FOXO1

Overview

Mutations in the FOXO1 gene, which encodes a member of the forkhead family of transcription factors, play a significant role in diffuse large B-cell lymphoma (DLBCL). Mutations primarily occur in the first exon, with significant portions affecting the N-terminal region and the Forkhead DNA binding domain.¹ These mutations are common in DLBCL, BL and, to a lesser extent, FL.^2,3 FOXO1 mutations can contribute to resistance to certain therapies, such as anti-CD20-based immunotherapies, by repressing MS4A1 (CD20) expression.⁴

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

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
BL	GAMBL genomes+capture	23.33
BL	Thomas cohort	28.00
BL	Panea cohort	21.80
DLBCL	GAMBL genomes	10.13
DLBCL	Schmitz cohort	7.23
DLBCL	Reddy cohort	2.40
DLBCL	Chapuy cohort	2.14
FL	GAMBL genomes	12.93

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	No	Yes	14.841	5.170
DLBCL	No	No	6.936	0.000
FL	No	Yes	18.992	103.028

[!NOTE] First described in BL in 2012 by Schmitz R. First described in DLBCL in 2011 by Morin RD. First described in FL in 2011 by Morin RD

## FOXO1 Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr13	41240294	C>T	R19Q
chr13	41240294	C>G	R19P
chr13	41240294	C>A	R19L
chr13	41240289	G>C	R21G
chr13	41240289	G>A	R21C
chr13	41240288	C>T	R21H
chr13	41240288	C>G	R21P
chr13	41240288	C>A	R21L
chr13	41240286	AG>GC	S22P
chr13	41240286	AG>GA	S22P
chr13	41240286	A>G	S22P
chr13	41240285	G>C	S22W
chr13	41240281	G>T	C23*
chr13	41240280	T>C	T24A
chr13	41240279	G>A	T24I
chr13	41240277	A>G	W25R
chr13	41240275	C>T	W25*
chr13	41240274	G>C	P26A
chr13	41240274	G>A	P26S
chr13	41240273	G>A	P26L
chr13	41240271	G>C	L27V

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

References

Trinh, D., Scott, D., Morin, R., Méndez-Lago, M., An, J., Jones, S., Mungall, A., Zhao, Y., Schein, J., Steidl, C., Connors, J., Gascoyne, R., & Marra, M. (2013). Analysis of FOXO1 mutations in diffuse large B-cell lymphoma.. Blood, 121 18, 3666-74 . https://doi.org/10.1182/blood-2013-01-479865.
Zhou, P., Blain, A., Newman, A., Zaka, M., Chagaluka, G., Adlar, F., Offor, U., Broadbent, C., Chaytor, L., Whitehead, A., Hall, A., O’Connor, H., Noorden, S., Lampert, I., Bailey, S., Molyneux, E., Bacon, C., Bomken, S., & Rand, V. (2019). Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif.. Blood advances, 3 14, 2118-2127 . https://doi.org/10.1182/bloodadvances.2018029546.
Grande BM, Gerhard DS, Jiang A, Griner NB, Abramson JS, Alexander TB, Allen H, Ayers LW, Bethony JM, Bhatia K, Bowen J, Casper C, Choi JK, Culibrk L, Davidsen TM, Dyer MA, Gastier-Foster JM, Gesuwan P, Greiner TC, Gross TG, Hanf B, Harris NL, He Y, Irvin JD, Jaffe ES, Jones SJM, Kerchan P, Knoetze N, Leal FE, Lichtenberg TM, Ma Y, Martin JP, Martin MR, Mbulaiteye SM, Mullighan CG, Mungall AJ, Namirembe C, Novik K, Noy A, Ogwang MD, Omoding A, Orem J, Reynolds SJ, Rushton CK, Sandlund JT, Schmitz R, Taylor C, Wilson WH, Wright GW, Zhao EY, Marra MA, Morin RD, Staudt LM. Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma. Blood. 2019 Mar 21;133(12):1313-1324. doi: 10.1182/blood-2018-09-871418. Epub 2019 Jan 7. PMID: 30617194; PMCID: PMC6428665.
Zerrouqi, A., Pyrzynska, B., Dwoyak, M., Morlino, G., Zapała, P., Miązek, N., Gołąb, J., & Winiarska, M. (2018). Abstract B51: FOXO1 determines non-Hodgkin lymphomas response to anti-CD20-based therapy. Cancer Research, 78. https://doi.org/10.1158/1538-7445.MOUSEMODELS17-B51.