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Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations
- 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;
- Lo, Kwok-Wai
- et al.
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.
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