EPSTEIN-BARR VIRUS AND CANCER ADDING EVIDENCES TO EBV INVOLVEMENT IN LYMPHOMAGENESIS

Despite significant steps into the understanding the Epstein-Barr virus-host interaction and its oncogenic potential have been made, its pathogenetic role has to be further investigated in order to fully understand the contribution of this virus and its tumorigenic potential in the development of its associated malignancies. A better understanding of the EBV life cycle and its gene products’ relevance in tumour development will help to define not only the pathogenesis of the EBV-associated malignancies, but also to design novel diagnostic and therapeutic approaches. Moreover, the global burden of EBV-associated malignancies can be further enlarged due to the idea of the so-called “hit-and-run” hypothesis, which claims that the virus can mediate an initial cellular transformation through an initial “hit”, while the maintenance of the transformed state is compatible with the gradual loss (“run”), after a number of cellular divisions, of viral genome. If so, it may mean that a larger proportion of EBV-related malignancies remains undetected, thus affecting not only the understanding in their pathogenetic mechanisms, but also the diagnostic and therapeutic approaches to them. We have investigated this possibility by applying conventional and nonconventional analysis tools on a series of BL cases, both classified as EBV positive and EBV negative relying on the gold-standard method of diagnosis (i.e. immunohistochemistry and EBER in situ hybridization technique). Interestingly, all the conventional methods were unable to identify the presence of viral vestiges in BL samples diagnosed as EBER-negative, while the miRNA profiling and their subsequent RT-qPCR analysis, along with the viral genome load investigation by qPCR assay, showed the presence of traces of Epstein-Barr virus DNA fragments. We also analysed a larger and more comprehensive series of typical EBV-associated lymphomas, including DLBCL and adult cHL. The analyses documented the consistent presence at a low level of one or more of the EBV nucleic acids tested in tumour cells of those B-cell lymphomas classified as EBV-negative by routine methods. The results obtained with these analyses, directly assessing the presence of the virus, suggest that EBV infection might have happened in a significantly greater proportion of B-cell lymphoma cases than commonly thought, according to the “hit-and-run” hypothesis: taken together, these findings expand the spectrum of B-cell lymphomas that can be linked with EBV infection.