history

## Overview

EBF1 is a critical transcription factor in early B-cell development, regulating the expression of key genes involved in B-cell differentiation, survival, and function. EBF1 is essential for proper B-cell receptor (BCR) signaling.¹ Mutations in EBF1 can impair BCR signaling pathways, affecting B-cell survival and proliferation.¹ EBF1 is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. This gene has some recurrent sites of mutations (hot spots) but the mutation pattern in DLBCL and FL implies the preferential accumulation of *inactivating mutations*.

## Relevance tier by entity

|Entity|Tier|Description |

## History

Mutations in this gene were first described in DLBCL and FL in 2021 by Hübschmann et al.¹

## Relevance tier by entity

|Entity|Tier|Description |

# ETS1

## Overview

ETS1 is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. This gene has some recurrent sites of mutations (hot spots). The mutation pattern in DLBCL implies the preferential accumulation of *inactivating mutations*.

## Relevance tier by entity

|Entity|Tier|Description |

# EZH2

## Overview

EZH2 encodes a histone methyltransferase that is a component of the polycomb repressive complex 2 (PRC2). This gene is recurrently mutated in both FL and DLBCL and has a common mutation hot spot (Y646) that affects the SET domain.¹ Mutations of this residue and some of the less common hotspots lead to enhanced methylation by PRC2.^2,3 Pharmacologic inhibitors of this activity such as tazemetostat have shown benefit in FL.³ EZH2 mutations are one of the defining features of the EZB genetic subgroup of DLBCL. Although mutations in EZH2 have been described in some BL patients, they are extremely rare in most studies.⁴

## Relevance tier by entity

|Entity|Tier|Description |

# FAS

## Overview

FAS encodes a cell surface receptor involved in the induction of apoptosis. FAS mutations are common in DLBCL and may be more frequent in primary gastric DLBCL.^1,2 Mutations also occur in FL at a lower rate.³ Although reported in one BL study,⁴ overall the evidence for FAS mutations in BL remains sparse. Mutations in FAS often lead to a loss of function, making lymphoma cells resistant to Fas ligand-induced apoptosis, thereby allowing malignant cells to evade immune surveillance.⁵ In mouse models, Fas mutations led to a significantly shorter lymphoma-specific survival and reduced sensitivity to chemotherapy.⁵

## Relevance tier by entity

|Entity|Tier|Description |

# FAT4

## Relevance tier by entity

|Entity|Tier|Description |

<!-- DLBCL: morinMutationalStructuralAnalysis2013 -->

<!-- MCL: zhangGenomicLandscapeMantle2014 -->

<!-- MZL: parryWholeExomeSequencing2013 -->

## History

Mutations in this gene were first described in BL in 2015 by Pighi et al⁴ and in DLBCL by Hübschmann et al.⁵

## Relevance tier by entity

|Entity|Tier|Description |

|:------:|:----:|--------------------------|

| |1 |high-confidence BL gene |

| |1 |high-confidence DLBCL gene|

# FBXW7

## Overview

FBXW7 mutations are found in a range of lymphoid malignancies, including B-cell lymphomas. These mutations often include missense mutations, deletions, frameshift mutations and splice-site mutations. Overall, these mutations are relatively rare in DLBCL and occur more frequently in other solid tumors as well as T-cell acute lymphocytic leukemia.¹ The most commonly observed mutations in those cancers are the hot spots R465 and R479.¹ In leukemias, FBXW7 mutations enhance the activity of leukemia-initiating cells by stabilizing oncogenic MYC.² Whether they have this role in DLBCL remains to be determined.

## Relevance tier by entity

|Entity|Tier|Description |

# FGFR3

## Relevance tier by entity

|Entity|Tier|Description |


<!-- ORIGIN: loveGeneticLandscapeMutations2012 -->

<!-- BL: loveGeneticLandscapeMutations2012 -->

# FLYWCH1

## Relevance tier by entity

|Entity|Tier|Description |


<!-- ORIGIN: schmitzBurkittLymphomaPathogenesis2012 -->

<!-- BL: schmitzBurkittLymphomaPathogenesis2012 -->

# FNDC1

## Relevance tier by entity

|Entity|Tier|Description |


<!-- ORIGIN: morinMutationalStructuralAnalysis2013 -->

<!-- DLBCL: morinMutationalStructuralAnalysis2013 -->

# FOXC1

## Overview

FOXC1 is a transcription factor that regulates genes involved in cell growth, differentiation, and survival. While specific data on FOXC1 mutations in DLBCL are currently limited, the functional role of FOXC1 in transcription regulation and its involvement in other cancers suggest that it could play a significant role in lymphoma pathogenesis. Further research is needed to explore the implications of FOXC1 mutations in DLBCL and other B-cell lymphomas. The rate of FOXC1 varies across studies and was high in only one cohort.¹ Owing to this, the actual prevalence in DLBCL remains unclear and should be studied further. *Without further support, this gene may be migrated to Tier 2.*

## Relevance tier by entity

|Entity|Tier|Description |

# 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 |


## References

1. *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.*

2. *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.*

3. *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.*

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. 2018 Jan 25;7(5):e1423183. doi: 10.1080/2162402X.2017.1423183. PMID: 29721381; PMCID: PMC5927521.*

5. *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.*

<!-- ORIGIN: morinFrequentMutationHistonemodifying2011 -->

<!-- BL: schmitzBurkittLymphomaPathogenesis2012 -->

<!-- BL: schmitzBurkittLymphomaPathogenesis2012 -->

# TIPARP

## Relevance tier by entity

|Entity|Tier|Description |


<!-- ORIGIN: reddyGeneticFunctionalDrivers2017 -->

<!-- DLBCL: reddyGeneticFunctionalDrivers2017 -->

# TLR2

## Relevance tier by entity

|Entity|Tier|Description |

<!-- ORIGIN: beaLandscapeSomaticMutations2013 -->

<!-- DLBCL: chapuyMolecularSubtypesDiffuse2018b -->

<!-- MCL: beaLandscapeSomaticMutations2013 -->

# TMEM30A

## Relevance tier by entity

|Entity|Tier|Description |

# TMSB4X

## Overview

TMSB4X is one of [a number of genes](https://github.com/morinlab/LLMPP/wiki/ashm) affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus.

## Relevance tier by entity

|Entity|Tier|Description |


<!-- ORIGIN: albuquerqueEnhancingKnowledgeDiscovery2017a -->

<!-- DLBCL: albuquerqueEnhancingKnowledgeDiscovery2017a -->