Whole-exome sequencing identifies multiple loss-of-function mutations of NF-[kappa]B pathway regulators in nasopharyngeal carcinoma

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 40; p. 11283
• Main Authors: Zheng, Hong, Dai, Wei, Cheung, Arthur Kwok Leung, Ko, Josephine Mun Yee, Kan, Rebecca, Wong, Bonnie Wing Yan, Leong, Merrin Man Long, Deng, Mingdan, Kwok, Tommy Chin Tung, Chan, Jimmy Yu-Wai, Kwong, Dora Lai-Wan, Lee, Anne Wing-Mui, Ng, Wai Tong, Ngan, Roger Kai Cheong, Yau, Chun Chung, Tung, Stewart, Lee, Victor Ho-fun, Lam, Ka-On, Kwan, Chung Kong, Li, Wing Sum, Yau, Stephen, Chan, Kwok-Wah, Lung, Maria Li
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 04.10.2016
• Subjects: Cell cycle; Cell growth; Genomics; Mutagenesis; Mutation; Pathogenesis; Proteins
• ISSN: 0027-8424; 1091-6490

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-kB signaling negative regulators NFKBIA, CYLD, and TNFAIP3. Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-kB activity and NPC cell growth. The identified loss-of-function mutations in NFKBIA leading to protein truncation contributed to the altered NF-kB activity, which is critical for NPC tumorigenesis. In addition, somatic mutations were found in several cancer-relevant pathways, including cell cycle-phase transition, cell death, EBV infection, and viral carcinogenesis. These data provide an enhanced road map for understanding the molecular basis underlying NPC.