HLA-A

Overview

Mutations in the HLA-B gene have been associated with a loss of cell surface expression of HLA class I molecules, which are essential for presenting tumor antigens to cytotoxic T cells. This is a common mechanism of immune escape in DLBCL. Deletions of this gene are more commonly reported than HLA-B mutations. The mutation pattern in DLBCL implies the preferential accumulation of inactivating mutations. Different analytical strategies relating to the mapping of sequencing data and subtracting common germline variants can complicate the detection of mutations in this and other HLA genes. Likely owing to this, the rate of mutations is highly variable across studies and the true mutation rate has not been firmly established.

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2019-08-20 : Desch : PMBL

Relevance tier by entity

Entity	Tier	Description
	2	relevance in PMBL/cHL/GZL not firmly established¹
	1	high-confidence DLBCL gene²

Mutation incidence in large patient cohorts (GAMBL reanalysis)

pathology	Samples	Incidence estimate
DLBCL	GAMBL without Reddy³	0.0985 [0.0808,0.1163]
DLBCL	GAMBL with Reddy³	0.0112 [0.0062,0.0162]
DLBCL	BC	0.0987 [0.0595,0.1378]
DLBCL	Dana-Farber	0.0924 [0.0598,0.125]
DLBCL	NCI	0.1106 [0.0823,0.139]
DLBCL	Reddy³	0.0037 [0,0.0089]
DLBCL	DLBCL_ICGC	0.0706 [0.0161,0.125]

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	No	No	4.995	22.371
DLBCL	No	Yes	14.841	190.534
FL	No	No	0.000	0.000

HLA-A Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr6	29910596	T>A	F46I
chr6	29910609	G>A	G50D

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

References

HLA-A Expression

Desch AK, Hartung K, Botzen A, Brobeil A, Rummel M, Kurch L, Georgi T, Jox T, Bielack S, Burdach S, Classen CF, Claviez A, Debatin KM, Ebinger M, Eggert A, Faber J, Flotho C, Frühwald M, Graf N, Jorch N, Kontny U, Kramm C, Kulozik A, Kühr J, Sykora KW, Metzler M, Müller HL, Nathrath M, Nüßlein T, Paulussen M, Pekrun A, Reinhardt D, Reinhard H, Rössig C, Sauerbrey A, Schlegel PG, Schneider DT, Scheurlen W, Schweigerer L, Simon T, Suttorp M, Vorwerk P, Schmitz R, Kluge R, Mauz-Körholz C, Körholz D, Gattenlöhner S, Bräuninger A. Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma. Leukemia. 2020 Jan;34(1):151–166.

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):3879–3884. PMCID: PMC3309757

Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, Leppa S, Pasanen A, Meriranta L, Karjalainen-Lindsberg ML, Nørgaard P, Pedersen M, Gang AO, Høgdall E, Heavican TB, Lone W, Iqbal J, Qin Q, Li G, Kim SY, Healy J, Richards KL, Fedoriw Y, Bernal-Mizrachi L, Koff JL, Staton AD, Flowers CR, Paltiel O, Goldschmidt N, Calaminici M, Clear A, Gribben J, Nguyen E, Czader MB, Ondrejka SL, Collie A, Hsi ED, Tse E, Au-Yeung RKH, Kwong YL, Srivastava G, Choi WWL, Evens AM, Pilichowska M, Sengar M, Reddy N, Li S, Chadburn A, Gordon LI, Jaffe ES, Levy S, Rempel R, Tzeng T, Happ LE, Dave T, Rajagopalan D, Datta J, Dunson DB, Dave SS. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell. 2017 Oct;171(2):481–494.e15. PMCID: PMC5659841