Association of GFPT2 expression with clinical outcomes in clear cell renal cell carcinoma.

e16543 Background: Progression of clear cell renal cell carcinoma (ccRCC) is driven in part by tumor microenvironment remodeling, including epithelial mesenchymal transition (EMT), stromal activation, and metabolic reprogramming. GFPT2, the rate-limiting enzyme of the hexosamine biosynthesis pathway, has been linked to extracellular matrix remodeling and EMT across cancers and is enriched in high-grade, advanced ccRCC. We hypothesized that GFPT2 expression identifies a microenvironment-associated program linked to adverse clinical outcomes in ccRCC. Methods: We analyzed mRNA expression and clinical outcomes in TCGA-KIRC (n = 498). Survival analyses employed Kaplan-Meier methods and multivariable Cox proportional hazards regression. Pearson correlations quantified GFPT2-microenvironment associations. Outcomes included overall survival (OS) and progression-free survival (PFS). Results: High GFPT2 expression (median cutoff) was associated with significantly worse OS and PFS (log-rank p < 0.001 for both). As a continuous variable, GFPT2 expression conferred markedly inferior OS (HR 1.74, 95% CI 1.49-2.04, p < 0.001) and PFS (HR 1.96, 95% CI 1.66-2.31, p < 0.001) in univariate analysis, with sustained independent prognostic significance after clinical adjustment (OS: HR 1.42, p < 0.001; PFS: HR 1.42, p < 0.001). GFPT2 expression demonstrated robust correlations with EMT effectors (VIM r = 0.29, FN1 r = 0.41, TWIST1 r = 0.29, SNAI1 r = 0.23), stromal collagens (COL1A1 r = 0.51, COL3A1 r = 0.40), and hypoxia signaling (Buffa score r = 0.45). In multivariable models incorporating EMT and stromal markers alongside clinical covariates, GFPT2 retained independent prognostic significance for OS (HR 1.26, 95% CI 1.02-1.54, p = 0.028) with borderline significance for PFS (HR 1.22, 95% CI 0.99-1.49, p = 0.057), indicating partial but incomplete mediation of GFPT2's adverse prognostic impact through microenvironment-associated transcriptional programs. Conclusions: GFPT2 expression independently predicts adverse survival outcomes in ccRCC through mechanisms partially, but not entirely, mediated by EMT- and stroma-related transcriptional reprogramming. These findings position GFPT2 as a candidate biomarker integrating metabolic dysregulation with microenvironment remodeling and warrant investigation as a therapeutic target in high-risk ccRCC. Multivariable Cox Model for Overall Survival (OS) and Progression-Free Survival (PFS). Variable OS: HR (95% CI) p-value PFS: HR (95% CI) p-value GFPT2 1.74 (1.49-2.04) <0.001 1.96 (1.66-2.31) <0.001 GFPT2* 1.42 (1.21-1.65) <0.001 1.42 (1.21-1.66) <0.001 GFPT2§ 1.26 (1.02-1.54) 0.028 1.22 (0.99-1.49) 0.057 GFPT2† 1.37 (1.15-1.64) <0.001 1.37 (1.15-1.64) <0.001 *Adjusted for Age, Sex, and Stage. §Adjusted for Age, Sex, and Stage, and EMT and stromal markers. †Adjusted for Age, Sex, and Stage, and EMT and BUFFA Hypoxia score.