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Cancer Res. 2019 Sep 4. pii: canres.3845.2018. doi: 10.1158/0008-5472.CAN-18-3845. [Epub ahead of print]

Clonal Mutations Activate the NF-κB Pathway to Promote Recurrence of Nasopharyngeal Carcinoma.

Author information

1
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center.
2
Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center.
3
Department of Medicine, Cedars-Sinai Medical Center.
4
Novogene Co, Ltd.
5
Sun Yat-sen University Cancer Center.
6
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine.
7
Experimental Research, Sun Yat-sen University Cancer Center.
8
Department of Pathology, Sun Yat-sen University Cancer Center.
9
Pathology, Sun Yat-sen University Cancer Center.
10
The Scientific and Technical Department, Novogene Bioinformatics Institute.
11
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center.
12
Department of VIP Inpatient, Sun Yat-sen University Cancer Center.
13
Department of Nasopharynx, State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University.
14
State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center.
15
Cancer Center, Sun Yat-sen University Cancer Center.
16
Department of Experimental Research, Sun Yat-sen University Cancer Center.
17
Deptment of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center;State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy.
18
Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagn.
19
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center.
20
Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center.
21
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center chmingy@mail.sysu.edu.cn.

Abstract

The genetic events occuring in recurrent nasopharyngeal carcinoma (rNPC) are poorly understood. Here, we performed whole-genome and whole-exome sequencing in 55 rNPC and 44 primarily diagnosed NPC (pNPC) patients; 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, 55.6-57.9% 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 local regional relapse than in those without relapse. Further, high nuclear NF-κB levels were an independent negative prognostic marker for locoregional relapse-free survival in pNPC. Lastly, 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.

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