TY - JOUR
T1 - Integrated pan-cancer map of EBV-associated neoplasms reveals functional host–virus interactions
AU - Chakravorty, Srishti
AU - Yan, Bingyu
AU - Wang, Chong
AU - Wang, Luopin
AU - Quaid, Joseph Taylor
AU - Lin, Chin Fang
AU - Briggs, Scott D.
AU - Majumder, Joydeb
AU - Canaria, D. Alejandro
AU - Chauss, Daniel
AU - Chopra, Gaurav
AU - Olson, Matthew R.
AU - Zhao, Bo
AU - Afzali, Behdad
AU - Kazemian, Majid
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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 >1,000 patients with 15 different cancer types, comparing virus and host factors of EBVþ 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. Overexpression 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 patients with EBVþ NK/T-cell lymphoma 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 subtypes based on patterns of IFN 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. Significance: This study provides a comprehensive map of the host cell-pathogen interactome in EBVþ malignancies. See related commentary by Mbulaiteye and Prokunina-Olsson, p. 5917.
AB - 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 >1,000 patients with 15 different cancer types, comparing virus and host factors of EBVþ 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. Overexpression 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 patients with EBVþ NK/T-cell lymphoma 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 subtypes based on patterns of IFN 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. Significance: This study provides a comprehensive map of the host cell-pathogen interactome in EBVþ malignancies. See related commentary by Mbulaiteye and Prokunina-Olsson, p. 5917.
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U2 - 10.1158/0008-5472.CAN-19-0615
DO - 10.1158/0008-5472.CAN-19-0615
M3 - Article
C2 - 31481499
AN - SCOPUS:85076061860
SN - 0008-5472
VL - 79
SP - 6010
EP - 6023
JO - Cancer Research
JF - Cancer Research
IS - 23
ER -