Cross-cancer transcriptomic analysis reveals conserved developmental, ferroptosis, and immune remodeling modules in Wilms tumor and oral cancer.
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BACKGROUND: Wilms tumor (nephroblastoma) is a pediatric renal malignancy driven by disrupted nephrogenesis, yet its transcriptomic relationship with ferroptosis and immune remodeling remains poorly characterized. METHODS: We analyzed GSE66405 microarray data (28 Wilms tumor samples) together with an oral cancer 10X single-cell reference dataset to evaluate six biologically defined modules: developmental/nephrogenesis, Wnt/beta-catenin, ferroptosis/iron metabolism, immune/inflammatory, extracellular matrix, and cell-cycle. Module scores were calculated as mean z-scores across curated gene sets, and inter-module Pearson correlations, co-expression network analyses, and unsupervised clustering were performed in Python using scipy, scikit-learn, networkx, and matplotlib. RESULTS: Developmental and Wnt programs formed the central transcriptomic axis of Wilms tumor, with WT1, SIX1, SIX2, PAX2, and CTNNB1 as hub genes (Pearson r = 0.868 between module scores, P < 0.001). The developmental module showed the strongest correlation with ferroptosis (r = 0.920, P < 0.001), while ferroptosis and immune modules were also tightly linked (r = 0.851, P < 0.001). Ferroptosis-related genes (HMOX1, FTL, SLC40A1, TFRC, GPX4, SLC7A11) and immune markers (CD68, CD163, CD8A, GZMB) were detected as secondary remodeling modules associated with the developmental core. Cross-cancer comparison revealed partial conservation of ferroptosis and immune module architecture in the oral cancer reference, whereas the developmental-Wnt axis remained Wilms tumor-specific. In vitro qRT-PCR validation in WiT49 (Wilms tumor) and CAL-27 (oral squamous cell carcinoma) cell lines confirmed differential ferroptosis gene expression: HMOX1 and TFRC were significantly upregulated in WiT49 cells (p < 0.001), while GPX4 and SLC7A11 were relatively higher in CAL-27 cells (p < 0.01), corroborating lineage-specific iron metabolism remodeling. CONCLUSION: These results link developmental dysregulation, iron metabolism, and immune remodeling in Wilms tumor and identify candidate modules for future functional validation. The developmental-Wnt axis constitutes a Wilms tumor-specific transcriptomic core, while ferroptosis and immune programs represent partially conserved stress-response modules that may offer cross-lineage therapeutic relevance. In vitro qRT-PCR experiments in WiT49 and CAL-27 cells corroborated these transcriptomic findings, confirming lineage-differential expression of core ferroptosis regulators across the two cancer contexts.