Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjogren's syndrome
Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjogren's syndrome
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DOI：
10.1182/blood-2013-05-503383
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发表时间：
2013-12-12
期刊：
影响因子：
20.3
通讯作者：
Mariette, Xavier
中科院分区：
文献类型：
--
作者：
Nocturne, Gaetane;Boudaoud, Saida;Mariette, Xavier
一些自身免疫性疾病，包括原发性干燥综合征（pSS），与淋巴瘤风险增加有关。TNFAIP 3编码在控制核因子κ B活化中起关键作用的A20蛋白，TNFAIP 3的多态性与几种自身免疫性疾病相关。TNFAIP 3的体细胞突变已经在经常与pSS相关的粘膜相关淋巴组织淋巴瘤亚型中观察到。我们研究了574例pSS患者（包括25例淋巴瘤患者）TNFAIP 3的生殖系和体细胞异常。另外19名患有pSS和淋巴瘤的患者可用于外显子组序列分析。A20的功能异常通过基因报告分析来评估。rs 2230926外显子变异与pSS合并淋巴瘤的风险增加相关（与对照组和无淋巴瘤的pSS患者相比，比值比分别为3.36 [95%置信区间，1.34-8.42]和3.26 [95%置信区间，1.31-8.12]; P = 0.011）。在20例具有配对的生殖系和淋巴瘤TNFAIP 3序列数据的患者中，12例（60%）具有A20功能异常：生殖系DNA中有6例，淋巴瘤DNA中有5例，两者中有1例。在pSS患者中，粘膜相关淋巴组织淋巴瘤的发生率甚至更高（77%）。这些变异体中的一些表现出核因子kB激活的控制受损。这些结果支持A20的生殖系和体细胞变异在自身免疫和淋巴瘤之间的转化中的关键作用。
Several autoimmune diseases, including primary Sjogren'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 kappa B 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 kB activation. These results support a key role for germline and somatic variations of A20 in the transformation between autoimmunity and lymphoma.