DECODING BURKITT LYMPHOMA AND ITS MIMICS IN AFRICA: 11Q ABERRATIONS, EPIGENETICS AND BCR PATHWAYS

Background: Burkitt lymphoma (BL) is a highly proliferative germinal center B-cell malignancy whose epidemiology in Africa is tightly linked to Epstein-Barr virus (EBV) and malaria exposure. However, a subset of aggressive B-cell lymphomas in endemic regions clinically and morphologically resembles BL but lacks IG::MYC rearrangements and instead harbors characteristic 11q copy-number imbalances (high-grade B-cell lymphoma with 11q aberration, HGBCL,11q). Concurrently, emerging multi-omics data indicate that epigenetic architecture, particularly DNA methylation and B-cell receptor (BCR) signaling status, delineate biologically meaningful BL subgroups with potential diagnostic and therapeutic consequences. Objectives: To decode Burkitt lymphoma and its mimics in Africa by integrating 11q genomic aberrations, EBV-associated DNA methylation subtypes, and BCR pathway phenotypes, including implications of absent surface immunoglobulin expression. Methods: We analyzed African BL biopsies and cell lines using cytogenetics (FISH for MYC and 11q probes), copy-number arrays, genome/exome sequencing, and Immunohistochemistry for phenotype and EBV. DNA methylation was profiled on Illumina platforms with consensus clustering, while BCR status was assessed via surface Ig staining and NGS/qPCR to identify MAPK-pathway lesions in BCR-negative tumors. We synthesized evidence from African biopsy cohorts and BL cell lines using: interphase FISH for MYC/BCL2/BCL6/IG loci; targeted probes for 11q gain/loss; high-density copy-number platforms (OncoScan/CytoScan); wholegenome/ exome sequencing and fusion validation; and immunohistochemistry to confirm BL phenotype and EBV status. DNA methylation was profiled on Illumina 450K/EPIC arrays and analyzed with unsupervised consensus partitioning, purity correction, and super-enhancer annotations to derive epigenetic clusters. BCR status was assessed by surface Ig (IgM/D/G/A) immunostaining and targeted NGS/qPCR to evaluate MAPK-pathway lesions in BCR-negative tumors. Results: We investigated African Burkitt lymphoma (BL) biopsies and cell lines using a multi-platform approach. Cytogenetic analyses included interphase FISH to detect MYC, BCL2, BCL6, and immunoglobulin loci, alongside targeted probes for 11q gain/loss. High-density copynumber profiling was performed with OncoScan and CytoScan arrays, complemented by whole-genome and exome sequencing with fusion validation. Immunohistochemistry confirmed BL phenotype and EBV status. DNA methylation profiling employed Illumina 450K and EPIC arrays, analyzed with unsupervised consensus clustering, purity correction, and integration with super-enhancer annotations to define epigenetic clusters. B-cell receptor (BCR) status was determined by immunostaining for surface Ig (IgM/D/G/A), while targeted NGS and qPCR were used to characterize mutational landscapes. Particular focus was given to BCR-negative tumors, where recurrent lesions in epigenetic regulators and activating KRAS mutations implicate compensatory MAPK pathway activation, distinguishing this subset from classical BCR-dependent BL. Conclusions: In African cohorts, decoding BL requires concurrent assessment of 11q architecture, EBV-anchored methylation subtypes, and BCR pathway status. This integrated framework sharpens the boundary between BL and HGBCL,11q, explains epigenetic diversity through EBV-linked remodeling, and uncovers a BCR-independent MAPK-addicted niche all with immediate implications for diagnostics (FISH panels plus methylation surrogates), risk stratification, and rational targeting of downstream pathways in resource-constrained endemic settings.