Biallelic DICER1 mutations occur in Wilms tumours. (13th May 2013)

• Record Type: Journal Article
• Authors: Wu, MK; Sabbaghian, N; Xu, B; Addidou‐Kalucki, S; Bernard, C; Zou, D; Reeve, AE; Eccles, MR; Cole, C; Choong, CS; Charles, A; Tan, TY; Iglesias, DM; Goodyer, PR; Foulkes, WD
• Is Part Of: Journal of pathology. Volume 230:Number 2(2013)
• Page Start: 154
• Page End: 164
• Publication Date: 2013-05-13
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4196
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p> <bold>DICER1 is an endoribonuclease central to the generation of microRNAs (miRNAs) and short interfering RNAs (siRNAs). Germline mutations in <italic>DICER1</italic> 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 <italic>DICER1</italic> mutation, were screened for somatic <italic>DICER1</italic> mutations and were found to bear specific mutations in either the RNase IIIa (<italic>n =</italic> 1) or the RNase IIIb domain (<italic>n =</italic> 2). In the two latter cases, we demonstrate that the germline and somatic <italic>DICER1</italic> mutations were <italic>in trans</italic>, 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 <italic>DICER1</italic> mutations (2.6%) in four individual WTs; one tumour had two very likely deleterious somatic mutations <italic>in trans</italic> in the RNase IIIb domain (c.5438A>G and c.5452G>A). <italic>In vitro</italic> 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 <italic>DICER1</italic>. Further we show that <italic>DICER1</italic> transcripts lacking exon 25 can be translated <italic>in vitro</italic>. This study has demonstrated that a subset of WTs exhibits two 'hits' in <italic>DICER1</italic>, 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.</bold> </p> </abstract>