LBS1:05 B-cell subset somatic mutations reveal lymphoma-like pathways in systemic lupus erythematosus

Objectives Systemic lupus erythematosus (SLE) patients have a 2–7-fold increased risk of hematologic malignancies, particularly B-cell non-Hodgkin lymphoma (B-NHL). Although germline susceptibility shared between SLE and B-NHL is minimal, somatic evolution of autoreactive B-cells has been implicated as a precursor to malignant transformation in autoimmune syndromes. We therefore aimed to characterize somatic alterations across SLE B-cell subsets, with an emphasis on double-negative (DN) B-cells, a central autoreactive population.Methods In a cohort of 35 SLE patients, we performed whole exome sequencing on FACS-isolated naïve (CD19+, IgD+), memory (MBC; CD19+, IgD-, CD27+), and DN (CD19+, IgD-, CD27-) from peripheral blood. Patient-matched buccal DNA was used to filter out germline variants, and somatic mutations detected by >=2 callers (Mutect2, Strelka2, and CaVEMan) were retained. Variant allele frequencies (VAFs) were compared across subsets to assess clonal dynamics. Associations with disease activity (SLEDAI-2KG), time since diagnosis, and age were evaluated. Pathway enrichment and lymphoma-associated mutations were interrogated in high-burden patients.Results DN and MBC proportions correlated with disease activity (rho=0.443, p=0.008; rho=0.354, p=0.037). DN and MBC had significantly higher somatic mutation burden than naïve cells (p=0.001 and p=0.017), consistent with expansion of antigen-experienced and/or autoreactive compartments under chronic inflammation ( figure 1A–B). Mutation burden in DN correlated with time since diagnosis, but not age, suggesting disease-associated acquisition and/or selective growth of mutated clones (figure 1C). Among mutations shared between MBC and DN, a disproportionate fraction expanded in DN (figure 1D). Shared mutations expanded in DN were enriched for B-cell activation and proliferation pathways, including NF-kB and B-cell receptor signalling (FDR