NFKBIA

Table of Contents

Overview
Experimental Evidence
Relevance tier by entity
Mutation incidence in large patient cohorts (GAMBL reanalysis)
- DLBCL
- FL
Mutation pattern and selective pressure estimates
Visualizations
- Protein
- Genome
Structure with HotMAPS hotspots
Expression
History
References

Overview

NFKBIA encodes IκBα, an inhibitor of NF-κB, which regulates the NF-κB signaling pathway by preventing the translocation of NF-κB to the nucleus. Mutations in NFKBIA can disrupt this regulation, leading to constitutive activation of NF-κB signaling, which has an important role in a subset of DLBCLs. Mutations and deletions in NFKBIA are observed in DLBCL and are associated with constitutive activation of the NF-κB pathway. These mutations often occur in the ABC subtype and are associated with the ST2 genetic subgroup of DLBCL.¹

Experimental Evidence

Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).²

Relevance tier by entity

Entity	Tier	Description
	1	High-confidence DLBCL gene
	2	Role of NFKBIA mutations in FL requires confirmation
	1	High-confidence PMBL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity	Collection	N	mutated	Incidence	95% CI
DLBCL	GAMBL without Reddy	1,089	45	0.0413	[0.0295,0.0531]
DLBCL	GAMBL with Reddy	2,088	81	0.0388	[0.0305,0.0471]
DLBCL	BC	231	8	0.0346	[0.0111,0.0582]
DLBCL	Dana-Farber	303	13	0.0429	[0.0201,0.0657]
DLBCL	NCI	470	18	0.0383	[0.0209,0.0556]
DLBCL	Reddy	999	36	0.0360	[0.0245,0.0476]
DLBCL	DLBCL_ICGC	85	6	0.0706	[0.0161,0.125]

FL

pathology	Collection	N	mutated	Incidence	CI
FL	GAMBL without Crouch	642	5	0.0078	[0.001,0.0146]
FL	GAMBL with Crouch	1,189	16	0.0135	[0.0069,0.02]
FL	BC	379	1	0.0026	[0,0.0078]
FL	Kalmbach	164	2	0.0122	[0,0.029]
FL	Crouch	547	11	0.0201	[0.0083,0.0319]
FL	FL_ICGC	99	2	0.0202	[0,0.0479]

Mutation pattern and selective pressure estimates

Entity	Missense dN/dS	Nonsense dN/dS	Q value
BL	2.5607	13.2640	1
FL	0.8275	4.1727	1
DLBCL	1.4673	20.7573	0

Visualizations

Protein

View coding variants in ProteinPaint hg19 or hg38

Genome

View all variants in GenomePaint hg19 or hg38

Structure with HotMAPS hotspots

Expression

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2009-09-15 : Lake : DLBCL 2019-12-10 : Wienand : PMBL 2023-07-26 : Russler-Germain : FL

References

Wienand K, Chapuy B, Stewart C, Dunford AJ, Wu D, Kim J, Kamburov A, Wood TR, Cader FZ, Ducar MD, Thorner AR, Nag A, Heubeck AT, Buonopane MJ, Redd RA, Bojarczuk K, Lawton LN, Armand P, Rodig SJ, Fromm JR, Getz G, Shipp MA. Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion. Blood Adv. 2019 Dec 10;3(23):4065–4080. PMCID: PMC6963251

Jungnickel B, Staratschek-Jox A, Bräuninger A, Spieker T, Wolf J, Diehl V, Hansmann ML, Rajewsky K, Küppers R. Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin’s lymphoma. J Exp Med. 2000 Jan 17;191(2):395–402. PMCID: PMC2195754

Lake A, Shield LA, Cordano P, Chui DTY, Osborne J, Crae S, Wilson KS, Tosi S, Knight SJL, Gesk S, Siebert R, Hay RT, Jarrett RF. Mutations of NFKBIA, encoding IkappaB alpha, are a recurrent finding in classical Hodgkin lymphoma but are not a unifying feature of non-EBV-associated cases. Int J Cancer. 2009 Sep 15;125(6):1334–1342.

Russler-Germain DA, Krysiak K, Ramirez CA, Mosior M, Watkins MP, Gomez F, Skidmore ZL, Trani L, Gao F, Geyer S, Cashen A, Mehta-Shah N, Kahl B, Bartlett N, Alderuccio J, Lossos I, Ondrejka S, Hsi E, Martin P, Leonard J, Griffith M, Griffith O, Fehniger T. Mutations associated with progression in follicular lymphoma predict inferior outcomes at diagnosis: Alliance A151303. Blood Advances. 2023;7:5524–5539.