Table of Contents

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.

Relevance tier by entity

Entity Tier Description
PMBL 1 high-confidence PMBL/cHL/GZL gene1
BL 2-a aSHM target; Although recurrent, the relevance of mutations in BL is tenuous2
DLBCL 1-a aSHM target and high-confidence DLBCL gene3
FL 1-a aSHM target and high-confidence FL gene3

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
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

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Expression

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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.
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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 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

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