Wilms tumour (WT) is an embryonal kidney neoplasia for which very few driver genes have
been identified. Here we identify DROSHA mutations in 12% of WT samples (26/222) using whole-exome
sequencing and targeted sequencing of 10 microRNA (miRNA)-processing genes. A recurrent
mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain is detected in
81% of the DROSHA-mutated tumours.
In addition, we identify non-recurrent mutations in other genes of this pathway
(DGCR8, DICER1, XPO5 and TARBP2). By assessing the miRNA expression pattern of the
DROSHA-E1147K-mutated tumours
and cell lines expressing this mutation, we determine that this variant leads to a
predominant downregulation of a subset of miRNAs. We confirm that the downregulation occurs
exclusively in mature miRNAs and not in primary miRNA transcripts, suggesting that the
DROSHA E1147K mutation affects
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.