| Literature DB >> 31484669 |
Rui You1,2,3, You-Ping Liu1,2,3, De-Chen Lin4, Qing Li5, Tao Yu1,2,3, Xiong Zou1,2,3, Mei Lin1,2,3, Xiao-Long Zhang2, Gui-Ping He1,2,3, Qi Yang1,2,3, Yi-Nuan Zhang1,2,3, Yu-Long Xie1,2,3, Rou Jiang1,2,3, Chen-Yan Wu2,6, Chao Zhang2,6, Cheng Cui5, Jing-Qi Wang5, Yue Wang5, Ai-Hua Zhuang2, Gui-Fang Guo2,7, Yi-Jun Hua1,2,3, Rui Sun1,2,3, Jing-Ping Yun2,6, Zhi-Xiang Zuo2, Ze-Xian Liu2, Xiao-Feng Zhu2, Tie-Bang Kang2, Chao-Nan Qian1,2,3, Hai-Qiang Mai1,2,3, Ying Sun2,8, Mu-Sheng Zeng2,3, Lin Feng2, Yi-Xin Zeng2,3, Ming-Yuan Chen9,2,3.
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. ©2019 American Association for Cancer Research.Entities:
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Year: 2019 PMID： 31484669 DOI： 10.1158/0008-5472.CAN-18-3845
Source DB: PubMed Journal: Cancer Res ISSN： 0008-5472 Impact factor: 12.701