Whole-exome sequencing identifies multiple loss-of-function mutations of NF-κB pathway regulators in nasopharyngeal carcinoma

作者：Hong Zheng, Wei Dai, Arthur Kwok Leung Cheung, Josephine Mun Yee Ko, Rebecca Kan, Bonnie Wing Yan Wong, Merrin Man‐Long Leong, Mingdan Deng, Tommy Chin Tung Kwok, Jimmy Yu‐Wai Chan, Dora Lai‐Wan Kwong, Anne W.M. Lee, Wai Tong Ng, Roger Kai Cheong Ngan, Chun Chung Yau, Stewart Y. Tung, Victor Lee, Ka-On Lam, Chung Kong Kwan, Wing Sum Li, Stephen S.‐T. Yau, Kwok-Wah Chan, Maria Li Lung · 发表于：Proceedings of the National Academy of Sciences · 年份：2016 · DOI：10.1073/pnas.1607606113 · 被引用次数：194 · 研究领域：NF-κB Signaling Pathways、interferon and immune responses、Plant Disease Resistance and Genetics

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-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3 Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-κB activity and NPC cell growth. The identified loss-of-function mutations in NFKBIA leading to protein truncation contributed to the altered NF-κB 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.