Abstract
BackgroundEpstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBVaGCs and the role EBV plays during this process remain poorly understood.MethodsWe applied whole-exome sequencing, EBV genome sequencing, and whole-genome bisulfite sequencing to multiple samples (n = 123) derived from the same patients (n = 25), which covered saliva samples and different histological stages from morphologically normal epithelial tissues to dysplasia and EBVaGCs. We compared the genomic landscape between EBVaGCs and their precursor lesions and traced the clonal evolution for each patient. We also analyzed genome sequences of EBV from samples of different histological types. Finally, the key molecular events promoting the tumor evolution were demonstrated by MTT, IC50, and colony formation assay in vitro experiments and in vivo xenograft experiments.ResultsOur analysis revealed increasing mutational burden and EBV load from normal tissues and low-grade dysplasia (LD) to high-grade dysplasia (HD) and EBVaGCs, and oncogenic amplifications occurred late in EBVaGCs. Interestingly, within each patient, EBVaGCs and HDs were monoclonal and harbored single-strain-originated EBV, but saliva or normal tissues/LDs had different EBV strains from that in EBVaGCs. Compared with precursor lesions, tumor cells showed incremental methylation in promotor regions, whereas EBV presented consistent hypermethylation. Dominant alterations targeting the PI3K-Akt and Wnt pathways were found in EBV-infected cells. The combinational inhibition of these two pathways in EBV-positive tumor cells confirmed their synergistic function.ConclusionsWe portrayed the (epi) genomic evolution process of EBVaGCs, revealed the extensive genomic diversity of EBV between tumors and normal tissue sites, and demonstrated the synergistic activation of the PI3K and Wnt pathways in EBVaGCs, offering a new potential treatment strategy for this disease.
Highlights
Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBV-associated GCs (EBVaGCs) and the role EBV plays during this process remain poorly understood
The driver landscape of EBVaGCs and their precursor lesions Primary EBVaGCs were identified by RNA in situ hybridization (RISH) using an Epstein-Barr-encoded RNA (EBER) probe (Fig. 1a, Additional file 1: Figure S1a)
107 samples comprising 62 EBVaGCs, 9 high-grade dysplasia (HD), 19 low-grade dysplasia (LD), and 17 normal tissues from 20 patients were subjected to whole-exome sequencing (Fig. 1b, Additional file 1: Tables S1-S2)
Summary
Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBVaGCs and the role EBV plays during this process remain poorly understood. Of all gastric carcinomas (GCs), approximately 10%, are associated with Epstein-Barr virus (EBV) [2]. EBV is linked with a variety of malignancies, including some lymphomas, undifferentiated nasopharyngeal carcinomas (NPCs), and EBV-associated GCs (EBVaGCs). Among these EBV-linked malignancies, EBVaGCs are most prevalent and account for more than 50,000 new cases each year worldwide [3].
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