Germline DICER1 mutations and familial cystic nephroma

Bahubeshi, Amin; Bal, Nebil; Frio, Thomas Rio; Hamel, Nancy; Pouchet, Carly; Yılmaz, Ahmet; Soglio, Dorothée Bouron‐Dal; Williams, Gretchen M.; Tischkowitz, Marc; Priest, John R.; Foulkes, William D.

doi:10.1136/jmg.2010.081216

Cited by 113 publications

(72 citation statements)

References 24 publications

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“…Initial clinical studies found that PPB and PPB-FTDS patients carry heterozygous DICER1 germline mutations and no homozygous loss of DICER1 was observed [6,33], which supported the DICER1 haplo-insufficiency hypothesis. However, this model was contradicted by recent studies showing that Dicer1-null cells (Kras G12D Trp53 −/ − Dicer1 −/ − ) from a mouse sarcoma cell line are competent for tumour formation, and that Pten/Dicer1 double-knockout mice develop primary fallopian tube tumours [17,34].…”

Section: Discussionmentioning

confidence: 84%

Recurrent DICER1 hotspot mutations in endometrial tumours and their impact on microRNA biogenesis

Chen

Wang

McMonechy

et al. 2015

The Journal of Pathology

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DICER1 plays a critical role in microRNA (miRNA) biogenesis. Recurrent somatic 'hotspot' mutations at the four metal-binding sites within the RNase IIIb domain of DICER1 were identified in ovarian sex cord-stromal tumours and have since been described in other paediatric tumours. In this study, we screened the RNase IIIb domain of DICER1 in 290 endometrial tumours and identified six cases with hotspot mutations, including two cases affected by an atypical G1809R mutation directly adjacent to a metal-binding site. Using Illumina and Sanger targeted resequencing, we observed and validated biallelic DICER1 mutations in several cases with hotspot mutations. Through in vitro DICER1 cleavage assays, small RNA deep sequencing and real-time PCR, we demonstrated that mutations adding a positively charged side chain to residue 1809 have similar detrimental effects on 5p miRNA production to mutations at the metal-binding sites. As expected, 5p miRNAs were globally reduced in tumours and cell lines with hotspot mutations. Pathway analysis of gene expression profiles indicated that genes de-repressed due to loss of 5p miRNAs are strongly associated with pathways regulating the cell cycle. Using a Dicer1-null mouse cell line model, we found that expression of DICER1 hotspot mutants promoted cell proliferation, whereas wild-type (WT) DICER1 inhibited cell proliferation. Furthermore, targets of let-7 family miRNAs are enriched among the up-regulated genes, suggesting that loss of let-7 may be impacting downstream pathways. Our results reveal that DICER1 hotspot mutations are implicated in common malignancies and may constitute a unique oncogenic pathway.

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Section: Discussionmentioning

confidence: 84%

Recurrent DICER1 hotspot mutations in endometrial tumours and their impact on microRNA biogenesis

Chen

Wang

McMonechy

et al. 2015

The Journal of Pathology

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“…Germline DICER1 mutations were first found in patients with renal tumors in 2010, but DICER1 mutations were not identified in the germline of any of 50 patients with sporadic Wilms' tumors (Bahubeshi et al 2010). This shows that although DICER1 mutations were later associated with Wilms' (Foulkes et al 2011;Slade et al 2011), they are not fully penetrant.…”

Section: The Mirna Pathway In Wilms' Tumorigenesismentioning

confidence: 99%

The yin and yang of kidney development and Wilms’ tumors

2015

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Wilms’ tumor, or nephroblastoma, is the most common pediatric renal cancer. The tumors morphologically resemble embryonic kidneys with a disrupted architecture and are associated with undifferentiated metanephric precursors. Here, we discuss genetic and epigenetic findings in Wilms’ tumor in the context of renal development. Many of the genes implicated in Wilms’ tumorigenesis are involved in the control of nephron progenitors or the microRNA (miRNA) processing pathway. Whereas the first group of genes has been extensively studied in normal development, the second finding suggests important roles for miRNAs in general—and specific miRNAs in particular—in normal kidney development that still await further analysis. The recent identification of Wilms’ tumor cancer stem cells could provide a framework to integrate these pathways and translate them into new or improved therapeutic interventions.

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“…The central importance of DICER1 in animal biology is emphasized by studies of Dicer1 knockout mice and of morpholino knockdown Dicer1 zebrafish, which demonstrated that null-Dicer1 embryos are incompatible with life [Bernstein et al, 2003;Wienholds et al, 2003]. Moreover, human heterozygous germline DICER1 mutations have been clearly associated with several rare childhood tumors such as pleuropulmonary blastoma (PPB) (MIM# 601200) Slade et al, 2011], cystic nephroma (CN) [Bahubeshi et al, 2010;Hill et al, 2009;Slade et al, 2011], ovarian sex-cord-stromal tumors, especially Sertoli-Leydig cell tumor (SLCT) [Rio Frio et al, 2011;Schultz et al, 2011;Slade et al, 2011], and multinodular goiter (MNG) [Rio Frio et al, 2011] (MIM# 138800). Deleterious germline DICER1 mutations have also been reported in single individuals with ciliary body medulloepithelioma, medulloblastoma, and Wilms tumor (WT) [Slade et al, 2011].…”

Section: Introductionmentioning

confidence: 98%

“…Most associated conditions occur in children under age 10 years, although ovarian tumors and MNG are described in children and in adults up to approximately 30 years of age. Because these diagnoses, especially when occurring in familial aggregations or with PPB, suggest the presence of a DICER1 mutation, we investigated several suspicious kindred using previously described molecular diagnostic methods [Bahubeshi et al, 2010;Rio Frio et al, 2011]. We report here DICER1 mutations in seven families, establishing an association between DICER1 mutations and uterine cervix embryonal rhabdomyosarcoma (cERMS), cervical primitive neuroectodermal tumor (cPNET), and juvenile intestinal polyps, providing further evidence linking DICER1 mutations to WT, and suggesting that congenital malformations such as pulmonary sequestration (PS) and perhaps transposition of the great arteries (TGA) may be rare phenotypic expressions.…”

Section: Introductionmentioning

confidence: 99%

Extending the phenotypes associated withDICER1mutations

Foulkes¹,

Bahubeshi²,

Hamel³

et al. 2011

Hum. Mutat.

181

127

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DICER1 is crucial for embryogenesis and early development. Forty different heterozygous germline DICER1 mutations have been reported worldwide in 42 probands that developed as children or young adults, pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian sex cord-stromal tumors (especially Sertoli-Leydig cell tumor [SLCT]), and/or multinodular goiter (MNG). We report DICER1 mutations in seven additional families that manifested uterine cervix embryonal rhabdomyosarcoma (cERMS, four cases) and primitive neuroectodermal tumor (cPNET, one case), Wilms tumor (WT, three cases), pulmonary sequestration (PS, one case), and juvenile intestinal polyp (one case). One carrier developed (age 25 years) a pleomorphic sarcoma of the thigh; another carrier had transposition of great arteries (TGA). These observations show that cERMS, cPNET, WT, PS, and juvenile polyps fall within the spectrum of DICER1-related diseases. DICER1 appears to be the first gene implicated in the etiology of cERMS, cPNET, and PS. Young adulthood sarcomas and perhaps congenital malformations such as TGA may also be associated.

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Germline DICER1 mutations and familial cystic nephroma

Cited by 113 publications

References 24 publications

Recurrent DICER1 hotspot mutations in endometrial tumours and their impact on microRNA biogenesis

Recurrent DICER1 hotspot mutations in endometrial tumours and their impact on microRNA biogenesis

The yin and yang of kidney development and Wilms’ tumors

Extending the phenotypes associated withDICER1mutations

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