Interpretation of EBV infection in pan-cancer genome considering viral life cycle: LiEB (Life cycle of Epstein-Barr virus)

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.

Potential prognostic impact of EBV RNA‐seq reads in gastric cancer: a reanalysis of The Cancer Genome Atlas cohort

“…RNA‐seq‐based EBV‐positive GC may exist as a distinct entity that includes EBER1/2 in situ hybridization‐positive EBVaGC. The 9% positivity rate of EBV in the original TCGA‐STAD study or the 7–10% as determined by in situ hybridization were much lower than the 49.6% observed here and the ~ 40% in another study that were obtained by reanalysis of a portion of the TCGA‐STAD data. These variable results suggest that the assignment of an appropriate cutoff value is essential and that the proportion of EBVaGC is higher than previously recognized.…”

Comprehensive Epstein-Barr Virus Transcriptome by RNA-Sequencing in Angioimmunoblastic T Cell Lymphoma (AITL) and Other Lymphomas

“…Resumption of a lytic cycle begins with the induction of viral transcription factors, particularly BZLF1 and BRLF1, and activation of viral promoters. Subsequently, the initiation complex, composed of the six viral factors, BMRF1, BSLF1, BBLF4, BBLF2/3, BALF5, and BALF2, is formed [61,62]. For our patients, apart from AIL26, BZLF1 was highly expressed while BRLF1 was little or not expressed.…”

Partial absence of PD‐1 expression by tumor‐infiltrating EBV‐specific CD8+ T cells in EBV‐driven lymphoepithelioma‐like carcinoma

“…40 However, recent data highlighted that EBV lytic genes are detected in EBV-associated malignancies as well. [41][42][43] Moreover, recent works suggest that EBV lytic cycle can contribute to carcinogenesis through the induction of oncogenic cytokine secretion and genome instability. 44,45 In NPC, recurrent induction of EBV lytic cycle contributes more profoundly to NPC carcinogenesis.…”

“…The oncogenic role of EBV has been attributed to the expression of latent genes providing growth and survival benefit to DNA‐damaged epithelial cells 40 . However, recent data highlighted that EBV lytic genes are detected in EBV‐associated malignancies as well 41‐43 . Moreover, recent works suggest that EBV lytic cycle can contribute to carcinogenesis through the induction of oncogenic cytokine secretion and genome instability 44,45 .…”