BRAF

Overview

BRAF mutations, particularly the BRAF V600E hot spot mutation, are primarily associated with hairy cell leukemia and are rare in other B-cell lymphomas. These mutations play a crucial role in the pathogenesis of HCL and have important diagnostic and therapeutic implications. Although they are rare, mutations in BRAF are reproducibly observed in some DLBCLs. Another hot spot, D594A, occurs in DLBCL. The role of these in lymphomagenesis remains poorly understood but functional evidence suggests they may contribute to aneuploidy.^{1^{## History}}

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2011-06-16 : Tiacci : DLBCL 2012-12-01 : Love : BL

## Relevance tier by entity

Entity	Tier	Description
	1	high-confidence MZL gene
	1	high-confidence DLBCL gene
	2	relevance in BL not firmly established

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
DLBCL	GAMBL genomes	2.29
DLBCL	Schmitz cohort	3.40
DLBCL	Reddy cohort	2.00
DLBCL	Chapuy cohort	5.56
BL	GAMBL genomes+capture	2.77
BL	Thomas cohort	NA
BL	Panea cohort	NA

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)
BL	No	No	4.754
DLBCL	No	No	5.565
FL	No	No	4.680

[!NOTE] First described in BL in 2012 by Love C. First described in DLBCL in 2012 by Lohr JG

## BRAF Hotspots

V600E The V600E mutation, which is common in other cancers including hairy cell leukemia, is observed in some DLBCL patients. This mutation mimics phosphorylation and leads to constitutive activation of the BRAF kinase. As a result, the V600E mutant continuously activates the MAPK/ERK signaling pathway, promoting cell proliferation and survival even in the absence of growth signals.

D594 Mutations of this residue have a distinct function than V600E. In particular, D594A results in a kinase-inactive form of BRAF. Unlike the V600E mutation, D594A does not directly activate the MAPK/ERK pathway. Instead, it induces aneuploidy and contributes to cancer progression through the activation of the related gene product CRAF. This activation leads to the downstream activation of the MEK/ERK pathway via CRAF, rather than BRAF.¹

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr7	140453155	C>T	D594N
chr7	140453154	T>G	D594A
chr7	140453154	T>C	D594G
chr7	140453145	A>T	L597Q
chr7	140453136	A>T	V600E
chr7	140453132	T>G	K601N

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

BRAF Expression

References

Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, Pucciarini A, Bigerna B, Pacini R, Wells VA, Sportoletti P, Pettirossi V, Mannucci R, Elliott O, Liso A, Ambrosetti A, Pulsoni A, Forconi F, Trentin L, Semenzato G, Inghirami G, Capponi M, Di Raimondo F, Patti C, Arcaini L, Musto P, Pileri S, Haferlach C, Schnittger S, Pizzolo G, Foà R, Farinelli L, Haferlach T, Pasqualucci L, Rabadan R, Falini B. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011 Jun 16;364(24):2305-15. doi: 10.1056/NEJMoa1014209. Epub 2011 Jun 11. PMID: 21663470; PMCID: PMC3689585.
Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, Cruz-Gordillo P, Knoechel B, Asmann YW, Slager SL, Novak AJ, Dogan A, Ansell SM, Link BK, Zou L, Gould J, Saksena G, Stransky N, Rangel-Escareño C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Hernández-Lemus E, Schwarz-Cruz y Celis A, Imaz-Rosshandler I, Ojesina AI, Jung J, Pedamallu CS, Lander ES, Habermann TM, Cerhan JR, Shipp MA, Getz G, Golub TR. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3879-84. doi: 10.1073/pnas.1121343109. Epub 2012 Feb 17. PMID: 22343534; PMCID: PMC3309757.