Intratumoral Leptin Expression and Tissue-Derived LEP rs2167270 Genotype Are Associated with Adverse Pathological Features and Substantial Prognosis in Sudanese Bladder Carcinoma

Abstract

Bladder carcinoma shows marked pathological and molecular heterogeneity, and tissue-based molecular markers may help identify tumors with aggressive pathological features. In African populations, including Sudan, molecular pathology data on bladder carcinoma remain limited. This study assessed whether intratumoral leptin expression and tissue-derived LEP rs2167270 genotype were associated with histological grade, pathological pT category, muscle invasion, and lymphovascular invasion in Sudanese bladder carcinoma. This retrospective, multicenter, tissue-based study included 153 formalin-fixed, paraffin-embedded bladder carcinoma specimens from four Sudanese institutions. Leptin expression was evaluated by immunohistochemistry and classified using the immunoreactive score. LEP rs2167270 was genotyped by PCR-RFLP using amplifiable FFPE tumor DNA. Assay reliability was evaluated by repeat genotyping and Sanger sequencing. The cohort was predominantly male (120/153, 78.4%), and urothelial carcinoma was the main tumor type (136/153, 88.9%). High-grade tumors were found in 49/136 urothelial carcinomas (36.0%). Muscle invasion was found in 54/149 tumors (36.2%), and lymphovascular invasion was present in 56/149 tumors (37.6%). Moderate-to-strong leptin immunoreactivity was more frequent in high-grade than low-grade tumors (61.2% vs 32.2%; p = 0.004), T2-or-higher than Ta tumors (64.8% vs 32.7%; p = 0.003), muscle-invasive than non-muscle-invasive tumors (64.8% vs 30.5%; p < 0.001), and lymphovascular invasion-positive tumors (64.3% vs 30.1%; p < 0.001). Valid tissue-derived LEP rs2167270 genotypes were obtained in 127 cases. The GG genotype was more frequent with stronger leptin staining (p = 0.005) and showed distributional differences by grade, pT category, muscle invasion, and lymphovascular invasion; however, the pT-category pattern did not show a clear stepwise increase in GG frequency with increasing pT category. PCR-RFLP was concordant with Sanger sequencing in 30 cases. Higher intratumoral leptin expression and tissue-derived LEP rs2167270 GG genotype were associated with adverse pathological features. Studies with matched normal DNA, larger African cohorts, clinical follow-up, and functional validation are needed to determine whether the tissue-derived genotype reflects germline variation, biological relevance, and prognostic value.