Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma.
Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma.
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DOI：
10.1084/jem.20120910
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发表时间：
2012-08-27
期刊：
影响因子：
--
通讯作者：
Elenitoba-Johnson KS
中科院分区：
文献类型：
--
作者：
Kiel MJ;Velusamy T;Betz BL;Zhao L;Weigelin HG;Chiang MY;Huebner-Chan DR;Bailey NG;Yang DT;Bhagat G;Miranda RN;Bahler DW;Medeiros LJ;Lim MS;Elenitoba-Johnson KS
脾边缘区淋巴瘤中的NOTCH 2突变与不良预后相关脾脏边缘区淋巴瘤是脾脏最常见的原发性淋巴瘤，目前对其基因水平的认识还不多。在这项研究中，使用全基因组DNA测序（WGS）和桑格测序的确认，我们观察到的突变，确定在几个基因，以前不知道是反复改变SMZL。特别是，我们在25/99例SMZL（约25%）和1/19例非脾MZL（约5%）病例中鉴定了NOTCH 2（一种编码边缘区B细胞发育所需蛋白质的基因）的复发性体细胞功能获得性突变。这些突变聚集在C-末端脯氨酸/谷氨酸/丝氨酸/苏氨酸（PEST）丰富的结构域附近，导致蛋白质截短，或者很少发生影响细胞外异源二聚化结构域（HD）的非同义取代。其他B细胞淋巴瘤和白血病中不存在NOTCH 2突变，如慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL; n = 15）、套细胞淋巴瘤（MCL; n = 15）、低度滤泡性淋巴瘤（FL; n = 44）、毛细胞白血病（HCL; n = 15）和反应性淋巴样增生（n = 14）。在SMZL患者中，NOTCH 2突变与不良临床结局（复发、组织学转化和/或死亡）相关（P = 0.002）。这些结果表明，NOTCH 2突变在SMZL的发病机制和进展中发挥作用，并与预后不良相关。
NOTCH2 mutations in splenic marginal zone lymphoma are associated with poor prognosis. Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (∼25%) cases of SMZL and in 1 of 19 (∼5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.
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DOI：
10.1084/jem.20110921
发表时间：
2011-07-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fabbri G;Rasi S;Rossi D;Trifonov V;Khiabanian H;Ma J;Grunn A;Fangazio M;Capello D;Monti S;Cresta S;Gargiulo E;Forconi F;Guarini A;Arcaini L;Paulli M;Laurenti L;Larocca LM;Marasca R;Gattei V;Oscier D;Bertoni F;Mullighan CG;Foá R;Pasqualucci L;Rabadan R;Dalla-Favera R;Gaidano G
通讯作者：
Gaidano G
影响因子：
7.3
作者：
Aster, Jon C.;Blacklow, Stephen C.;Pear, Warren S.
通讯作者：
Pear, Warren S.
影响因子：
5.3
作者：
Chiang, Mark Y.;Xu, Mina L.;Aster, Jon C.
通讯作者：
Aster, Jon C.
影响因子：
4.8
作者：
Gupta-Rossi, N;Le Bail, O;Israël, A
通讯作者：
Israël, A
影响因子：
64.5
作者：
ELLISEN, LW;BIRD, J;SKLAR, J
通讯作者：
SKLAR, J