Table of Contents

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

Experimental Evidence

Driver mutations affecting this gene in FL/DLBCL/BL have been experimentally demonstrated to cause a gain of function (GOF).1

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
MZL 1 High-confidence MZL gene
PMBL 2 Role of FOXO1 mutations in PMBL requires confirmation

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 70 0.0643 [0.0497,0.0788]
DLBCL GAMBL with Reddy 2,088 94 0.0450 [0.0361,0.0539]
DLBCL BC 231 26 0.1126 [0.0718,0.1533]
DLBCL Dana-Farber 303 5 0.0165 [0.0022,0.0308]
DLBCL NCI 470 34 0.0723 [0.0489,0.0958]
DLBCL Reddy 999 24 0.0240 [0.0145,0.0335]
DLBCL DLBCL_ICGC 85 5 0.0588 [0.0088,0.1088]

FL

pathology Collection N mutated Incidence CI
FL GAMBL without Crouch 642 72 0.1121 [0.0877,0.1366]
FL GAMBL with Crouch 1,189 161 0.1354 [0.116,0.1549]
FL BC 379 52 0.1372 [0.1026,0.1718]
FL Kalmbach 164 19 0.1159 [0.0669,0.1648]
FL Crouch 547 89 0.1627 [0.1318,0.1936]
FL FL_ICGC 99 1 0.0101 [0,0.0298]

BL

pathology Collection N mutated Incidence CI
BL GAMBL without Panea 309 71 0.2209 [0.175,0.2668]
BL GAMBL without ICGC/Zhou 320 79 0.2457 [0.1986,0.2928]
BL GAMBL with Panea 410 93 0.2202 [0.1803,0.26]
BL BLGSP 219 57 0.2603 [0.2022,0.3184]
BL Zhou/ICGC 90 14 0.1556 [0.0807,0.2304]
BL Panea 101 22 0.2178 [0.1373,0.2983]

Mutation pattern and selective pressure estimates

Entity Missense dN/dS Nonsense dN/dS Q value
BL 15.5943 4.6053 0e+00
FL 7.6016 13.8747 0e+00
DLBCL 2.1729 3.7171 2e-04

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
Structure with HotMAPS hotspots

Visualizations

Protein

View coding variants in ProteinPaint hg19 or hg38

Genome

View all variants in GenomePaint hg19 or hg38

Expression

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2011-07-27 : Morin : DLBCL 2012-10-04 : Schmitz : BL 2021-07-15 : Duns : PMBL

References

1.
Trinh DL, Scott DW, Morin RD, Mendez-Lago M, An J, Jones SJM, Mungall AJ, Zhao Y, Schein J, Steidl C, Connors JM, Gascoyne RD, Marra MA. Analysis of FOXO1 mutations in diffuse large B-cell lymphoma. Blood. 2013;121(18):3666–3674. PMCID: PMC3643765
2.
Schmitz R, Young RM, Ceribelli M, Jhavar S, Xiao W, Zhang M, Wright G, Shaffer AL, Hodson DJ, Buras E, Liu X, Powell J, Yang Y, Xu W, Zhao H, Kohlhammer H, Rosenwald A, Kluin P, Müller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Ogwang MD, Reynolds SJ, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pittaluga S, Wilson W, Waldmann TA, Rowe M, Mbulaiteye SM, Rickinson AB, Staudt LM. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. 2012 Oct 4;490(7418):116–120. PMCID: PMC3609867
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
4.
Pyrzynska B, Dwojak M, Zerrouqi A, Morlino G, Zapala P, Miazek N, Zagozdzon A, Bojarczuk K, Bobrowicz M, Siernicka M, Machnicki MM, Gobessi S, Barankiewicz J, Lech-Maranda E, Efremov DG, Juszczynski P, Calado D, Golab J, Winiarska M. FOXO1 promotes resistance of non-Hodgkin lymphomas to anti-CD20-based therapy. Oncoimmunology [Internet]. 2018 Jan [cited 2024 Dec 20];7(5):e1423183. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927521/ PMCID: PMC5927521
5.
Duns G, Viganò E, Ennishi D, Sarkozy C, Hung SS, Chavez E, Takata K, Rushton C, Jiang A, Ben-Neriah S, Woolcock BW, Slack GW, Hsi ED, Craig JW, Hilton LK, Shah SP, Farinha P, Mottok A, Gascoyne RD, Morin RD, Savage KJ, Scott DW, Steidl C. Characterization of DLBCL with a PMBL gene expression signature. Blood. 2021 Jul 15;138(2):136–148.

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