title: Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjogren's syndrome.
abstract: Several autoimmune diseases, including primary Sjögren's syndrome (pSS), are associated with an increased risk for lymphoma. Polymorphisms of TNFAIP3, which encodes the A20 protein that plays a key role in controlling nuclear factor κB activation, have been associated with several autoimmune diseases. Somatic mutations of TNFAIP3 have been observed in the mucosa-associated lymphoid tissue lymphoma subtype frequently associated with pSS. We studied germline and somatic abnormalities of TNFAIP3 in 574 patients with pSS, including 25 with lymphoma. Nineteen additional patients with pSS and lymphoma were available for exome sequence analysis. Functional abnormalities of A20 were assessed by gene reporter assays. The rs2230926 exonic variant was associated with an increased risk for pSS complicated by lymphoma (odds ratio, 3.36 [95% confidence interval, 1.34-8.42], and odds ratio, 3.26 [95% confidence interval, 1.31-8.12], vs controls and pSS patients without lymphoma, respectively; P = .011). Twelve (60%) of the 20 patients with paired germline and lymphoma TNFAIP3 sequence data had functional abnormalities of A20: 6 in germline DNA, 5 in lymphoma DNA, and 1 in both. The frequency was even higher (77%) among pSS patients with mucosa-associated lymphoid tissue lymphoma. Some of these variants showed impaired control of nuclear factor κB activation. These results support a key role for germline and somatic variations of A20 in the transformation between autoimmunity and lymphoma.
authors.affiliation: Institut national de la santé et de la recherche médicale, Unité 1012, Université Paris-Sud, Le Kremlin Bicêtre, France;
authors.forename: Gaetane
authors.initials: G
authors.lastname: Nocturne
authors.forename: Saida
authors.initials: S
authors.lastname: Boudaoud
authors.forename: Corinne
authors.initials: C
authors.lastname: Miceli-Richard
authors.forename: Say
authors.initials: S
authors.lastname: Viengchareun
authors.forename: Thierry
authors.initials: T
authors.lastname: Lazure
authors.forename: Joanne
authors.initials: J
authors.lastname: Nititham
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Taylor
authors.forename: Averil
authors.initials: A
authors.lastname: Ma
authors.forename: Florence
authors.initials: F
authors.lastname: Busato
authors.forename: Judith
authors.initials: J
authors.lastname: Melki
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lessard
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Sivils
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Dubost
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.forename: Jacques Eric
authors.initials: JE
authors.lastname: Gottenberg
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.forename: Jorg
authors.initials: J
authors.lastname: Tost
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Xavier
authors.initials: X
authors.lastname: Mariette
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D018095:Germ-Line Mutation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D018442:Lymphoma, B-Cell, Marginal Zone / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012859:Sjogren's Syndrome / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3