Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations2017-01-18 13:33:26
Nature Communications; January 18, 2017: /DOI:10.1038/ncomms14121
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
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.
Nasopharyngeal carcinoma (NPC) is one of the most aggressive head and neck cancers and frequently metastasizes to distant lymph nodes and organs1,2. Its distinct etiology linked with latent infection of the oncogenic Epstein-Barr virus (EBV) and characteristic heavy lymphocyte infiltration often distinguish NPC from other head and neck cancers. In fact, EBV-associated NPC is endemic in Southern China and Southeast Asia, contrasting with the epidemic Human Papillomavirus (HPV)-associated head and neck cancer in some Western countries. Due to the intrinsic invasiveness and asymptomatic nature of the disease, majority of NPC patients are diagnosed with advanced diseases (60–70% cases) with poor outcome. Thus far, there is no effective targeted therapy for advanced NPC.
NPC is a complex malignancy with etiology and pathology involving both EBV infection and a combination of multiple genetic aberrations. Unlike other head and neck cancers, the scarcity of NPC genomic data to date hinders the understanding of NPC biology, disease progression and rational therapy design for better treatments. The extensive stromal components of these often small-sized tumours present major challenges for comprehensive and precise genomic characterization.
Here we report the genomic landscape of the first and largest cohort of microdissected EBV-positive NPC of more than 100 cases. Our study suggests that the somatic mutation rate of NPC is substantially higher than that reported previously3 and reveals that majority of NPCs display activation of the NF-κB signalling pathway as a result of somatic inactivating mutations in negative regulators of NF-κB.
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