No conflicts of interest were declared.
Biallelic DICER1 mutations occur in Wilms tumours
Article first published online: 13 MAY 2013
Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 230, Issue 2, pages 154–164, June 2013
How to Cite
Wu, M., Sabbaghian, N., Xu, B., Addidou-Kalucki, S., Bernard, C., Zou, D., Reeve, A., Eccles, M., Cole, C., Choong, C., Charles, A., Tan, T., Iglesias, D., Goodyer, P. and Foulkes, W. (2013), Biallelic DICER1 mutations occur in Wilms tumours. J. Pathol., 230: 154–164. doi: 10.1002/path.4196
- Issue published online: 13 MAY 2013
- Article first published online: 13 MAY 2013
- Accepted manuscript online: 5 APR 2013 01:46PM EST
- Manuscript Accepted: 29 MAR 2013
- Manuscript Revised: 20 MAR 2013
- Manuscript Received: 15 FEB 2013
- paediatric tumours;
- exon splicing silencer
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.