Abstract
Epstein Barr virus (EBV) is the etiologic agent involved in numerous human cancers. After infecting the host, EBV establishes a latent infection, with low levels of messenger RNA (mRNA) and protein expression, evolved to evade immune recognition. Conversely, EBV microRNAs (miRNA) are expressed ubiquitously and abundantly within infected cells. Their role in tumor biology and clinical outcomes across the spectrum of cancer is not fully explained. Here, we applied our bioinformatics pipeline for quantitative EBV miRNA detection to examine sequencing data of 8,955 individual tumor samples across 27 tumor types representing the breadth of cancer. We uncover an association of intermediate levels of viral miRNA with decreased survival in adult acute myeloid leukemia (AML) patients (P = 0.00013). Prognostic modeling of this association suggests that increased EBV miRNA levels represent an independent risk factor for poor patient outcomes. Furthermore, we explore differences in expression between elevated and absent viral miRNA loads in adult AML tumors finding that EBV positivity was associated with proinflammatory signals. Together, given no associations were found for pediatric AML, our analyses suggests EBV positivity has the potential for being a prognostic biomarker and might represent a surrogate measure related to immune impairment in adult patients.
Highlights
Epstein Barr virus (EBV) is linked to 1.5% of all human cancers across the world[1] based on known viral-containing malignancies such as Burkitt Lymphoma (BL), nasopharyngeal carcinoma (NPC), stomach cancer, and diffuse large B cell lymphoma (DLBCL)
To better assess the presence of EBV across a spectrum of cancers, we examined 27 different tumor types for the presence of 44 EBV miRNAs as well as smaller fragments of other viral non-coding RNAs including Epstein Barr virus encoded small RNAs (EBERs) (Methods and Supplementary Fig. S1)
The samples were predominantly drawn from the The Cancer Genome Atlas (TCGA) and TARGET datasets, and we included 19 EBV-associated eBL tumors that our group has previously sequenced (Methods, Table 1)[14]
Summary
Epstein Barr virus (EBV) is linked to 1.5% of all human cancers across the world[1] based on known viral-containing malignancies such as Burkitt Lymphoma (BL), nasopharyngeal carcinoma (NPC), stomach cancer, and diffuse large B cell lymphoma (DLBCL). The ability to control the virus and EBV reactivation may serve indirectly as a surrogate of general host immune competence An example of such interplay is the inflammatory effects of EBV on gastric cancers through pro-inflammatory molecule expression such as cytokines responsible for increase in growth in EBV infected cells (IL5,IL6)[9]. Genomic studies have focused on viral messenger RNA (mRNA) transcriptome evaluation, such studies are limited by the low levels of viral mRNA expression and have focused on further understanding the role of EBV in cancer cell biology. These were mainly limited to studying classic cases of EBV-associated malignancies, such as BL and NPC2,11. More intriguing a recent study of approximately 2300 individuals from a more limited set of 13 cancers from TCGA study showed the presence of any EBV miRNAs was correlated with poor survival in low stage malignancies[16]
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