map of EBV-associated neoplasms reveals functional host-virus interactions

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Integrated pan-cancer map of EBV-associated neoplasms reveals functional host-virus interactionsSrishti Chakravorty, Bingyu Yan, Chong Wang, Luopin Wang, Joseph Taylor Quaid, Chin Fang Lin, Scott D Briggs, Joydeb Majumder, D. Alejandro Canaria, Daniel Chauss, Gaurav Chopra, Matthew R. Olson, Bo Zhao, Behdad Afzali and Majid Kazemian





DOI: 10.1158/0008-5472.CAN-19-0615


AAbstract

Epstein-Barr virus (EBV) is a complex oncogenic symbiont. The molecular mechanisms governing EBV carcinogenesis remain elusive and the functional interactions between virus and host cells are incompletely defined. Here we present a comprehensive map of the host cell-pathogen interactome in EBV-associated cancers. We systematically analyzed RNA-sequencing from >1000 patients with 15 different cancer types, comparing virus and host factors of EBV+ to EBV- tissues. EBV preferentially integrated at highly accessible regions of the cancer genome with significant enrichment in super-enhancer architecture. Twelve EBV transcripts, including LMP1 and LMP2, correlated inversely with EBV reactivation signature. Over-expression of these genes significantly suppressed viral reactivation, consistent with a "virostatic" function. In cancer samples, hundreds of novel frequent missense and nonsense variations in virostatic genes were identified, and variant genes failed to regulate their viral and cellular targets in cancer. For example, one-third of EBV+ NK/T-cell lymphoma patients carried two novel nonsense variants (Q322X, G342X) of LMP1 and both variant proteins failed to restrict viral reactivation, confirming loss of virostatic function. Host cell transcriptional changes in response to EBV infection classified tumors into two molecular sub-types based on patterns of interferon signature genes and immune checkpoint markers, such as PD-L1 and IDO1. Overall, these findings uncover novel points of interaction between a common oncovirus and the human genome and identify novel regulatory nodes and druggable targets for individualized EBV and cancer-specific therapies.