Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations

Yvonne Y Li; Grace T Y Chung; Vivian W Y Lui; Ka-Fai To; Brigette B Y Ma; Chit Chow; John K S Woo; Kevin Y Yip; Jeongsun Seo; Edwin P Hui; Michael K F Mak; Maria Rusan; Nicole G Chau; Yvonne Y Y Or; Marcus H N Law; Peggy P Y Law; Zoey W Y Liu; Hoi-Lam Ngan; Pok-Man Hau; Krista R Verhoeft; Peony H Y Poon; Seong-Keun Yoo; Jong-Yeon Shin; Sau-Dan Lee; Samantha W M Lun; Lin Jia; Anthony W H Chan; Jason Y K Chan; Paul B S Lai; Choi-Yi Fung; Suet-Ting Hung; Lin Wang; Ann Margaret V Chang; Simion I Chiosea; Matthew L Hedberg; Sai-Wah Tsao; Andrew C van Hasselt; Anthony T C Chan; Jennifer R Grandis; Peter S Hammerman; Kwok-Wai Lo

doi:10.1038/ncomms14121

Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations

Nat Commun. 2017 Jan 18:8:14121. doi: 10.1038/ncomms14121.

Authors

Yvonne Y Li¹, Grace T Y Chung², Vivian W Y Lui^{3

4}, Ka-Fai To², Brigette B Y Ma⁵, Chit Chow², John K S Woo⁶, Kevin Y Yip⁷, Jeongsun Seo⁸, Edwin P Hui⁵, Michael K F Mak², Maria Rusan¹, Nicole G Chau¹, Yvonne Y Y Or², Marcus H N Law², Peggy P Y Law², Zoey W Y Liu², Hoi-Lam Ngan⁴, Pok-Man Hau², Krista R Verhoeft⁴, Peony H Y Poon⁴, Seong-Keun Yoo⁸, Jong-Yeon Shin⁸, Sau-Dan Lee⁷, Samantha W M Lun², Lin Jia⁹, Anthony W H Chan², Jason Y K Chan⁶, Paul B S Lai¹⁰, Choi-Yi Fung⁴, Suet-Ting Hung⁴, Lin Wang¹¹, Ann Margaret V Chang¹², Simion I Chiosea¹¹, Matthew L Hedberg¹³, Sai-Wah Tsao⁹, Andrew C van Hasselt⁶, Anthony T C Chan⁵, Jennifer R Grandis¹⁴, Peter S Hammerman¹, Kwok-Wai Lo²

Affiliations

¹ 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.
² 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.
³ School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
⁴ Department of Pharmacology and Pharmacy, School of Biomedical Sciences, Li-Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
⁵ 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.
⁶ Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
⁷ Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong, China.
⁸ Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 10-799, Republic of Korea.
⁹ School of Biomedical Sciences and Center for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
¹⁰ Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
¹¹ Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA.
¹² Institute of Pathology, St. Luke's Medical Center, Quezon City 1112, Philippines.
¹³ Medical Scientist Training Program, University of Pittsburgh-Carnegie Mellon University, Pittsburgh, Pennsylvania 15261, USA.
¹⁴ Department of Otolaryngology, University of California San Francisco, San Francisco, California 94113, USA.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma / genetics*
Carcinoma / metabolism
Carcinoma / physiopathology
Cell Proliferation
Deubiquitinating Enzyme CYLD / genetics
Deubiquitinating Enzyme CYLD / metabolism
Epstein-Barr Virus Infections / genetics*
Epstein-Barr Virus Infections / metabolism
Epstein-Barr Virus Infections / physiopathology
Epstein-Barr Virus Infections / virology
Exome*
Genome, Human
Herpesvirus 4, Human / genetics
Herpesvirus 4, Human / metabolism
Humans
Mutation*
NF-KappaB Inhibitor alpha / genetics
NF-KappaB Inhibitor alpha / metabolism
NF-kappa B / genetics
NF-kappa B / metabolism*
Nasopharyngeal Carcinoma
Nasopharyngeal Neoplasms / genetics*
Nasopharyngeal Neoplasms / metabolism
Nasopharyngeal Neoplasms / physiopathology
Signal Transduction*
TNF Receptor-Associated Factor 3 / genetics
TNF Receptor-Associated Factor 3 / metabolism
Viral Matrix Proteins / genetics
Viral Matrix Proteins / metabolism
Whole Genome Sequencing

Substances

EBV-associated membrane antigen, Epstein-Barr virus
NF-kappa B
NFKBIA protein, human
TNF Receptor-Associated Factor 3
TRAF3 protein, human
Viral Matrix Proteins
NF-KappaB Inhibitor alpha
CYLD protein, human
Deubiquitinating Enzyme CYLD

Abstract

Publication types

MeSH terms

Substances

Grants and funding