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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Carcinogenesis / drug effects
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Carcinogenesis / genetics
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Carcinogenesis / immunology
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p15 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Epstein-Barr Virus Infections / genetics
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Epstein-Barr Virus Infections / immunology*
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Epstein-Barr Virus Infections / therapy
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Epstein-Barr Virus Infections / virology
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Female
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Gene Expression Regulation, Viral / immunology
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Herpesvirus 4, Human / genetics*
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Herpesvirus 4, Human / immunology
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Herpesvirus 4, Human / pathogenicity
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Host-Pathogen Interactions / genetics
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Host-Pathogen Interactions / immunology
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Humans
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Methionine Adenosyltransferase / antagonists & inhibitors
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Methionine Adenosyltransferase / metabolism
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Mice
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NF-kappa B / metabolism
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Nasopharyngeal Carcinoma / genetics
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Nasopharyngeal Carcinoma / immunology*
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Nasopharyngeal Carcinoma / therapy
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Nasopharyngeal Carcinoma / virology
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Nasopharyngeal Neoplasms / genetics
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Nasopharyngeal Neoplasms / immunology*
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Nasopharyngeal Neoplasms / therapy
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Nasopharyngeal Neoplasms / virology
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Nasopharynx / immunology
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Nasopharynx / pathology
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Nasopharynx / surgery
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Nasopharynx / virology
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Receptor, Transforming Growth Factor-beta Type II / genetics
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Receptor, Transforming Growth Factor-beta Type II / metabolism
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Sequence Deletion
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology
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Tumor Escape / drug effects
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Tumor Escape / genetics*
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Whole Genome Sequencing
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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CDKN2A protein, human
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CDKN2B protein, human
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Cyclin-Dependent Kinase Inhibitor p15
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Cyclin-Dependent Kinase Inhibitor p16
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NF-kappa B
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MAT2A protein, human
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Methionine Adenosyltransferase
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Receptor, Transforming Growth Factor-beta Type II
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TGFBR2 protein, human