Details

Autor(en) / Beteiligte

• Nocturne, Gaetane
• Boudaoud, Saida
• Miceli-Richard, Corinne
• Viengchareun, Say
• Lazure, Thierry
• Nititham, Joanne
• Taylor, Kimberly E.
• Ma, Averil
• Busato, Florence
• Melki, Judith
• Lessard, Christopher J.
• Sivils, Kathy L.
• Dubost, Jean-Jacques
• Hachulla, Eric
• Gottenberg, Jacques Eric
• Lombès, Marc
• Tost, Jorg
• Criswell, Lindsey A.
• Mariette, Xavier

Titel

Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjögren's syndrome

Ist Teil von

• Blood, 2013-12, Vol.122 (25), p.4068-4076

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2013

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. •77% of patients with primary Sjögren's syndrome and mucosa-associated lymphoid tissue lymphoma have functional abnormalities of A20.•A20 inactivation plays a key role in lymphomagenesis in the context of autoimmunity.