# Characterization of Alternative Splicing in High-Risk Wilms’ Tumors

## TL;DR

This study explores how alternative splicing in high-risk Wilms’ tumors relates to fetal kidney development stages and identifies genes linked to tumor heterogeneity.

## Contribution

The study introduces a novel approach using Pareto task inference and cell deconvolution to map Wilms’ tumor heterogeneity to developmental stages.

## Key findings

- Tumors and normal kidney samples cluster in latent space according to fetal kidney developmental stages.
- Genes alternatively spliced in different tumor regions are linked to epithelial-to-mesenchymal transition and muscle development.
- Putative splicing regulators associated with kidney development were identified through motif enrichment analysis.

## Abstract

The significant heterogeneity of Wilms’ tumors between different patients is thought to arise from genetic and epigenetic distortions that occur during various stages of fetal kidney development in a way that is poorly understood. To address this, we characterized the heterogeneity of alternative mRNA splicing in Wilms’ tumors using a publicly available RNAseq dataset of high-risk Wilms’ tumors and normal kidney samples. Through Pareto task inference and cell deconvolution, we found that the tumors and normal kidney samples are organized according to progressive stages of kidney development within a triangle-shaped region in latent space, whose vertices, or “archetypes”, resemble the cap mesenchyme, the nephrogenic stroma, and epithelial tubular structures of the fetal kidney. We identified a set of genes that are alternatively spliced between tumors located in different regions of latent space and found that many of these genes are associated with the epithelial-to-mesenchymal transition (EMT) and muscle development. Using motif enrichment analysis, we identified putative splicing regulators, some of which are associated with kidney development. Our findings provide new insights into the etiology of Wilms’ tumors and suggest that specific splicing mechanisms in early stages of development may contribute to tumor development in different patients.