title: Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Grace T Y
authors.initials: GT
authors.lastname: Chung
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.|Department of Pharmacology and Pharmacy, School of Biomedical Sciences, Li-Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Vivian W Y
authors.initials: VW
authors.lastname: Lui
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.affiliation: State Key Laboratory of Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Brigette B Y
authors.initials: BB
authors.lastname: Ma
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Chit
authors.initials: C
authors.lastname: Chow
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: John K S
authors.initials: JK
authors.lastname: Woo
authors.affiliation: Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Yip
authors.affiliation: Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 10-799, Republic of Korea.
authors.forename: Jeongsun
authors.initials: J
authors.lastname: Seo
authors.affiliation: State Key Laboratory of Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Hui
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Michael K F
authors.initials: MK
authors.lastname: Mak
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Rusan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Chau
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yvonne Y Y
authors.initials: YY
authors.lastname: Or
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Marcus H N
authors.initials: MH
authors.lastname: Law
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Peggy P Y
authors.initials: PP
authors.lastname: Law
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Zoey W Y
authors.initials: ZW
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Pharmacy, School of Biomedical Sciences, Li-Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Hoi-Lam
authors.initials: HL
authors.lastname: Ngan
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Pok-Man
authors.initials: PM
authors.lastname: Hau
authors.affiliation: Department of Pharmacology and Pharmacy, School of Biomedical Sciences, Li-Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Krista R
authors.initials: KR
authors.lastname: Verhoeft
authors.affiliation: Department of Pharmacology and Pharmacy, School of Biomedical Sciences, Li-Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Peony H Y
authors.initials: PH
authors.lastname: Poon
authors.affiliation: Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 10-799, Republic of Korea.
authors.forename: Seong-Keun
authors.initials: SK
authors.lastname: Yoo
authors.affiliation: Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 10-799, Republic of Korea.
authors.forename: Jong-Yeon
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Sau-Dan
authors.initials: SD
authors.lastname: Lee
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Samantha W M
authors.initials: SW
authors.lastname: Lun
authors.affiliation: School of Biomedical Sciences and Center for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Anthony W H
authors.initials: AW
authors.lastname: Chan
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jason Y K
authors.initials: JY
authors.lastname: Chan
authors.affiliation: Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
authors.affiliation: Department of Pharmacology and Pharmacy, School of Biomedical Sciences, Li-Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Choi-Yi
authors.initials: CY
authors.lastname: Fung
authors.affiliation: Department of Pharmacology and Pharmacy, School of Biomedical Sciences, Li-Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Suet-Ting
authors.initials: ST
authors.lastname: Hung
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Pathology, St. Luke's Medical Center, Quezon City 1112, Philippines.
authors.forename: Ann Margaret V
authors.identifier: 0000-0002-9036-3678
authors.initials: AM
authors.lastname: Chang
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Simion I
authors.initials: SI
authors.lastname: Chiosea
authors.affiliation: Medical Scientist Training Program, University of Pittsburgh-Carnegie Mellon University, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Hedberg
authors.affiliation: School of Biomedical Sciences and Center for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Sai-Wah
authors.initials: SW
authors.lastname: Tsao
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: van Hasselt
authors.affiliation: State Key Laboratory of Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Department of Otolaryngology, University of California San Francisco, San Francisco, California 94113, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Department of Anatomical &Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D049109:Cell Proliferation; D000074749:Deubiquitinating Enzyme CYLD / Q000235:genetics / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D059472:Exome; D015894:Genome, Human; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism; D000073336:Whole Genome Sequencing
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D014763:Viral Matrix Proteins; D000072000:NF-KappaB Inhibitor alpha; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD