Exome and genome sequencing of nasopharynx cancer identifies NF-\u03baB pathway activating mutations

Yvonne Y Li ,Andrew C Van Hasselt,Ann Margaret V Chang,Krista R Verhoeft,Sau-Dan Lee,Zoey W Y Liu,Michael K F Mak,Pok-Man Hau,Edwin P Hui,Jeong‐Sun Seo ,Jong-Yeon Shin,Anthony W.h Chan ,Ka‐Fai To ,Grace Tin‐Yun Chung ,Samantha Wei‐Man Lun ,Lin Wang,Man Fai Law ,Simion I Chiosea,Seong-Keun Yoo ,John K S Woo ,Peggy P.y Law ,Chit Chow,Choi-Yi Fung,Suet-Ting Hung,Lin Jia,Maria Rusan,Vivian Wai Yan Lui ,Paul Bo San Lai ,Kevin Y Yip,Nicole G Chau,Hextan Y S Ngan ,P.w.f Poon ,Peter S Hammerman,Sai‐Wah Tsao ,Matthew L Hedberg,Yvonne Yan-Yan Or ,B Brigette ,Jennifer R Grandis,Kwok Wai Lo

doi:10.1038/ncomms14121

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

Results

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

HKNPC-090T 1 0 –1 –2

I I IS

Methods