Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma
Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma
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外显子组测序鉴定自然杀伤/T细胞淋巴瘤中 DDX3X 的体细胞突变
DOI：
10.1038/ng.3358
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发表时间：
2015-09-01
期刊：
影响因子：
30.8
通讯作者：
Chen, Sai-Juan
中科院分区：
文献类型：
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作者：
Jiang, Lu;Gu, Zhao-Hui;Chen, Sai-Juan
自然杀伤/T细胞淋巴瘤（Natural Killer/T-cell Lymphoma，NKTCL）是一种CD 56+和cytoCD 3+淋巴细胞恶性增殖的恶性淋巴瘤，临床表现为侵袭性，好发于亚洲和南美人群。NKTCL的分子发病机制在很大程度上仍然难以捉摸。我们通过全外显子组测序鉴定了25名NKTCL患者的体细胞基因突变，并通过靶向测序在80人的扩展验证组中证实了这些突变。复发性突变最常位于RNA解旋酶基因DDX 3X（21/105例受试者，20.0%）、肿瘤抑制因子（TP 53和MGA）、JAK-STAT通路分子（STAT 3和STAT 5 B）和表观遗传修饰因子（MLL 2、ARID 1A、EP 300和ASXL 3）。与野生型蛋白相比，DDX 3X突变体表现出RNA解旋活性降低，对NK细胞中细胞周期进程的抑制作用以及NF-κB和MAPK通路的转录激活丧失。临床上，DDX 3X突变的患者预后不良。因此，我们的工作有助于了解NKTCL的发病机制。
Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56+ and cytoCD3+ lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.