Table of Contents

Overview

FAS encodes a cell surface receptor involved in the induction of apoptosis. FAS mutations are common in DLBCL and may be more frequent in primary gastric DLBCL.1,2 Mutations also occur in FL at a lower rate.3 Although reported in one BL study,4 overall the evidence for FAS mutations in BL remains sparse. Mutations in FAS often lead to a loss of function, making lymphoma cells resistant to Fas ligand-induced apoptosis, thereby allowing malignant cells to evade immune surveillance.5 In mouse models, Fas mutations led to a significantly shorter lymphoma-specific survival and reduced sensitivity to chemotherapy.5

Experimental Evidence

Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).6

Relevance tier by entity

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

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 101 0.0927 [0.0755,0.11]
DLBCL GAMBL with Reddy 2,088 148 0.0709 [0.0599,0.0819]
DLBCL BC 231 20 0.0866 [0.0503,0.1228]
DLBCL Dana-Farber 303 24 0.0792 [0.0488,0.1096]
DLBCL NCI 470 51 0.1085 [0.0804,0.1366]
DLBCL Reddy 999 47 0.0470 [0.0339,0.0602]
DLBCL DLBCL_ICGC 85 6 0.0706 [0.0161,0.125]

FL

pathology Collection N mutated Incidence CI
FL GAMBL without Crouch 642 27 0.0421 [0.0265,0.0576]
FL GAMBL with Crouch 1,189 47 0.0395 [0.0285,0.0506]
FL BC 379 18 0.0475 [0.0261,0.0689]
FL Kalmbach 164 8 0.0488 [0.0158,0.0817]
FL Crouch 547 20 0.0366 [0.0208,0.0523]
FL FL_ICGC 99 1 0.0101 [0,0.0298]

Mutation pattern and selective pressure estimates

Entity Missense dN/dS Nonsense dN/dS Q value
BL 4.8173 0.0000 1
FL 12.3562 199.5630 0
DLBCL 7.2337 54.9424 0

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Expression

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References

1.
Wohlfart S, Sebinger D, Gruber P, Buch J, Polgar D, Krupitza G, Rosner M, Hengstschläger M, Raderer M, Chott A, Müllauer L. FAS (CD95) mutations are rare in gastric MALT lymphoma but occur more frequently in primary gastric diffuse large B-cell lymphoma. The American Journal of Pathology. 2004 Mar;164(3):1081–1089. PMCID: PMC1614721
2.
Scholl V, Stefanoff CG, Hassan R, Spector N, Renault IZ. Mutations within the 5’ region of FAS/CD95 gene in nodal diffuse large B-cell lymphoma. Leuk Lymphoma. 2007 May;48(5):957–963.
3.
Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJM, Connors JM, Hirst M, Gascoyne RD, Marra MA. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011 Jul 27;476(7360):298–303. PMCID: PMC3210554
4.
Panea R, Love C, Shingleton JR, Reddy A, Bailey J, Moormann A, Otieno J, Ong’echa J, Oduor C, Schroêder K, Masalu N, Chao N, Agajanian M, Major M, Fedoriw Y, Richards K, Rymkiewicz G, Miles R, Alobeid B, Bhagat G, Flowers C, Ondrejka S, Hsi E, Choi W, Au-Yeung R, Hartmann W, Lenz G, Meyerson H, Lin YY, Zhuang Y, Luftig M, Waldrop A, Dave T, Thakkar D, Sahay H, Li G, Palus B, Seshadri V, Kim S, Gascoyne R, Levy S, Mukhopadhyay M, Dunson D, Dave S. The whole genome landscape of Burkitt lymphoma subtypes. Blood. 2019;
5.
Rys RN, Venkataraman M, Zeng J, Mann KK, Johnson N. Fas Mutations in Non-Hodgkin’s Lymphoma (NHL): Implications for Disease Progression and Therapeutic Resistance. Blood [Internet]. 2019 Nov [cited 2024 Dec 17];134(Supplement_1):1520–1520. Available from: https://ashpublications.org/blood/article/134/Supplement_1/1520/427201/Fas-Mutations-in-NonHodgkins-Lymphoma-NHL
6.
Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, Park AY, Yin Q, Damko E, Jang SB, Raunser S, Robinson CV, Siegel RM, Walz T, Wu H. The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol. 2010 Nov;17(11):1324–1329. PMCID: PMC2988912
7.
Spina V, Khiabanian H, Messina M, Monti S, Cascione L, Bruscaggin A, Spaccarotella E, Holmes AB, Arcaini L, Lucioni M, Tabbò F, Zairis S, Diop F, Cerri M, Chiaretti S, Marasca R, Ponzoni M, Deaglio S, Ramponi A, Tiacci E, Pasqualucci L, Paulli M, Falini B, Inghirami G, Bertoni F, Foà R, Rabadan R, Gaidano G, Rossi D. The genetics of nodal marginal zone lymphoma. Blood. 2016 Sep 8;128(10):1362–1373. PMCID: PMC5016706

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