Abstract
Epstein–Barr virus (EBV) is a gammaherpesvirus linked to a number of lymphoid and epithelial malignancies, including Burkitt lymphoma (BL) in which its frequency ranges from 30% in sporadic cases to 100% in the endemic ones. The possible contribution of EBV to BL pathogenesis is largely unknown. It has been suggested that EBV may be associated with all of the cases, including those diagnosed as EBV negative by a mechanism of hit-and-run. Early during oncogenesis, viral genes are essential for initiating disease. Progressively, viral genome is lost to escape the immune system and host mutations accumulate in proto-oncogenic cell. The main problem with the hit-and-run hypothesis is the lack of evidence in primary tumors. The routine methods applied to detect the virus [i.e., immunohistochemistry and EBV-encoded RNAs (EBER) in situ hybridization (ISH)] have a low specificity and accuracy. The aim of this study was to identify the most suitable method to detect EBV infection in pathology samples by applying conventional and non-conventional methods (i.e., EBV-microRNAs detection and EBV viral load measurement). We investigated a total of 10 cases and we found that all the samples (n = 6) diagnosed as EBV negative by immunohistochemistry and EBER-ISH demonstrated the presence of EBV-microRNAs and EBV genome. This points at the possibility that EBV might have contributed to lymphomagenesis in all our patients, and propose microRNAs detection as the most specific and sensitive tool to recognize EBV vestiges. It is worth noting that our data would have considerable implications for EBV-related diseases control. By using anti-EBV vaccines, one could potentially prevent also some cancers less suspected of a viral origin because of viral genome loss.
Highlights
Epstein–Barr virus (EBV) is a gammaherpesvirus that persistently infects over 90% of adults, usually without consequence (Queen et al, 2013)
By applying in situ hybridization (ISH) for EBV, we observed that only four samples retained the EBV-encoded RNAs, as demonstrated by the black signal revealed in the nucleus of about 70–95% of neoplastic cells (Figure 1A)
EBV-encoded RNAs (EBER)-positive Burkitt lymphoma (BL) samples showed a clear expression of viral miRNAs and all EBER-negative cases presented some degree of expression of at least one EBV-miRNA (Figure 2A)
Summary
Epstein–Barr virus (EBV) is a gammaherpesvirus that persistently infects over 90% of adults, usually without consequence (Queen et al, 2013). The role of EBV is further confounded by the less than total association of the virus with histologically similar tumors This may be explained by the hit-and-run hypothesis for viral-induced lymphomagenesis which proposes that after eliciting a heritable change in the gene-expression pattern of the host cell, the genome of tumor viruses may be completely lost (Ambinder, 2000; Minarovits et al, 2011). It seems inevitable that a cancer, with time, will evolve to be independent from viral gene functions, allowing viral genome loss This results in an inverse correlation between the number of viral genes expressed in these tumor cells and their associated cellular mutations (Rochford et al, 2005) as it has been recently demonstrated in cell lines and tumor samples (Abate et al, 2015). Focusing on viruspositive cancers provide little information about genome loss, and the difficulty of analyzing spontaneous cancers, where the molecular changes driving transformation are almost always unknown, makes firm functional conclusions hard to draw (Stevenson et al, 2010)
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