1. Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations.
- Author
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Li, Yvonne Y, Chung, Grace TY, Lui, Vivian WY, To, Ka-Fai, Ma, Brigette BY, Chow, Chit, Woo, John KS, Yip, Kevin Y, Seo, Jeongsun, Hui, Edwin P, Mak, Michael KF, Rusan, Maria, Chau, Nicole G, Or, Yvonne YY, Law, Marcus HN, Law, Peggy PY, Liu, Zoey WY, Ngan, Hoi-Lam, Hau, Pok-Man, Verhoeft, Krista R, Poon, Peony HY, Yoo, Seong-Keun, Shin, Jong-Yeon, Lee, Sau-Dan, Lun, Samantha WM, Jia, Lin, Chan, Anthony WH, Chan, Jason YK, Lai, Paul BS, Fung, Choi-Yi, Hung, Suet-Ting, Wang, Lin, Chang, Ann Margaret V, Chiosea, Simion I, Hedberg, Matthew L, Tsao, Sai-Wah, van Hasselt, Andrew C, Chan, Anthony TC, Grandis, Jennifer R, Hammerman, Peter S, and Lo, Kwok-Wai
- Subjects
Humans ,Herpesvirus 4 ,Human ,Epstein-Barr Virus Infections ,Carcinoma ,Nasopharyngeal Neoplasms ,TNF Receptor-Associated Factor 3 ,NF-kappa B ,Viral Matrix Proteins ,Signal Transduction ,Cell Proliferation ,Mutation ,Genome ,Human ,Exome ,NF-KappaB Inhibitor alpha ,Whole Genome Sequencing ,Deubiquitinating Enzyme CYLD ,Nasopharyngeal Carcinoma ,Genome ,Human ,Herpesvirus 4 - Abstract
Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.
- Published
- 2017