Genomic profiling of Burkitt lymphoma in adults: Novel molecular insights and implications for outcomes.

Abstract

7085 Background: The real-world treatment outcomes of Burkitt lymphoma (BL) from low-middle income countries appear to be inferior (<60%). Delays in diagnosis, treatment interruptions and toxicities are often attributed as the reasons for poor outcomes. However, biological differences could also explain the observed differences. However, there is limited information on the molecular profile of adult BL from developing countries. Methods: We evaluated a cohort of adult BL (histopathologically confirmed) who received treatment at our centre between 2012-2019. The data on demography, stage, HIV status, treatment type, response and survival was recorded. The formalin-fixed paraffin blocks were subjected to targeted next-generation sequencing using the hybrid capture based targeted panel- SOPHiA Lymphoma Solution which identifies single nucleotide variants (SNVs), indels from 73 genes and gene amplification events in 68 genes. Results: Among a total of 165 patients, the adequate quality DNA was extracted from 76 patients(83% males). Median age was 34 years ;67% patients had stage III/IV disease,10% were HIV positive. Treatment regimen were high-dose methotrexate based-74 %, 24%- DA-EPOCH. Rituximab was given to 83% of patients. Complete response was seen in 69% of patients. 67 cases (88.2%) harboured at least one somatic variant, while no variants were detected in 9 cases (11.8%) within the genes covered by the targeted panel. A total of 712 somatic variants were identified across the cohort. Based on ACMG/AMP classification, 88 variants (12.4%) were categorized as oncogenic and 318 variants (44.7%) as likely oncogenic. This indicates a substantial mutational burden in Burkitt lymphoma, despite its classical characterization as a MYC-driven malignancy. Considering only oncogenic and likely oncogenic variants, the most recurrently mutated genes were KMT2D, CREBBP, ARID1A, EP300 and TP53 . TP53 showed the highest number of confirmed oncogenic variants (22 variants) and also accounted for the largest number of missense mutations (16 out of 158 missense variants). Mutations in PTPRD and ITPKB were mutually exclusive (p = 0.051), as were mutations in CCND3 and KMT2D (p = 0.053). These patterns suggest possible distinct molecular subsets of Burkitt lymphoma, potentially reflecting alternative oncogenic pathways driven either by aberrant cell cycle regulation ( CCND3 ) or by epigenetic dysregulation (KMT2D ). Conclusions: Our data suggests that histopathologically confirmed BL have complex mutational landscape characterized by frequent alterations in epigenetic regulators, tumour suppressor genes, and key signalling molecules which can lead to inferior outcomes.