Author: Grande, Bruno
Though generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in over 90% of cases in malaria-endemic regions and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumour EBV status or geographic origin. In this thesis, I describe an integrative analysis of whole genome and transcriptome sequencing data generated from a large cohort of endemic and sporadic paediatric BL patients. This analysis revealed that the mutational landscape of BL genomes is primarily shaped by four different processes, and that at least two of them—aberrant somatic hypermutation and defects in DNA mismatch repair—appear associated with the presence of EBV. After identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, I explored the incidence of mutations affecting genes and pathways involved with BL pathogenesis and found that EBV-positive tumours had significantly fewer driver mutations, especially among genes with roles in apoptosis, and that this difference did not exist when comparing geographic subtypes of BL. I also identified a subset of immunoglobulin variable region genes encoding clonal B-cell receptors (BCRs) that were disproportionally used in the tumours, including IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Many of these results suggest that tumour EBV status defines a specific BL entity irrespective of geographic origin with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply potential improvements that could be brought to BL therapy. This includes the rational use of DNA-damaging chemotherapy in some BL patients and targeted agents such as the CDK4/6 inhibitor palbociclib in others. The importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk and Src family kinases among these patients. Lastly, the identification of USP7 as a tumour-suppressor gene in BL highlights the potential clinical utility of MDM2 inhibitors in treating patients with otherwise wild-type TP53.
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Thesis advisor: Morin, Ryan
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