Elevated FGR protein expression identifies a high-risk subset of diffuse large B-cell lymphoma and a potential therapeutic target

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, and despite effective first-line immunochemotherapy a substantial proportion of patients develop relapse/refractory (RR) disease, underscoring the need for practical biomarkers beyond clinical risk scores. Methods: DLBCL treated with first-line R-CHOP. FGR staining was scored using an immunoreactive score (IRS), and high expression was defined as IRS ≥ 2. Associations with RR events and survival were assessed by Kaplan-Meier analysis and Cox regression, and predictive performance at 5 years was compared with the International Prognostic Index (IPI) using Receiver operating characteristic (ROC) analysis. External validation was performed using a publicly available gene-expression dataset. Results: High FGR expression was observed in 64 of 91 tumors (70.3%) and was associated with a higher 5-year RR rate (29.7% vs 7.4%, P = 0.021). In Kaplan-Meier analyses, progression-free survival (PFS) was 69.1% in the high-expression group versus 92.1% in the low-expression group (P = 0.093), and overall survival (OS) was 80.0% versus 96.2% (P = 0.050); separation was more pronounced in the non-germinal center B-cell (non-GCB) subgroup. In multivariable Cox regression, high FGR remained independently associated with inferior 5-year PFS (HR 4.73, 95% CI 1.03-21.65; P = 0.045) and showed a strong trend toward inferior 5-year OS (HR 6.52, 95% CI 0.79-53.99; P = 0.082). ROC analysis suggested that FGR and IPI had similar discrimination at 5 years in this cohort. In external validation, FGR mRNA expression was elevated in non-GCB cases, and high FGR expression (upper quartile) was associated with a trend toward inferior OS. Conclusion: Elevated FGR protein expression identifies a subset of DLBCL patients with increased treatment failure and inferior outcomes, particularly within non-GCB subtypes, supporting prospective validation in larger, less selected cohorts and further mechanistic studies of the FGR/Src-family kinase axis as a candidate therapeutic target.