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 Chow, Chit and Velapasamy, Sharmila and Or, Yvonne Y. Y. and Siu, Pui Kei and El Ghamrasni, Samah and Prokopec, Stephenie and Wu, Man and Kwan, Johnny S. H. and Liu, Yuchen 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 (2021) Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-kappa B activation and immune escape. Nature Communications, 12 (1). ISSN 2041-1723, DOI https://doi.org/10.1038/s41467-021-24348-6.
Full text not available from this repository.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-kappa B 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-kappa B-driven and immune-protected, yet potentially druggable, cancer. The genomic characterisation of nasopharyngeal carcinoma (NPC) remains crucial. Here, the authors perform whole-genome sequencing for 70 NPCs with EBV gene expression, report the somatic alterations and EBV-mediated effects converging on NF-kappa B activation and immune escape and identify targetable homozygous MTAP deletions.
| Item Type: | Article |
|---|---|
| Funders: | University of Toronto, Canada Research Chairs, Canada Foundation for Innovation, Leaders Opportunity Fund, CFI[32383], Ontario Ministry of Research and Innovation, Ontario Research Fund Small Infrastructure Program, Hong Kong Research Grants Council[AoE/M-401/20], Hong Kong Research Grants Council[T12-401/13-R], Chinese University of Hong Kong, Health and Medical Research Fund of Research Grant Council, Hong Kong[05162386], General Research Fund of Research Grant Council, Hong Kong[14113620], Faculty Innovation Award of Research Grant Council, Hong Kong[FIA2020/A/01], Hong Kong Research Grants Council[CRF-C7027-16G], Ministry of Education, Malaysia[FP006-2019A], Academy of Sciences Malaysia[MR/P013201 (IF016-2017)], University of Malaya Impact-Oriented Interdisciplinary Research Grant Programme[IIRG008A-19FNW], Health and Medical Research Fund (HMRF) from the Food and Health Bureau, The Government of the Hong Kong[SAR 15160691], University-Industry Collaboration Program (Innovation and Technology Fund, Hong Kong government, Hong Kong SAR)[UIM/329], University-Industry Collaboration Program (Lee's Pharmaceutical (HK) Limited)[UIM/329], Hong Kong Cancer Fund, Hong Kong SAR, School of Biomedical Sciences, Faculty of Medicine, CUHK, Faculty of Medicine[4620513], VC's One-off Discretionary Fund[VCF2014017], NSFC/RGC Joint Research Scheme of Research Grant Council, Hong Kong[81861168033], UK Research & Innovation (UKRI) Medical Research Council UK (MRC)[MR/P013201 (IF016-2017)] |
| Uncontrolled Keywords: | Epstein-barr-virus;Antitumor-activity;Mutations;Expression;Recurrent;Deletion;Pathway;Safety;DNA |
| Subjects: | R Medicine R Medicine > RA Public aspects of medicine R Medicine > RK Dentistry |
| Divisions: | Faculty of Dentistry |
| Depositing User: | Ms Zaharah Ramly |
| Date Deposited: | 19 Sep 2022 04:03 |
| Last Modified: | 19 Sep 2022 04:03 |
| URI: | http://eprints.um.edu.my/id/eprint/34686 |
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