Abstract
We report a novel transcriptomic analysis workflow called LiEB (Life cycle of Epstein-Barr virus) to characterize distributions of oncogenic virus, Epstein-Barr virus (EBV) infection in human tumors. We analyzed 851 The Cancer Genome Atlas whole-transcriptome sequencing (WTS) data to investigate EBV infection by life cycle information using three-step LiEB workflow: 1) characterize virus infection generally; 2) align transcriptome sequences against a hybrid human-EBV genome, and 3) quantify EBV gene expression. Our results agreed with EBV infection status of public cell line data. Analysis in stomach adenocarcinoma identified EBV-positive cases involving PIK3CA mutations and/or CDKN2A silencing with biologically more determination, compared to previous reports. In this study, we found that a small number of colorectal adenocarcinoma cases involved with EBV lytic gene expression. Expression of EBV lytic genes was also observed in 3% of external colon cancer cohort upon WTS analysis. Gene set enrichment analysis showed elevated expression of genes related to E2F targeting and interferon-gamma responses in EBV-associated tumors. Finally, we suggest that interpretation of EBV life cycle is essential when analyzing its infection in tumors, and LiEB provides high capability of detecting EBV-positive tumors. Observation of EBV lytic gene expression in a subset of colon cancers warrants further research.
Highlights
Several types of human cancers involve the infection of oncogenic viruses within the host genome
The lytic replication cycle begins when the early transcription factors (TFs) are induced; viral promoters activated by the TFs facilitate the formation of the initiation complex, which is composed of six viral gene products: BMRF1, BSLF1, BBLF4, BBLF2/3, BALF5, and BALF213,14
We first identified the 286 infection-positive samples (33.61%) using VirusSeq (Fig. 2a). These Epstein-Barr virus (EBV)-positive samples identified using VirusSeq were mapped against the four EBV strains (GenBank accession: AJ507799, AY961628, AG876, DQ279927, and M80517M75989) using Spliced Transcripts Alignment to a Reference (STAR) approach; 88 WTS samples (10.34%) were distinguished to selectively contain sequences aligned against the hybrid transcriptome
Summary
Several types of human cancers involve the infection of oncogenic viruses within the host genome. In regard to the biological impact of EBV infection in human cancer[19], entrance into the EBV lytic cycle begins upon differentiation of B lymphocytes towards plasma cells[21] and often contributes to EBV-associated tumors[22]. Sought to analyze NGS data from the perspective of the EBV life cycle considering the correlation between the lytic EBV stage and human cancers. Combining current knowledge regarding the genes related to each EBV stage with abundant WTS/WGS data, we analyzed the correlation between EBV lytic genes and the human genome in cancer cases. We hypothesized that in addition to viral infection, the pattern of gene expression related to the viral stage is important in virus-associated carcinogenesis. We found out that EBV expression in a small proportion of colon cancers
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