Abstract A007: Patterns of DNA methylation in HIV-associated DLBCL

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype worldwide. While outcomes remain suboptimal, mutational and gene expression profiling have uncovered potential therapeutic vulnerabilities. As both oncogenes and tumor suppressors are aberrantly or differentially methylated in DLBCL, methylation profiling is actively being explored to inform understanding of biology and expand therapeutic options. People with HIV have an elevated risk of developing DLBCL with unique molecular patterns. With respect to methylation, HIV alters B cell development, is shown affect epigenetic regulators implicated in lymphomagenesis and induces hypomethylation in the blood. However, the DNA methylation profile of HIV-associated (HIV+) DLBCL is incompletely understood. To begin to characterize the impact of HIV on the DLCBL methylation, we conducted whole genome, enzymatic-methylation sequencing on pre-treatment DLBCL tumors inclusive of HIV status. Across all tumors, CpG islands had decreased methylation, with a slight trend towards hypomethylation in HIV+ tumors. However, when combined with previously reported array-based methylation levels from a HIV-inclusive lymphoma cohort, HIV+ tumors had significant decreased methylation in CpG islands compared to HIV- (p=0. 004). We also see low levels of methylation at repetitive elements, characteristic of cancer and genomic instability, although again, not different by HIV status. Analysis of individual CpG sites showed and clustering of the top 10% of most variable genes, highlight hypomethylation within the HIV+ tumors. Differential methylation analysis revealed over 200, 000 sites and 687 regions with significant differential methylation (FDR0. 01 0. 25) between HIV- and HIV+ tumors, with the majority having decreased methylation in HIV+ tumors. Including regions located in the promoters of genes implicated in DLBCL like HDAC9, FOXP2, and SOX2/9. Overall, we showcase additional molecular differences when stratifying DLBCL by HIV status, including increased hypomethylation in HIV+ tumors. Hypomethylation, particularly in repetitive elements, is associated with increased genomic instability. This supports our previous findings where we observed HIV+ tumors from this cohort had increased microsatellite instability. These results further highlight the distinct molecular biology of HIV+ DLBCL with potential implications for clinical use. Citation Format: Samantha Beck, Marriam Mponda, Edwards Kasonkanji, Grant Fischer, Tamiwe Tomoka, Matthew S. Painschab, Yuri Fedoriw. Patterns of DNA methylation in HIV-associated DLBCL abstract. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7 (3Suppl): Abstract nr A007.