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.