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Biallelic DICER1 mutations occur in Wilms tumours
1Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.
The Journal of Pathology
|April 27, 2013
Summary
DICER1 mutations are implicated in Wilms tumour (WT) development. This study found that a subset of WTs exhibits two DICER1 gene mutations, supporting a two-hit hypothesis in tumourigenesis.
Area of Science:
- Genetics and Molecular Biology
- Oncology
- Biochemistry
Background:
- DICER1 is a crucial endoribonuclease for microRNA (miRNA) and small interfering RNA (siRNA) biogenesis.
- Germline DICER1 mutations are linked to a rare tumour predisposition syndrome, including Wilms tumour (WT).
- The role of somatic DICER1 mutations in sporadic WT remains largely unexplored.
Purpose of the Study:
- To investigate the presence and significance of somatic DICER1 mutations in Wilms tumours.
- To determine if the two-hit hypothesis applies to DICER1 mutations in WT pathogenesis.
- To explore the functional consequences of identified DICER1 mutations.
Main Methods:
- Screening of germline and somatic DICER1 mutations in familial and sporadic Wilms tumours.
- Application of the two-hit hypothesis to analyze mutation patterns (in trans).
- In vitro studies to assess the impact of specific mutations on DICER1 transcript and protein.
Main Results:
- Deleterious somatic DICER1 mutations were identified in 2.6% of sporadic WTs.
- In familial cases, germline and somatic DICER1 mutations were found in trans, supporting the two-hit model.
- Somatic mutations led to exon 25 skipping in DICER1 transcripts, a novel finding with in vitro translation evidence.
Conclusions:
- A subset of Wilms tumours arises from a two-hit mechanism involving DICER1 mutations.
- Somatic DICER1 mutations, including those causing exon skipping, are key events in a proportion of WTs.
- These findings highlight DICER1 as a significant tumour suppressor gene in Wilms tumourigenesis.
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