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.
- cancer syndrome
- tumour predisposition
- clinical genetics
- paediatric oncology
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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.