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

Document Type

Article

Publication Date

7-7-2021

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.

Keywords

Epstein-barr-virus, Antitumor-activity, Mutations, Expression, Recurrent, Deletion, Pathway, Safety, DNA

Publication Title

Nature Communications

Divisions

Dentistry

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)]

Volume

12

Issue

1

Publisher

Nature Portfolio

Publisher Location

HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY

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