Integrative network toxicology and transcriptomic analyses identify DCP1B and HAS2 as key prognostic biomarkers in formaldehyde-associated Wilms tumor.

Abstract

Background and objectivesWilms tumor, a common childhood malignancy, has been hypothesized to be associated with environmental factors such as formaldehyde exposure. As a potential endocrine disruptor with reported pro-proliferative effects, the molecular mechanism underlying the role of formaldehyde in Wilms tumor remains unclear. This study systematically investigated the mechanisms linking formaldehyde exposure to Wilms tumor using network toxicology and transcriptomic analysis.MethodsTranscriptomic data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases, whereas formaldehyde-related targets were predicted using the Search Tool for Interactions of Chemicals and Comparative Toxicogenomics databases. Candidate genes were screened through differential expression (|log2FC| > 2.5, p < 0.05) and weighted gene coexpression network analyses. Prognostic key genes were identified using univariate and Lasso-Cox regression, with nomogram construction and survival analysis. Single-cell RNA sequencing data (GSE223373) were further analyzed to characterize cellular heterogeneity and the cell-type-specific expression patterns of the identified key genes.ResultsSeventy-nine candidate genes associated with Wilms tumor were identified using multidimensional intersection analysis. These genes were significantly involved in pathways such as microRNAs in cancer and the cell cycle. Univariate Cox and Lasso-Cox regression analyses identified DCP1B and HAS2 as key genes closely associated with the prognosis of patients with Wilms tumor. Kaplan-Meier survival analysis demonstrated that higher expressions of DCP1B and HAS2 were significantly associated with better overall survival in these patients. The nomogram model constructed based on the two key genes demonstrated excellent calibration (area under the curve > 0.8) and clinical applicability. Network analysis identified NEAT1, the hsa-let-7 microRNA, and transcription factors such as PDX1 and E2F1 were as core regulatory nodes. Single-cell analysis demonstrated pronounced stromal expansion within Wilms tumor specimens and further revealed that DCP1B was preferentially enriched in tumor epithelial cells, whereas HAS2 exhibited a stromal-skewed distribution, predominantly within mesangial cells.ConclusionsDCP1B and HAS2 were identified as key prognostic genes for Wilms tumor. These findings suggest that formaldehyde exposure is associated with Wilms tumor pathogenesis through the potential involvement of cancer-associated microRNA pathways and cell cycle signaling, which could contribute to dysregulated cell proliferation and apoptosis.