Wilms tumor exhibits relatively few mutations, and currently no targeted therapies are available to treat the pediatric kidney cancer. To characterize Wilms tumor mutational landscapes and elucidate potentially targetable downstream molecular effects, Tiburcio and colleagues performed integrated genomic and transcriptomic sequencing using Wilms tumor samples. Genomic sequencing revealed four Wilms tumor mutational subclasses involving miRNA processing, MYCN/MAX, chromatin remodeling, and kidney development. The miRNA processing mutational subclass featured mutations in DROSHA, a gene encoding a miRNA processing enzyme. Transcriptomic sequencing using mutant DROSHA samples identified miRNA depletion and subsequent de-repression of miRNA target transcripts. Gene set enrichment analysis showed that miRNA processing ablation resulted in enhanced expression of proliferation and mesenchymal genes. Furthermore, CRISPR interference-mediated DROSHA abrogation increased expression of acyl-CoA synthetase long-chain family member 4, which can facilitate ferroptosis. Accordingly, modeling DROSHA mutations via DROSHA depletion sensitized Wilms tumor cells to glutathione peroxidase 4 inhibitor-mediated ferroptosis. Taken together,...

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