title: Biallelic DICER1 mutations occur in Wilms tumours.
abstract: 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.
authors.affiliation: Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: M K
authors.initials: MK
authors.lastname: Wu
authors.forename: N
authors.initials: N
authors.lastname: Sabbaghian
authors.forename: B
authors.initials: B
authors.lastname: Xu
authors.forename: S
authors.initials: S
authors.lastname: Addidou-Kalucki
authors.forename: C
authors.initials: C
authors.lastname: Bernard
authors.forename: D
authors.initials: D
authors.lastname: Zou
authors.forename: A E
authors.initials: AE
authors.lastname: Reeve
authors.forename: M R
authors.initials: MR
authors.lastname: Eccles
authors.forename: C
authors.initials: C
authors.lastname: Cole
authors.forename: C S
authors.initials: CS
authors.lastname: Choong
authors.forename: A
authors.initials: A
authors.lastname: Charles
authors.forename: T Y
authors.initials: TY
authors.lastname: Tan
authors.forename: D M
authors.initials: DM
authors.lastname: Iglesias
authors.forename: P R
authors.initials: PR
authors.lastname: Goodyer
authors.forename: W D
authors.initials: WD
authors.lastname: Foulkes
mesh_terms: D000818:Animals; D019556:COS Cells; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005091:Exons; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D043244:Ribonuclease III / Q000235:genetics*; D009396:Wilms Tumor / Q000175:diagnosis / Q000235:genetics*
chemical_list: C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases