Plasma IgG N-Glycosylation as a Novel Biomarker of Disease Severity and Prognosis in Diffuse Large B-Cell Lymphoma, Not Otherwise Specified

Background: Diffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous lymphoma with variable clinical outcomes despite established molecular and clinical prognostic models. Immunoglobulin G (IgG) N-glycosylation regulates antibody effector functions and reflects systemic immune status, but plasma IgG N-glycosylation has not previously been systematically investigated in DLBCL. We evaluated whether plasma IgG N-glycosylation is altered in DLBCL and examined its associations with molecular subtype, established prognostic indices, and clinical outcomes. Methods: Plasma samples were obtained from 54 treatment-naïve patients with pathologically confirmed DLBCL, not otherwise specified (NOS), and 54 age- and sex-matched healthy controls. IgG N-glycans were analyzed using capillary gel electrophoresis with laser-induced fluorescence (CGE-LIF), resolving 27 glycan peaks that were summarized into six derived glycosylation traits: agalactosylation (G0), monogalactosylation (G1), digalactosylation (G2), sialylation (S), bisecting N-acetylglucosamine (B), and core fucosylation (CF). Associations with disease status, cell-of-origin subtype, prognostic indices (International Prognostic Index (IPI), Age-Adjusted International Prognostic Index (aaIPI), revised International Prognostic Index (R-IPI), National Comprehensive Cancer Network International Prognostic index (NCCN-IPI), Central Nervous System International Prognostic Index (CNS-IPI) and inflammation-based cumulative prognostic score system (ICPS)) progression-free survival (PFS), overall survival (OS), and relapse were assessed using multivariable regression and Cox proportional hazards models adjusted for age and sex. Multiple testing was controlled using the Benjamini–Hochberg false discovery rate. Results: Compared with healthy controls, patients with DLBCL, NOS exhibited significantly increased agalactosylation and decreased digalactosylation and sialylation, consistent with a pro-inflammatory IgG glycosylation profile. The non-germinal center B-cell-like (non-GCB) subtype showed significantly lower monogalactosylation than germinal center B-cell like (GCB) DLBCL. Across multiple established prognostic indices, increasing clinical risk was consistently associated with increased agalactosylation and reduced digalactosylation. During follow-up, 20 patients (37%) relapsed, and 21 (39%) died. Increased agalactosylation was independently associated with shorter PFS, whereas reduced sialylation predicted both inferior PFS and an increased risk of relapse. Conclusions: Plasma IgG N-glycosylation is profoundly altered in DLBCL, NOS and is associated with molecular subtype, established prognostic indices, and clinically relevant outcomes. These findings identify plasma IgG N-glycosylation as a promising minimally invasive biomarker that reflects disease biology and provides prognostic information beyond conventional clinical risk models. Given the exploratory nature and modest size of this cohort, these findings should be considered hypothesis-generating and require validation in larger prospective cohorts.