1. Clonal Mutations Activate the NF-κB Pathway to Promote Recurrence of Nasopharyngeal Carcinoma
- Author
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Mei Lin, Chao Zhang, Xiaolong Zhang, Jing-Qi Wang, Ai-Hua Zhuang, Xiong Zou, Zhixiang Zuo, Yi-Jun Hua, Rou Jiang, Gui-Ping He, Zexian Liu, Qing X. Li, Jing-Ping Yun, Tao Yu, Xiao Feng Zhu, Qi Yang, Yue Wang, De-Chen Lin, Yu-Long Xie, You-Ping Liu, Rui Sun, Ming-Yuan Chen, Lin Feng, Chen-Yan Wu, Mu Sheng Zeng, Yi-Nuan Zhang, Cheng Cui, Yi Xin Zeng, Gui-Fang Guo, Rui You, Chao-Nan Qian, Ying Sun, Tiebang Kang, and Hai-Qiang Mai
- Subjects
0301 basic medicine ,Cancer Research ,Nasopharyngeal neoplasm ,Biology ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Carcinoma ,medicine ,Humans ,Gene ,Exome ,Mutation ,Nasopharyngeal Carcinoma ,NF-kappa B ,Nasopharyngeal Neoplasms ,NF-κB ,medicine.disease ,030104 developmental biology ,Oncology ,Nasopharyngeal carcinoma ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Biomarker (medicine) ,Neoplasm Recurrence, Local - Abstract
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, and NFKBIA) were significantly mutated in both pNPC and rNPC. Notably, mutations in TRAF3, CYLD, and NFKBIA were 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 chemosensitivity in vitro and in 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. Significance: This 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
- Published
- 2019
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