Clonal Mutations Activate the NF-kappa B Pathway to Promote Recurrence of Nasopharyngeal Carcinoma
Clonal Mutations Activate the NF-kappa B Pathway to Promote Recurrence of Nasopharyngeal Carcinoma
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克隆突变激活 NF-kappa B 通路促进鼻咽癌复发
DOI：
10.1158/0008-5472.can-18-3845
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发表时间：
2019
期刊：
影响因子：
11.2
通讯作者：
Zu
中科院分区：
文献类型：
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作者：
You Rui;Liu You-Ping;Lin De-Chen;Li Qing;Yu Tao;Zou Xiong;Lin Mei;Zhang Xiao-Long;He Gui-Ping;Yang Qi;Zhang Yi-Nuan;Xie Yu-Long;Jiang Rou;Wu Chen-Yan;Zhang Chao;Cui Cheng;Wang Jing-Qi;Wang Yue;Zhuang Ai-Hua;Guo Gui-Fang;Hua Yi-Jun;Sun Rui;Yun Jing-Ping;Zu
对于复发性鼻咽癌（rNPC）中发生的遗传事件知之甚少。在这里，我们对 55 名 rNPC 患者和 44 名初诊 NPC (pNPC) 患者进行了全基因组和全外显子组测序，其中 7 名患者具有配对的 rNPC 和 pNPC 样本。整合先前发表的 pNPC 外显子组数据进行分析。 rNPC 和 pNPC 组织具有相似的突变负担，但 rNPC 样本中克隆突变的数量有所增加。 TP53 和三个 NF-κB 通路成分（TRAF3、CYLD 和 NFKBIA）在 pNPC 和 rNPC 中均发生显着突变。值得注意的是，TRAF3、CYLD和NFKBIA的突变在rNPC中都是克隆性的，然而，其中55.6%至57.9%的突变在pNPC中是克隆性的。一般来说，rNPC 中 NF-κB 通路相关基因的克隆突变数量显着高于 pNPC。 NF-κB 突变克隆在 NPC 复发期间被选择和/或富集。克隆性 NF-κB 突变体样品中 NF-κB 转位至细胞核的量显着高于亚克隆 NF-κB 突变体样品。此外，局部复发的 pNPC 样本中 NF-κB 蛋白的核丰度显着高于未复发的 pNPC 样本。此外，高核 NF-κB 水平是 pNPC 局部无复发生存的独立阴性预后标志。最后，抑制 NF-κB 可增强体外和体内的放射敏感性和化学敏感性。总之，克隆突变激活NF-κB通路在促进NPC复发中发挥着重要作用。此外，NF-κB 的核积聚是预测局部无复发生存的重要生物标志物。意义这项研究揭示了促进鼻咽癌进展和复发的遗传事件，具有潜在的预后和治疗意义。参见 Sehgal 和 Barbie 的相关评论，第 17 页。 5915
The genetic events occurring in recurrent nasopharyngeal carcinoma (rNPC) are poorly understood. Here, we performed whole-genome and whole-exome sequencing in 55 patients with rNPC and 44 primarily diagnosed NPC (pNPC), with 7 patients having paired rNPC and pNPC samples. Previously published pNPC exome data were integrated for analysis. rNPC and pNPC tissues had similar mutational burdens, however, the number of clonal mutations was increased in rNPC samples. TP53 and three NF-κB pathway components (TRAF3, CYLD, andNFKBIA) were significantly mutated in both pNPC and rNPC. Notably, mutations inTRAF3, CYLD, andNFKBIAwere all clonal in rNPC, however, 55.6% to 57.9% of them were clonal in pNPC. In general, the number of clonal mutations in NF-κB pathway–associated genes was significantly higher in rNPC than in pNPC. The NF-κB mutational clonality was selected and/or enriched during NPC recurrence. The amount of NF-κB translocated to the nucleus in samples with clonal NF-κB mutants was significantly higher than that in samples with subclonal NF-κB mutants. Moreover, the nuclear abundance of NF-κB protein was significantly greater in pNPC samples with locoregional relapse than in those without relapse. Furthermore, high nuclear NF-κB levels were an independent negative prognostic marker for locoregional relapse-free survival in pNPC. Finally, inhibition of NF-κB enhanced both radiosensitivity and chemosensitivityin vitroandin vivo. In conclusion, NF-κB pathway activation by clonal mutations plays an important role in promoting the recurrence of NPC. Moreover, nuclear accumulation of NF-κB is a prominent biomarker for predicting locoregional relapse-free survival.SignificanceThis study uncovers genetic events that promote the progression and recurrence of nasopharyngeal carcinoma and has potential prognostic and therapeutic implications.See related commentary by Sehgal and Barbie, p. 5915