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Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape.

Jeff P BruceKa-Fai ToVivian Wai Yan LuiGrace T Y ChungYuk-Yu ChanChi Man TsangKevin Y YipBrigette Buig Yue MaJohn K S WooEdwin Pun HuiMichael K F MakSau-Dan LeeChit ChowSharmila VelapasamyYvonne Y Y OrPui Kei SiuSamah El GhamrasniStephenie D ProkopecMan WuJohnny S H KwanYuchen LiuJason Ying-Kuen ChanC Andrew van HasseltLawrence S YoungChristopher W DawsonIan Charles PatersonLee Fah YapSai-Wah TsaoFei-Fei LiuAnthony T C ChanTrevor J PughKwok-Wai Lo
Published in: Nature communications (2021)
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.
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