Genotype-phenotype correlations in Wilms tumor initiation

Wilms tumor, the most common pediatric kidney cancer, arises from abnormal embryonic kidney development. Therapy resistance and tumor recurrence remain major challenges, likely driven by the presence of Cancer Stem Cells (CSCs). Here, we elucidate the earliest pathogenic events in genomically engineered mouse models exhibiting loss of Wt1 or LIN28B overexpression, two Wilms tumor driver genes. Loss of Wt1 causes a spatially and temporarily lineage-specific phenotype, with the first blastemal-like cells appearing in combined nephrogenic and stromal conditional loss of Wt1 . In contrast, LIN28B overexpression leads to postnatal blastemal overgrowth with presence of cells co-expressing the Ncam1, Aldh1a2, Six2, and Cited1 CSC markers, suggesting a mixed and unstable uninduced/induced blastemal population, and revealing cellular heterogeneity within early tumors. Our findings demonstrate a detailed framework of the earliest pathogenic events, and corresponding cancer stem cell marker expression patterns, driven by biologically distinct mutated genes.