TY - JOUR
T1 - Characterization of Alternative Splicing in High-Risk Wilms’ Tumors
AU - Trink, Yaron
AU - Urbach, Achia
AU - Dekel, Benjamin
AU - Hohenstein, Peter
AU - Goldberger, Jacob
AU - Kalisky, Tomer
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/4/20
Y1 - 2024/4/20
N2 - 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.
AB - 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.
KW - Wilms’ tumors
KW - alternative mRNA splicing
KW - cell deconvolution
KW - pareto task inference
UR - http://www.scopus.com/inward/record.url?scp=85191414300&partnerID=8YFLogxK
U2 - 10.3390/ijms25084520
DO - 10.3390/ijms25084520
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C2 - 38674106
AN - SCOPUS:85191414300
SN - 1661-6596
VL - 25
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 8
M1 - 4520
ER -