The Importance of MTHFD2 Expression in Renal Cell Carcinoma

Objective: Renal cell carcinoma (RCC) carries a poor prognosis at advanced stages. Identifying reliable prognostic biomarkers is essential for improved clinical management. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a key mitochondrial enzyme in the folate cycle, is overexpressed in various rapidly proliferating malignancies. However, its prognostic value in RCC remains underexplored. For this reason, we purposed to search the prognostic role of MTHFD2 expression in RCC. Materials and Methods: This study included 124 RCC patients who applied radical nephrectomy between 2015 and 2020. Immunohistochemical analysis of MTHFD2 expression was performed on paraffin-embedded tumor samples. Expression levels were classified using a histoscore-based system: low (grades 0–1) and high (grades 2–3). Correlations between MTHFD2 expression and clinical/pathological parameters were evaluated, and survival analysis was conducted. Results: MTHFD2 overexpression was detected in 53% of tumors and was absent in adjacent non-tumor tissues. High expression was significantly associated with adverse prognostic features, including higher histological grade, sarcomatoid differentiation, advanced pT stage, and presence of distant metastases (all p < 0.05). Patients with high MTHFD2 expression had significantly reduced overall survival (p < 0.001). Remarkably, early-stage tumors (pT1–2) with high MTHFD2 expression were linked to shorter survival compared to more advanced tumors (pT3–4) with low expression. Conclusion: Our results pointed out that high expression of MTHFD2 is associated with poor prognosis in RCC and may function as an independent prognostic biomarker. These findings underscore the potential of MTHFD2 in risk stratification and as a therapeutic target in RCC.