NOTCH1

Overview

The relevance of NOTCH1 mutations in various malignancies has been well established. However, due to minimal support in the original primary data and very few mutations reported in subsequent BL studies, this gene is very unlikely to be relevant in BL.

Experimental Evidence

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

Relevance tier by entity

Entity	Tier	Description
	3	Mutations are unlikely to be relevant to BL
	1	High-confidence DLBCL gene
	1	High-confidence MCL gene
	1	High-confidence MZL gene

Warnings

The variants reported in this gene in BL failed QC

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity	Collection	N	mutated	Incidence	95% CI
DLBCL	GAMBL without Reddy	1,089	61	0.0560	[0.0424,0.0697]
DLBCL	GAMBL with Reddy	2,088	95	0.0455	[0.0366,0.0544]
DLBCL	BC	231	6	0.0260	[0.0055,0.0465]
DLBCL	Dana-Farber	303	12	0.0396	[0.0176,0.0616]
DLBCL	NCI	470	42	0.0894	[0.0636,0.1152]
DLBCL	Reddy	999	34	0.0340	[0.0228,0.0453]
DLBCL	DLBCL_ICGC	85	1	0.0118	[0,0.0347]

MCL

pathology	Collection	N	mutated	Incidence	CI
MCL	GAMBL	160	9	0.0561	[0.0205,0.0918]
MCL	BC_MCL	103	6	0.0583	[0.013,0.1035]
MCL	Barcelona	57	3	0.0526	[0,0.1106]

BL

pathology	Collection	N	mutated	Incidence	CI
BL	GAMBL without Panea	309	5	0.0154	[0.0017,0.0292]
BL	GAMBL without ICGC/Zhou	320	15	0.0196	[0.0046,0.0346]
BL	GAMBL with Panea	410	17	0.0201	[0.0067,0.0335]
BL	BLGSP	219	3	0.0137	[0,0.0291]
BL	Zhou/ICGC	90	2	0.0222	[0,0.0527]
BL	Panea	101	12	0.1188	[0.0557,0.1819]

Mutation pattern and selective pressure estimates

Entity	Missense dN/dS	Nonsense dN/dS	Q value
BL	0.9748	0.000	1.0000
FL	0.6272	0.000	1.0000
DLBCL	0.7026	1.642	0.0913

NOTCH1 Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr9	139401207	C>T	V1288I
chr9	139401199	G>C	D1290E

Visualizations

Protein

View coding variants in ProteinPaint hg19 or hg38

Genome

View all variants in GenomePaint hg19 or hg38

Expression

Representative Mutations

BL

Rating ★ ☆ ☆ ☆ ☆

All Mutations

BL

1061 1096 324 508 513

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2011-07-31 : Pasqualucci : DLBCL 2012-08-27 : Rossi : MZL 2012-12-01 : Love : BL 2013-11-05 : Bea : MCL

References

Ryan RJH, Petrovic J, Rausch DM, Zhou Y, Lareau CA, Kluk MJ, Christie AL, Lee WY, Tarjan DR, Guo B, Donohue LKH, Gillespie SM, Nardi V, Hochberg EP, Blacklow SC, Weinstock DM, Faryabi RB, Bernstein BE, Aster JC, Pear WS. A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas. Cell Rep. 2017 Oct 17;21(3):784–797. PMCID: PMC5687286

Love C, Sun Z, Jima D, Li G, Zhang J, Miles R, Richards KL, Dunphy CH, Choi WWL, Srivastava G, Lugar PL, Rizzieri DA, Lagoo AS, Bernal-Mizrachi L, Mann KP, Flowers CR, Naresh KN, Evens AM, Chadburn A, Gordon LI, Czader MB, Gill JI, Hsi ED, Greenough A, Moffitt AB, McKinney M, Banerjee A, Grubor V, Levy S, Dunson DB, Dave SS. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet. 2012 Dec;44(12):1321–1325. PMCID: PMC3674561

Rossi D, Trifonov V, Fangazio M, Bruscaggin A, Rasi S, Spina V, Monti S, Vaisitti T, Arruga F, Famà R, Ciardullo C, Greco M, Cresta S, Piranda D, Holmes A, Fabbri G, Messina M, Rinaldi A, Wang J, Agostinelli C, Piccaluga PP, Lucioni M, Tabbò F, Serra R, Franceschetti S, Deambrogi C, Daniele G, Gattei V, Marasca R, Facchetti F, Arcaini L, Inghirami G, Bertoni F, Pileri SA, Deaglio S, Foà R, Dalla-Favera R, Pasqualucci L, Rabadan R, Gaidano G. The coding genome of splenic marginal zone lymphoma: Activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med. 2012 Aug 27;209(9):1537–1551. PMCID: PMC3428941