ITPKB

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
aSHM regions
ITPKB Hotspots
Expression
History
References

Overview

The ITPKB gene encodes inositol-trisphosphate 3-kinase B, an enzyme involved in the regulation of intracellular calcium levels and PI3K/Akt signaling pathways. Mutations in ITPKB have been linked to various B-cell lymphomas, including DLBCL, PMBCL and, less commonly, FL.^1,2 ITPKB is one of a number of genes affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. These mutations are associated with the BN2 genetic subgroup of DLBCL. The mutation pattern in ITPKB implies selection for loss-of-function mutations.

Experimental Evidence

Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).³

Relevance tier by entity

Entity	Tier	Description
	1	High-confidence DLBCL gene
	2	Role of ITPKB 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	77	0.0707	[0.0555,0.0859]
DLBCL	GAMBL with Reddy	2,088	144	0.0690	[0.0581,0.0798]
DLBCL	BC	231	11	0.0476	[0.0202,0.0751]
DLBCL	Dana-Farber	303	27	0.0891	[0.057,0.1212]
DLBCL	NCI	470	32	0.0681	[0.0453,0.0909]
DLBCL	Reddy	999	67	0.0671	[0.0516,0.0826]
DLBCL	DLBCL_ICGC	85	7	0.0824	[0.0239,0.1408]

FL

pathology	Collection	N	mutated	Incidence	CI
FL	GAMBL without Crouch	642	20	0.0312	[0.0177,0.0446]
FL	GAMBL with Crouch	1,189	46	0.0387	[0.0277,0.0496]
FL	BC	379	11	0.0290	[0.0121,0.0459]
FL	Kalmbach	164	7	0.0427	[0.0117,0.0736]
FL	Crouch	547	26	0.0475	[0.0297,0.0654]
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	0.5058	10.7458	1.0000
FL	1.8122	1.8423	1.0000
DLBCL	1.2607	2.5737	0.0075

aSHM regions

chr_name	hg19_start	hg19_end	region	regulatory_comment
chr1	226864857	226873452	intron	weak_enhancer
chr1	226920563	226927885	TSS	active_promoter
chr1	226921088	226927982	intron-1	enhancer

ITPKB Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr1	226925148	G>C	Y4*
chr1	226925148	G>T	Y4*

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Expression

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2015-02-12 : Reichel : PMBL 2018-04-12 : Schmitz : DLBCL

References

Reichel J, Chadburn A, Rubinstein PG, Giulino-Roth L, Tam W, Liu Y, Gaiolla R, Eng K, Brody J, Inghirami G, Carlo-Stella C, Santoro A, Rahal D, Totonchy J, Elemento O, Cesarman E, Roshal M. Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood. 2015 Feb 12;125(7):1061–1072.

Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, Roulland S, Kasbekar M, Young RM, Shaffer AL, Hodson DJ, Xiao W, Yu X, Yang Y, Zhao H, Xu W, Liu X, Zhou B, Du W, Chan WC, Jaffe ES, Gascoyne RD, Connors JM, Campo E, Lopez-Guillermo A, Rosenwald A, Ott G, Delabie J, Rimsza LM, Tay Kuang Wei K, Zelenetz AD, Leonard JP, Bartlett NL, Tran B, Shetty J, Zhao Y, Soppet DR, Pittaluga S, Wilson WH, Staudt LM. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med. 2018 Apr 12;378(15):1396–1407. PMCID: PMC6010183

Tiacci E, Ladewig E, Schiavoni G, Penson A, Fortini E, Pettirossi V, Wang Y, Rosseto A, Venanzi A, Vlasevska S, Pacini R, Piattoni S, Tabarrini A, Pucciarini A, Bigerna B, Santi A, Gianni AM, Viviani S, Cabras A, Ascani S, Crescenzi B, Mecucci C, Pasqualucci L, Rabadan R, Falini B. Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. Blood. 2018 May 31;131(22):2454–2465. PMCID: PMC6634958