@article{221b06c892174bbb8f240beef04cb757,
title = "Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape",
abstract = "Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.",
author = "Bruce, {Jeff P.} and To, {Ka Fai} and Lui, {Vivian W.Y.} and Chung, {Grace T.Y.} and Chan, {Yuk Yu} and Tsang, {Chi Man} and Yip, {Kevin Y.} and Ma, {Brigette B.Y.} and Woo, {John K.S.} and Hui, {Edwin P.} and Mak, {Michael K.F.} and Lee, {Sau Dan} and Chit Chow and Sharmila Velapasamy and Or, {Yvonne Y.Y.} and Siu, {Pui Kei} and {El Ghamrasni}, Samah and Stephenie Prokopec and Man Wu and Kwan, {Johnny S.H.} and Yuchen Liu and Chan, {Jason Y.K.} and {van Hasselt}, {C. Andrew} and Young, {Lawrence S.} and Dawson, {Christopher W.} and Paterson, {Ian C.} and Yap, {Lee Fah} and Tsao, {Sai Wah} and Liu, {Fei Fei} and Chan, {Anthony T.C.} and Pugh, {Trevor J.} and Lo, {Kwok Wai}",
note = "Funding Information: All authors declare no competing interests directly related to the current study. V.W.Y. Lui receives funding from a University-Industry Collaboration Program (UIM/329) by the Innovation and Technology Fund, Hong Kong government, and Lee{\textquoteright}s Pharmaceutical (Hong Kong Limited) for the period of 2018–2020, and also served as a scientific consultant for Novartis Pharmaceutical (Hong Kong) Limited (Oct 2015-Oct 2016). B.B. Y. Ma received speaker{\textquoteright}s honorarium and serves in the advisory board of Bristol-Myers Squibb (BMS), MSD and Novartis, Hong Kong. She has received a research grant from Novartis and Boerhinger Ingelheim. E.P. Hui received speaker{\textquoteright}s honoraria and serves in the advisory board of Merck Sharp & Dohme (MSD) and Merck Serono. A.T.C. Chan received research and travel grants from MSD, Pfizer, and Roche. The other authors declare no competing interests. Funding Information: T.J.P. was supported by the Princess Margaret Cancer Foundation; Canada Research Chairs program; Canada Foundation for Innovation, Leaders Opportunity Fund, CFI #32383; and the Ontario Ministry of Research and Innovation, Ontario Research Fund Small Infrastructure Program. K.W.L. was supported by Research Grant Council, Hong Kong (Areas of Excellence Scheme – AoE/M-401/20; Theme-based Research Scheme - T12-401/13-R; Collaborative Research Fund - C4001-18GF, C7027-16 G, C5012-15E; General Research Fund − 14104415, 14138016, 14117316, 14101721), Core Utilities of Cancer Genome and Pathobiology, Focused Innovations Scheme and Faculty Strategic Research (4620513) of the Faculty of Medicine, and VC{\textquoteright}s One-off Discretionary Fund (VCF2014017, VCF2014015), the Chinese University of Hong Kong. C.M.T. was supported by the Health and Medical Research Fund (05162386, 13142201), General Research Fund (14113620, 17110315), Faculty Innovation Award (FIA2020/A/01) and NSFC/RGC Joint Research Scheme (N_HKU735/18 and 81861168033) of Research Grant Council, Hong Kong. S.W.T. was supported by Research Grant Council Hong Kong (CRF-C7027-16G; GRF-17116416, GRF-17104617, GRF-17111917, GRF-17114818, GRF-17122420, NSFC/RGC-N_HKU735/18 and 81861168033). L.F.Y. was supported by Fundamental Research Grant Scheme (FP006-2019A) from the Ministry of Higher Education Malaysia, Newton-Ungku Omar Fund MR/P013201 (IF016-2017) from the Academy of Sciences Malaysia and Medical Research Council UK, and University of Malaya Impact-Oriented Interdisciplinary Research Grant Programme (IIRG008A-19FNW). V.W.Y.L. was supported by the Research Grant Council, Hong Kong (General Research Fund − 17114814, 17121616, 14168517; Research Impact Fund -R4015-19F, R4017-18), the Health and Medical Research Fund (HMRF#15160691) from the Food and Health Bureau, The Government of the Hong Kong SAR; University-Industry Collaboration Program (UIM/329; Innovation and Technology Fund, Hong Kong government, Hong Kong SAR and Lee{\textquoteright}s Pharmaceutical (HK) Limited); the Hong Kong Cancer Fund, Hong Kong SAR; Start-up Fund from the School of Biomedical Sciences, Faculty of Medicine, CUHK. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
day = "1",
doi = "10.1038/s41467-021-24348-6",
language = "English (US)",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}