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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-\u03baB pathway, including <jats:italic>CYLD<\/jats:italic>, <jats:italic>TRAF<\/jats:italic>3, <jats:italic>NFKBIA<\/jats:italic> and <jats:italic>NLRC5,<\/jats:italic> in a total of 41% of cases. Functional analysis confirmed inactivating <jats:italic>CYLD<\/jats:italic> mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-\u03baB signalling, and we observed mutual exclusivity among tumours with somatic NF-\u03baB pathway aberrations and LMP1-overexpression, suggesting that NF-\u03baB activation is selected for by both somatic and viral events during NPC pathogenesis.<\/jats:p>","DOI":"10.1038\/ncomms14121","type":"journal-article","created":{"date-parts":[[2017,1,18]],"date-time":"2017-01-18T11:42:53Z","timestamp":1484739773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":254,"title":["Exome and genome sequencing of nasopharynx cancer identifies NF-\u03baB pathway activating mutations"],"prefix":"10.1038","volume":"8","author":[{"given":"Yvonne Y","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace T. 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