Recurrent somatic mutation in DROSHA is a frequent event in Wilms tumor and induces microRNA profile changes. WilmsMutationInDROSHA

Wilms tumor (WT) is an embryonal kidney neoplasia for which very few driver genes and molecular pathways have been identified. Using whole-exome sequencing and target sequencing of ten core miRNA processing genes, we identified DROSHA mutations in 12% of WT samples (26/222); in 80% of the DROSHA-mutated tumors, a recurrent mutation (E1147K) affecting a conserved metal-binding residue of the RNase IIIb domain was detected. In addition, we identified non-recurrent truncating and missense mutations in other genes of this pathway (DGCR8, DICER, XPO5 and TARBP2). By assessing the miRNA expression pattern of the recurrent DROSHA-E1147K mutated tumors and cell lines expressing this mutated protein, we determined that the E1147K mutation leads to a predominant down-regulation of a subset of mature miRNAs. We confirmed that the down-regulation occurred exclusively in mature miRNAs and not primary miRNA transcripts, suggesting that the DROSHA E1147K mutation affects correct processing of primary miRNAs. Our data underscore the pivotal role of the miRNA biogenesis pathway in WT tumorigenesis, particularly the major miRNA processing gene DROSHA.