IRF8

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bibliography: 'morinlab.bib' csl: 'NLM.csl' link-citations: true

IRF8

Overview

IRF8 (Interferon Regulatory Factor 8) is a transcription factor critical for the development and function of B lymphocytes. Mutations in IRF8 have been implicated in various lymphoid malignancies, most predominantly in FL and DLBCL. IRF8 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. Coding and non-coding mutations in IRF8 are associated with the EZB subgroup of DLBCL. There is preliminary evidence that IRF8 mutations contribute to immune evasion by downregulating CD74 and HLA-DM in DLBCL. These are crucial for processing and presentation of self antigens.

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%%
timeline
    title Publication timing
      2011-07-27 : Morin : DLBCL
      2019-09-05 : Mottok : PMBL
      2019-09-26 : Panea : BL

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Relevance tier by entity

Entity	Tier	Description
	1	high-confidence PMBL/cHL/GZL gene[@mottokIntegrativeGenomicAnalysis2019b]
	2-a	aSHM target; Although recurrent, the relevance of mutations in BL is tenuous [@paneaWholeGenomeLandscape2019]
	1-a	aSHM target and high-confidence DLBCL gene [@morinFrequentMutationHistonemodifying2011]
	1-a	aSHM target and high-confidence FL gene [@morinFrequentMutationHistonemodifying2011]

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
BL	GAMBL genomes+capture	2.31
BL	Thomas cohort	1.30
BL	Panea cohort	6.90
DLBCL	GAMBL genomes	8.03
DLBCL	Schmitz cohort	10.43
DLBCL	Reddy cohort	7.61
DLBCL	Chapuy cohort	10.26
FL	GAMBL genomes	12.01

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	Yes	No	1.360	0.000
DLBCL	Yes	Yes	6.806	0.000
FL	Yes	Yes	28.663	102.572

aSHM regions

chr_name	hg19_start	hg19_end	region	regulatory_comment
chr16	85931918	85933977	TSS	active_promoter

IRF8 Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr16	85936688	T>C	Y23H
chr16	85936701	T>G	I27S
chr16	85936784	T>G	S55A
chr16	85936788	T>C	I56T
chr16	85942602	G>T	A61S
chr16	85942618	A>G	K66R
chr16	85942671	T>C	C84R
chr16	85942692	G>A	D91N

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

IRF8 Expression

References

1. Wright GW, Huang DW, Phelan JD, Coulibaly ZA, Roulland S, Young RM, Wang JQ, Schmitz R, Morin RD, Tang J, Jiang A, Bagaev A, Plotnikova O, Kotlov N, Johnson CA, Wilson WH, Scott DW, Staudt LM. A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications. Cancer Cell. 2020 Apr 13;37(4):551-568.e14. doi: 10.1016/j.ccell.2020.03.015. PMID: 32289277; PMCID: PMC8459709.
2. Qiu Z, Khalife J, Lin AP, Ethiraj P, Jaafar C, Chiou L, Huelgas-Morales G, Aslam S, Arya S, Gupta YK, Dahia PLM, Aguiar RCT. IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHC CII complexes. bioRxiv [Preprint]. 2023 Oct 15:2023.10.14.560755. doi: 10.1101/2023.10.14.560755. PMID: 37873241; PMCID: PMC10592808.
3. 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.