EBV AND MYC IN BURKITT LYMPHOMA: WHICH IS THE MAIN ACTOR?

ABSTRACT Burkitt Lymphoma remains an enigmatic gem in cancer research. It was the first human tumour to be discovered to be having a link to a virus (Epstein-Barr virus). The tumour was discovered to be having a genetic alteration involving an oncogene MYC and leading to its over-expression, it was also discovered to successively responding to chemotherapeutic treatment alone successfully. A lot of scientific work have focused on finding the molecular biology of the disease, some have been successful others are still on course to dissect further discoveries. This study focuses on investigating the roles played by EBV and MYC in Burkitt lymphoma development and or with a view of possibly understanding the best practice on the disease diagnostic platform. After the discovery of EBV virus by Epstein and Barr, the pathogen has been under intense studies to discover its role in Burkitt lymphoma development. The possible contributory role 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. (Paper 1) Aimed at identification of a suitable method of detect EBV infection in pathologic samples, by an application of conventional and non-conventional methods (i.e., EBV-microRNAs detection and EBV viral load measurement). Diagnosis of Burkitt lymphoma has had some challenges by the fact that it has borderline or gray zone disease that makes morphology alone difficult. Immunohistochemistry as a method of BL diagnosis has been proposed as an alternative confirmatory after the initial cytology results. Despite its adoption by several clinical laboratories, the performance of the assay in routine practice remains undefined. Immunohistochemistry IHC studies can be hampered by technical difficulties that are related to fixation, methods, antibody choice and scoring of staining. The cut-off values for considering case “positive” lack uniformity. (Paper 2) Aimed to standardize MYC IHC by defining the intensity of staining and the percentage of positive cells, correlate MYC gene alterations with MYC protein expression and compare the Double Hit and Double Expresses status in terms of Overall Survival and Progression Free Survival. MYC family members largely share their target genes; they can compensate and substitute for each other in both physiological and pathological conditions. Previous studies demonstrated a cross regulating expression of MYC family members; in particular, it was shown that MYC and MYCN reciprocally control their expression via auto-regulatory loops and via repressing each other at defined promoter sites. MYCN expression has not been systematically studied so far. Recently, while assessing the degree of correlation between MYC gene rearrangement by fluorescent in situ hybridization (FISH) and MYC protein expression by immunohistochemistry (IHC) in aggressive B-cell lymphomas, we observed few BL cases lacking MYC protein expression despite carrying the typical t(8;14) translocation (EAHP 2017, personal communication) (Paper 3) Aimed to better characterize such BL cases lacking MYC protein expression, evaluate whether the cross-talk between the MYC gene family members does also exist in BL, and explore the genetic landscape of these rare BL cases.