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Biallelic DICER1 mutations occur in Wilms tumours
Author(s) -
Wu MK,
Sabbaghian N,
Xu B,
AddidouKalucki S,
Bernard C,
Zou D,
Reeve AE,
Eccles MR,
Cole C,
Choong CS,
Charles A,
Tan TY,
Iglesias DM,
Goodyer PR,
Foulkes WD
Publication year - 2013
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4196
Subject(s) - germline , missense mutation , biology , germline mutation , somatic cell , genetics , mutation , exon , ribonuclease iii , dicer , endoribonuclease , cancer research , rnase p , microbiology and biotechnology , gene , rna , small interfering rna , rna interference
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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.