Biallelic DICER1 mutations occur in Wilms tumours

Authors

  • MK Wu,

    1. Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada
    Search for more papers by this author
  • N Sabbaghian,

    1. Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada
    Search for more papers by this author
  • B Xu,

    1. Division of Pediatric Pathology, Montreal Children's Hospital, McGill University Health Center, Montreal, Quebec, Canada
    Search for more papers by this author
  • S Addidou-Kalucki,

    1. Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada
    Search for more papers by this author
  • C Bernard,

    1. Division of Pediatric Pathology, Montreal Children's Hospital, McGill University Health Center, Montreal, Quebec, Canada
    Search for more papers by this author
  • D Zou,

    1. Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand
    Search for more papers by this author
  • AE Reeve,

    1. Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand
    Search for more papers by this author
  • MR Eccles,

    1. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
    Search for more papers by this author
  • C Cole,

    1. School of Paediatrics and Child Health (SPACH), University of Western Australia (M561) Crawley, WA, Australia
    Search for more papers by this author
  • CS Choong,

    1. School of Paediatrics and Child Health (SPACH), University of Western Australia (M561) Crawley, WA, Australia
    2. Department of Endocrinology, Princess Margaret Hospital for Children, Perth, WA, Australia
    Search for more papers by this author
  • A Charles,

    1. School of Paediatrics and Child Health (SPACH), University of Western Australia (M561) Crawley, WA, Australia
    2. Department of Paediatric Pathology, Princess Margaret Hospital for Children, Perth, WA, Australia
    Search for more papers by this author
  • TY Tan,

    1. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia
    Search for more papers by this author
  • DM Iglesias,

    1. Department of Pediatrics, Montreal Children's Hospital Research Institute, McGill University, Montréal, Québec, Canada
    Search for more papers by this author
  • PR Goodyer,

    1. Department of Pediatrics, Montreal Children's Hospital Research Institute, McGill University, Montréal, Québec, Canada
    Search for more papers by this author
  • WD Foulkes

    Corresponding author
    1. Research Institute of the McGill University Health Center, Montréal, Québec, Canada
    2. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montréal, Québec, Canada
    • Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada
    Search for more papers by this author

  • No conflicts of interest were declared.

Correspondence to: WD Foulkes, Program in Cancer Genetics, Gerald Bronfman Center for Clinical Research in Cancer, Department of Oncology, McGill University, 546 Pine Avenue West, Montreal, QC H2W 1S6, Canada. E-mail: william.foulkes@mcgill.ca

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.

Ancillary