Journal Article

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

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

2017

Overview

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 , TRAF 3, 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. Nasopharyngeal cancer is frequently characterized by Epstein-Barr virus infection. Here, using genomic analyses, the authors find that the tumours harbour mutations in genes involved in the NF-κB signalling pathway or overexpress a viral oncoprotein, latent membrane protein 1.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 692/4028/67/1536 / 692/4028/67/69 / 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 / Humanities and Social Sciences / Humans / multidisciplinary / Mutation / Nasopharyngeal Carcinoma / Nasopharyngeal Neoplasms - genetics / Nasopharyngeal Neoplasms - metabolism / Nasopharyngeal Neoplasms - physiopathology / NF-kappa B - genetics / NF-kappa B - metabolism / NF-KappaB Inhibitor alpha - genetics / NF-KappaB Inhibitor alpha - metabolism / Science / Science (multidisciplinary) / 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