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Exome and genome sequencing of nasopharynx cancer identifies NF-?B 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-?B 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-?B signalling, and we observed mutual exclusivity among tumours with somatic NF-?B pathway aberrations and LMP1-overexpression, suggesting that NF-?B activation is selected for by both somatic and viral events during NPC pathogenesis.

SUBMITTER: Li YY 

PROVIDER: S-EPMC5253631 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Li Yvonne Y YY   Chung Grace T Y GT   Lui Vivian W Y VW   To Ka-Fai KF   Ma Brigette B Y BB   Chow Chit C   Woo John K S JK   Yip Kevin Y KY   Seo Jeongsun J   Hui Edwin P EP   Mak Michael K F MK   Rusan Maria M   Chau Nicole G NG   Or Yvonne Y Y YY   Law Marcus H N MH   Law Peggy P Y PP   Liu Zoey W Y ZW   Ngan Hoi-Lam HL   Hau Pok-Man PM   Verhoeft Krista R KR   Poon Peony H Y PH   Yoo Seong-Keun SK   Shin Jong-Yeon JY   Lee Sau-Dan SD   Lun Samantha W M SW   Jia Lin L   Chan Anthony W H AW   Chan Jason Y K JY   Lai Paul B S PB   Fung Choi-Yi CY   Hung Suet-Ting ST   Wang Lin L   Chang Ann Margaret V AM   Chiosea Simion I SI   Hedberg Matthew L ML   Tsao Sai-Wah SW   van Hasselt Andrew C AC   Chan Anthony T C AT   Grandis Jennifer R JR   Hammerman Peter S PS   Lo Kwok-Wai KW  

Nature communications 20170118

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 f  ...[more]

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