Biallelic DICER1 mutations occur in Wilms tumours

DICER1 is an endoribonuclease central to the generation of microRNAs ( miRNAs ) and short interfering RNAs ( siRNAs ). Germline mutations in DICER1 have been associated with a pleiotropic tumour predisposition syndrome and Wilms tumour ( WT ) is a rare manifestation of this syndrome. Three WTs , each in a child with a deleterious germline DICER1 mutation, were screened for somatic DICER1 mutations and were found to bear specific mutations in either the RNase IIIa ( n = 1) or the RNase IIIb domain ( n = 2). In the two latter cases, we demonstrate that the germline and somatic DICER1 mutations were in trans , suggesting that the two‐hit hypothesis of tumour formation applies for these examples of WT . Among 191 apparently sporadic WTs , we identified five different missense or deletion somatic DICER1 mutations (2.6%) in four individual WTs ; one tumour had two very likely deleterious somatic mutations in trans in the RNase IIIb domain (c. 5438A >G and c. 5452G >A). In vitro studies of two somatic single‐base substitutions (c. 5429A >G and c. 5438A >G) demonstrated exon 25 skipping from the transcript, a phenomenon not previously reported in DICER1 . Further we show that DICER1 transcripts lacking exon 25 can be translated in vitro . This study has demonstrated that a subset of WTs exhibits two ‘hits’ in DICER1 , suggesting that these mutations could be key events in the pathogenesis of these tumours. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.