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J Med Genet 48:273-278 doi:10.1136/jmg.2010.083790
  • Original article

DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome

Editor's Choice
  1. Nazneen Rahman1
  1. 1Section of Cancer Genetics, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, UK
  2. 2The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
  3. 3Pediatric Oncology, Addenbrooke's Hospital, Cambridge, UK
  4. 4Department of Pediatric Oncology, Great Ormond Street Hospital, London, UK
  5. 5Pediatric Oncology, Nottingham University Hospital, Nottingham, UK
  6. 6Pediatric Oncology, Birmingham Children's Hospital, Birmingham, UK
  7. 7Department of Haematology and Oncology, Royal Aberdeen Children's Hospital, Aberdeen, Scotland, UK
  8. 8Department of Pediatric Oncology, Alder Hey Children's Hospital, Liverpool, UK
  9. 9Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK
  10. 10Department of Clinical Genetics, St George's Hospital, London, UK
  11. 11Department of Clinical Genetics, Great Ormond Street Hospital, London, UK
  12. 12Pediatric Oncology, Children's Hospital for Wales, Cardiff, UK
  13. 13Section of Pediatrics, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, UK
  14. 14Department of Pediatrics, Derriford Hospital, Plymouth, UK
  15. 15Department of Histopathology, School of Medicine, Cardiff University, Cardiff, UK
  16. 16Department of Histopathology, Royal Brompton Hospital, UK
  17. 17The National Heart and Lung Institute, Imperial College, London, UK
  18. 18Department of Histopathology and Pediatric Laboratory Medicine, Great Ormond Street Hospital, London, UK
  19. 19International PPB Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, USA
  20. 20Molecular Haematology and Cancer Biology, Institute of Child Health, London, UK
  21. 21Childhood Cancer Research Group, Department of Pediatrics, University of Oxford, Oxford, UK
  1. Correspondence to Professor Nazneen Rahman, Professor of Human Genetics, Section of Cancer Genetics, The Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK; nazneen.rahman{at}icr.ac.uk
  • Received 4 August 2010
  • Revised 26 October 2010
  • Accepted 24 November 2010
  • Published Online First 25 January 2011

Abstract

Background Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB).

Aim To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer.

Methods and results The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional DICER1 mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli–Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli–Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. DICER1 mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli–Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from DICER1 mutation-positive patients showed universal retention of the wild-type allele. DICER1 truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations.

Conclusion Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli–Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which DICER1 mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition ‘DICER1 syndrome’.

Accession numbers The cDNA Genbank accession number for the DICER1 sequence reported in this paper is NM_030621.2.

Footnotes

  • Funding The Childhood Cancer Research Group receives funding from the Department of Health and the Scottish Ministers. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health and the Scottish Ministers. IS is supported by the Michael and Betty Kadoorie Cancer Genetics Research Programme. We acknowledge NHS funding to the NIHR Biomedical Research Centre. This work was supported by Cancer Research UK (grants C8620_A9024 and C8620_A8857) and the Institute of Cancer Research (UK).

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the NHS National Research Ethics Service.

  • Provenance and peer review Not commissioned; externally peer reviewed.