, Cheung M, Jiang A, Coyle KM, Cleary KLS, Thomas N, Hilton LK, Michaud N, Daigle S, Davidson J, Bushell K, Yu S, Rys RN, Jain M, Shepherd L, Marra MA, Kuruvilla J, Crump M, Mann K, Assouline S, Connors JM, Steidl C, Cragg MS, Scott DW, Johnson NA, Morin RD. Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma. Blood Adv. 2020 Jul 14;4(13):2886-2898. doi: 10.1182/bloodadvances.2020001696. PMID: 32589730; PMCID: PMC7362366.