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

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.

• Authors: 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, Kwok-Wai Lo
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 4193 (07 07 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34234122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CDKN2A protein, human
• CDKN2B protein, human
• Cyclin-Dependent Kinase Inhibitor p15
• Cyclin-Dependent Kinase Inhibitor p16
• NF-kappa B
• MAT2A protein, human
• Methionine Adenosyltransferase
• Receptor, Transforming Growth Factor-beta Type II
• TGFBR2 protein, human

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinogenesis (drug effects, genetics, immunology)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p15 (genetics)
• Cyclin-Dependent Kinase Inhibitor p16 (genetics)
• Epstein-Barr Virus Infections (genetics, immunology, therapy, virology)
• Female
• Gene Expression Regulation, Viral (immunology)
• Herpesvirus 4, Human (genetics, immunology, pathogenicity)
• Host-Pathogen Interactions (genetics, immunology)
• Humans
• Methionine Adenosyltransferase (antagonists & inhibitors, metabolism)
• Mice
• NF-kappa B (metabolism)
• Nasopharyngeal Carcinoma (genetics, immunology, therapy, virology)
• Nasopharyngeal Neoplasms (genetics, immunology, therapy, virology)
• Nasopharynx (immunology, pathology, surgery, virology)
• Receptor, Transforming Growth Factor-beta Type II (genetics, metabolism)
• Sequence Deletion
• Signal Transduction (drug effects, genetics, immunology)
• Tumor Escape (drug effects, genetics)
• Whole Genome Sequencing
• Xenograft Model Antitumor Assays