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. Kwan, Yuchen 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 () and Kwok-Wai Lo ()
Additional contact information
Jeff P. Bruce: Princess Margaret Cancer Centre, University Health Network
Ka-Fai To: The Chinese University of Hong Kong
Vivian W. Y. Lui: The Chinese University of Hong Kong
Grace T. Y. Chung: The Chinese University of Hong Kong
Yuk-Yu Chan: The Chinese University of Hong Kong
Chi Man Tsang: The Chinese University of Hong Kong
Kevin Y. Yip: The Chinese University of Hong Kong
Brigette B. Y. Ma: The Chinese University of Hong Kong
John K. S. Woo: The Chinese University of Hong Kong
Edwin P. Hui: The Chinese University of Hong Kong
Michael K. F. Mak: The Chinese University of Hong Kong
Sau-Dan Lee: The Chinese University of Hong Kong
Chit Chow: The Chinese University of Hong Kong
Sharmila Velapasamy: The Chinese University of Hong Kong
Yvonne Y. Y. Or: The Chinese University of Hong Kong
Pui Kei Siu: The Chinese University of Hong Kong
Samah El Ghamrasni: Princess Margaret Cancer Centre, University Health Network
Stephenie Prokopec: Princess Margaret Cancer Centre, University Health Network
Man Wu: The Chinese University of Hong Kong
Johnny S. H. Kwan: The Chinese University of Hong Kong
Yuchen Liu: The Chinese University of Hong Kong
Jason Y. K. Chan: The Chinese University of Hong Kong
C. Andrew van Hasselt: The Chinese University of Hong Kong
Lawrence S. Young: Warwick Medical School, University of Warwick
Christopher W. Dawson: Warwick Medical School, University of Warwick
Ian C. Paterson: University of Malaya
Lee-Fah Yap: University of Malaya
Sai-Wah Tsao: The University of Hong Kong
Fei-Fei Liu: Princess Margaret Cancer Centre, University Health Network
Anthony T. C. Chan: The Chinese University of Hong Kong
Trevor J. Pugh: Princess Margaret Cancer Centre, University Health Network
Kwok-Wai Lo: The Chinese University of Hong Kong

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24348-6

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