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

• Main Authors: Bruce, Jeff P., To, Ka-Fai, Lui, Vivian W. Y., Chung, Grace T. Y., Chan, Yuk-Yu, Tsang, Chi Man, Yip, Kevin Y., Ma, Brigette B. Y., Woo, John K. S., Hui, Edwin P., Mak, Michael K. F., Lee, Sau-Dan, Chow, Chit, Velapasamy, Sharmila, Or, Yvonne Y. Y., Siu, Pui Kei, El Ghamrasni, Samah, Prokopec, Stephenie, Wu, Man, Kwan, Johnny S. H., Liu, Yuchen, Chan, Jason Y. K., van Hasselt, C. Andrew, Young, Lawrence S., Dawson, Christopher W., Paterson, Ian C., Yap, Lee-Fah, Tsao, Sai-Wah, Liu, Fei-Fei, Chan, Anthony T. C., Pugh, Trevor J., Lo, Kwok-Wai
• Format: Article
• Published: Nature Portfolio 2021
• Subjects: R Medicine; RA Public aspects of medicine; RK Dentistry
• Online Access: http://eprints.um.edu.my/34686/

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.