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 We retrospectively evaluated FGR protein expression by immunohistochemistry (IHC) in 91 patients with de novo 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.