Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations.
Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations.
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鼻咽癌外显子组和基因组测序鉴定NF-κB通路激活突变
DOI：
10.1038/ncomms14121
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发表时间：
2017-01-18
影响因子：
16.6
通讯作者：
Lo KW
中科院分区：
文献类型：
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作者：
Li YY;Chung GT;Lui VW;To KF;Ma BB;Chow C;Woo JK;Yip KY;Seo J;Hui EP;Mak MK;Rusan M;Chau NG;Or YY;Law MH;Law PP;Liu ZW;Ngan HL;Hau PM;Verhoeft KR;Poon PH;Yoo SK;Shin JY;Lee SD;Lun SW;Jia L;Chan AW;Chan JY;Lai PB;Fung CY;Hung ST;Wang L;Chang AM;Chiosea SI;Hedberg ML;Tsao SW;van Hasselt AC;Chan AT;Grandis JR;Hammerman PS;Lo KW
鼻咽癌是一种以EB病毒(EBV)感染和密集淋巴细胞浸润为特征的侵袭性头颈部肿瘤。鼻咽癌基因组数据的缺乏阻碍了对鼻咽癌生物学、疾病进展和合理治疗设计的了解。在这里，我们对111例EBV阳性鼻咽癌进行了全外显子组测序(WES)，其中15例接受了进一步的全基因组测序(WGS)，以确定其突变情况。我们在总共41%的病例中发现了多种NF-κB途径的负调控因子，包括CyLD、TRAF3、NFKBIA和NLRC5的基因组异常丰富。功能分析证实，失活的CyLD突变是鼻咽癌细胞生长的驱动因素。EB病毒癌蛋白潜伏膜蛋白1(LMP1)具有结构性激活NF-κB信号的功能，我们观察到存在体细胞性NF-κB途径异常和LMP1过表达的肿瘤之间的排他性，提示在鼻咽癌发病过程中，躯体事件和病毒事件都选择了NF-κB的激活。鼻咽癌常以EB病毒感染为特征。在这里，作者使用基因组分析发现，肿瘤中包含与NF-κB信号通路有关的基因突变，或者过度表达病毒癌蛋白-潜伏膜蛋白1。
Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis. Nasopharyngeal cancer is frequently characterized by Epstein-Barr virus infection. Here, using genomic analyses, the authors find that the tumours harbour mutations in genes involved in the NF-κB signalling pathway or overexpress a viral oncoprotein, latent membrane protein 1.