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.
Highlights
Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration
Ninety-seven subjects were from Southeast Asia where NPC is endemic and eight from the United States (Supplementary Table 1 and Supplementary Data 1)
We identified a total of seven genes significantly mutated above background rates in Asian NPCs: TP53, NRAS, NF-kB pathway genes, CYLD, TRAF3 and NFKBIA, the major histocompatibility complex (MHC) class I gene HLA-A, and the transcriptional regulator MED12L, a gene previously reported to be mutated in mouse and human HNSCC9 (Supplementary Data 3 and 4)
Summary
We identified a total of seven genes significantly mutated above background rates in Asian NPCs: TP53, NRAS, NF-kB pathway genes, CYLD, TRAF3 and NFKBIA, the major histocompatibility complex (MHC) class I gene HLA-A, and the transcriptional regulator MED12L, a gene previously reported to be mutated in mouse and human HNSCC9 (Supplementary Data 3 and 4). We identified two individual’s tumours with hypermutator phenotypes (HKNPC-003, HKNPC033) with 2,051 and 817 somatic mutations in coding regions, respectively (Fig. 2); both tumours harboured mutations of mismatch repair genes, including MSH6 (HKNPC-003) and MLH1 (HKNPC-033) Both patients with hypermutated tumours had poor overall survival of B12 and 19 months, respectively. Selected copy number variants (CNVs) were further validated and confirmed by a b
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