Abstract 737: NF-κB pathway activation by clonal mutations contributes to the recurrence of nasopharyngeal carcinoma

Abstract

Abstract Objectives: Identification and characterization of the genomic features that potentially drive NPC recurrence. Methods: We performed whole-genome/whole-exome sequencing of fresh tumors and corresponding blood samples from 55 rNPC and 44 pNPC patients. Additionally, previously published pNPC exome data were integrated for analysis. Immunohistochemistry and histologic analyses were performed to identify novel biomarkers among the differential mutational events between pNPC and rNPC in independent cohorts of 148 rNPC and 237 pNPC samples with complete clinical follow-up. Results: 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 (P < 0.05). In general, the number of clonal mutations in NF-κB pathway-associated genes was significantly higher in rNPC than in pNPC (P < 0.05). Moreover, the nuclear abundance of NF-κB protein was significantly greater in pNPC samples with local regional relapse than in those without relapse (P = 0.006). Further, in both the pNPC training and validation cohorts, high nuclear NF-κB levels were an independent negative prognostic marker for locoregional relapse-free survival (LRRFS) in pNPC. Accordingly, concurrent chemotherapy for patients with high nuclear NF-κB reduced the rate of locoregional relapse. Lastly, we functionally validated that inhibition of NF-κB enhanced both radiosensitivity and chemosensitivity in NPC cells, strongly supporting our in vivo results. 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 LRRFS and suggesting treatment for pNPC patients. Finally, blocking NF-κB activity may be a novel and effective therapeutic modality for treating NPC. Citation Format: Rui You, You-Ping Liu, Ming-Yuan Chen. NF-κB pathway activation by clonal mutations contributes to the recurrence of nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 737.