Expanding the Genetic Blueprint of Wilms Tumor: An Account of 71 Novel Variants across 16 Genes with Novel Implications for Wilms Tumor Pathogenesis

A BSTRACT Background: While Wilms tumor (WT) is primarily associated with mutations in WT1, CTNNB1 and WTX genes, these alterations account for only ~30% of cases, suggesting a broader, unexplored genetic landscape. Objective: The objective of this study was to comprehensively characterize novel genetic variants in WT through whole-genome sequencing analysis of paired tumor and normal renal tissues. Materials and Methods: Somatic exonic variants (paired, malignant, and normal renal tissues) in the whole genome of the study cohort were filtered for exonic regions, annotated using multiple prediction tools (SIFT, MutationTaster, Combined Annotation Dependent Depletion [CADD]), and analyzed for functional relevance using cBioPortal and STRING databases. Results: Seventy-one variants in 16 genes were consistently present across the study cohort. Statistically, KRT18, CNN2, MUC16, MUC19 , and FCGBP harbor 74.6% (53/71) of the variations identified. Six genes ( MAST2, MUC19, KRT3, MUC16, FCGBP , and ANKRD36 ) were predicted to have a “high” likelihood of being involved in cancer. Twenty-three variants pertaining to KRT18, CNN2, WDR89, MTCH2, DDX11, GXYLT1 , and ANKRD36 had a CADD score >20, with 10 KRT18 variants having DANN scores ≥0.75. Significant clustering of variants in “hotspot-exons” pertaining to KRT18 (exon 1), CNN2 (exon 7), and MUC16 (exons 23 and 56) was observed. The implicated genes were found to interact with multiple pathways involved in cell cycle regulation, apoptosis, immune signaling, and developmental processes. Conclusions: This study significantly expands WT’s genetic landscape by identifying 71 variants across 16 genes, including several genes with established roles in other cancers ( MUC16, KRT18, FCGBP ) that have not been previously implicated in WT, as well as genes with limited prior cancer associations. The identification of mutation hotspots and WT-specific gene associations provides new insights into WT development and potential therapeutic targets. These findings warrant further functional studies to validate their role in WT pathogenesis and potential as diagnostic or therapeutic targets.