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

Jeff P. Bruce, Ka Fai To, Vivian W.Y. Lui, Grace T.Y. Chung, Yuk Yu Chan, Chi Man Tsang, Kevin Y. Yip, Brigette B.Y. Ma, John K.S. Woo, Edwin P. Hui, Michael K.F. Mak, Sau Dan Lee, Chit Chow, Sharmila Velapasamy, Yvonne Y.Y. Or, Pui Kei Siu, Samah El Ghamrasni, Stephenie Prokopec, Man Wu, Johnny S.H. KwanYuchen Liu, Jason Y.K. Chan, C. Andrew van Hasselt, Lawrence S. Young, Christopher W. Dawson, Ian C. Paterson, Lee Fah Yap, Sai Wah Tsao, Fei Fei Liu, Anthony T.C. Chan, Trevor J. Pugh, Kwok Wai Lo

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Article number4193
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape'. Together they form a unique fingerprint.

Cite this