STAT6

Table of Contents

Overview

The STAT6 gene, which encodes a transcription factor involved in the JAK-STAT signaling pathway, plays a significant role in the pathogenesis of various lymphomas, including diffuse large B-cell lymphoma (DLBCL). Below is a summary of the common mutations in the STAT6 gene identified in DLBCL. Mutations in the DNA binding domain of STAT6 are common in PMBCL and more rare in DLBCL.

Experimental Evidence

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

Relevance tier by entity

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Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity	Collection	N	mutated	Incidence	95% CI
DLBCL	GAMBL without Reddy	1,089	40	0.0367	[0.0256,0.0479]
DLBCL	GAMBL with Reddy	2,088	78	0.0374	[0.0292,0.0455]
DLBCL	BC	231	9	0.0390	[0.014,0.0639]
DLBCL	Dana-Farber	303	14	0.0462	[0.0226,0.0698]
DLBCL	NCI	470	12	0.0255	[0.0113,0.0398]
DLBCL	Reddy	999	38	0.0380	[0.0262,0.0499]
DLBCL	DLBCL_ICGC	85	5	0.0588	[0.0088,0.1088]

FL

pathology	Collection	N	mutated	Incidence	CI
FL	GAMBL without Crouch	642	107	0.1667	[0.1378,0.1955]
FL	GAMBL with Crouch	1,189	210	0.1766	[0.1549,0.1983]
FL	BC	379	52	0.1372	[0.1026,0.1718]
FL	Kalmbach	164	37	0.2256	[0.1616,0.2896]
FL	Crouch	547	103	0.1883	[0.1555,0.2211]
FL	FL_ICGC	99	18	0.1818	[0.1058,0.2578]

Mutation pattern and selective pressure estimates

Entity	Missense dN/dS	Q value
BL	3.1720	1
FL	35.8882	0
DLBCL	5.9221	0

STAT6 Hotspots

Recurrent mutations at the D419 amino acid residue are a common feature in DLBCL, specifically affecting the germinal center B (GCB) cell subtype. These mutations lead to the activation of the JAK/STAT signaling pathway, contributing to lymphomagenesis².

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr12	57496671	C>G	G416R
chr12	57496666	G>T	N417K
chr12	57496662	C>T	D419N
chr12	57496662	C>G	D419H
chr12	57496662	C>A	D419Y
chr12	57496661	T>G	D419A
chr12	57496661	T>C	D419G
chr12	57496661	T>A	D419V
chr12	57496658	T>G	N420T
chr12	57496658	T>C	N420S
chr12	57496656	T>C	N421D
chr12	57496654	A>C	N421K

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Expression

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2009-08-06 : Ritz : PMBL 2015-01-22 : Yildiz : DLBCL 2017-05-01 : Albuquerque : DLBCL 2017-10-10 : Reddy : DLBCL 2018-04-12 : Schmitz : DLBCL 2018-05-01 : Chapuy : DLBCL 2018-10-01 : Arthur : DLBCL 2021-05-05 : Hubschmann : DLBCL

References

Mentz M, Keay W, Strobl CD, Antoniolli M, Adolph L, Heide M, Lechner A, Haebe S, Osterode E, Kridel R, Ziegenhain C, Wange LE, Hildebrand JA, Shree T, Silkenstedt E, Staiger AM, Ott G, Horn H, Szczepanowski M, Richter J, Levy R, Rosenwald A, Enard W, Zimber-Strobl U, von Bergwelt-Baildon M, Hiddemann W, Klapper W, Schmidt-Supprian M, Rudelius M, Bararia D, Passerini V, Weigert O. PARP14 is a novel target in STAT6 mutant follicular lymphoma. Leukemia. 2022 Sep;36(9):2281–2292. PMCID: PMC9417990

Morin RD, Assouline S, Alcaide M, Mohajeri A, Johnston RL, Chong L, Grewal J, Yu S, Fornika D, Bushell K, Nielsen TH, Petrogiannis-Haliotis T, Crump M, Tosikyan A, Grande BM, MacDonald D, Rousseau C, Bayat M, Sesques P, Froment R, Albuquerque M, Monczak Y, Oros KK, Greenwood C, Riazalhosseini Y, Arseneault M, Camlioglu E, Constantin A, Pan-Hammarstrom Q, Peng R, Mann KK, Johnson NA. Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas. Clin Cancer Res. 2016 May 1;22(9):2290–2300.

Ritz O, Guiter C, Castellano F, Dorsch K, Melzner J, Jais JP, Dubois G, Gaulard P, Möller P, Leroy K. Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma. Blood. 2009 Aug 6;114(6):1236–1242. PMCID: PMC2824656

Yildiz M, Li H, Bernard D, Amin NA, Ouillette P, Jones S, Saiya-Cork K, Parkin B, Jacobi K, Shedden K, Wang S, Chang AE, Kaminski MS, Malek SN. Activating STAT6 mutations in follicular lymphoma. Blood. 2015 Jan 22;125(4):668–679. PMCID: PMC4729538