<i>DICER1</i>
            Mutations in Familial Pleuropulmonary Blastoma

Hill, D. Ashley; Ivanovich, Jennifer; Priest, John R.; Gurnett, Christina A.; Dehner, Louis P.; Desruisseau, David M.; Jarzembowski, Jason A.; Wikenheiser-Brokamp, Kathryn A.; Suarez, Brian K.; Whelan, Alison; Williams, Gretchen M.; Bracamontes, Dawn; Messinger, Yoav; Goodfellow, Paul J.

doi:10.1126/science.1174334

Cited by 621 publications

(504 citation statements)

References 6 publications

(6 reference statements)

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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: 85%

“…DICER1 germline mutations are known to predispose carriers to cancer [5], such as familial pleuropulmonary blastoma (PPB) [6]. Furthermore, heterozygous germline DICER1 mutations have been identified in PPB-related familial tumour-dysplasia syndrome (PPB-FTDS), multinodular goitre (MNG), Sertoli-Leydig cell tumour (SLCT), cystic nephroma (CN), Wilms' tumour, cervical embryonal rhabdomyosarcoma (cERM) and pineoblastoma [7][8][9][10].…”

Section: J Chen Et Almentioning

confidence: 99%

“…The mutational analyses of DICER1 have previously focused on rare paediatric cancers [6][7][8][9][10][11][13][14][15][16]. In this study, we investigated the prevalence of DICER1 mutations in a spectrum of more common malignancies.…”

Section: J Chen Et Almentioning

confidence: 99%

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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: 85%

Section: J Chen Et Almentioning

confidence: 99%

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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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“…There is increasing evidence, in fact, that specific miRNAs may be responsible at large for disease heterogeneity, functioning as regulators of tumorigenicity, invasion and metastasis (Tavazoie et al, 2008). Moreover, genetic defects in key components of the miRNA biosynthetic pathway have been described in tumors (Hill et al, 2009;Melo et al, 2009Melo et al, , 2010, and several genes involved in BC progression have been identified as targets of miRNAs that, in turn, are found deregulated in BC cells (Garzon et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer

et al. 2012

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Estrogen effects on mammary epithelial and breast cancer (BC) cells are mediated by the nuclear receptors ERa and ERb, transcription factors that display functional antagonism with each other, with ERb acting as oncosuppressor and interfering with the effects of ERa on cell proliferation, tumor promotion and progression. Indeed, hormone-responsive, ERa þ BC cells often lack ERb, which when present associates with a less aggressive clinical phenotype of the disease. Recent evidences point to a significant role of microRNAs (miRNAs) in BC, where specific miRNA expression profiles associate with distinct clinical and biological phenotypes of the lesion. Considering the possibility that ERb might influence BC cell behavior via miRNAs, we compared miRNome expression in ERb þ vs ERbÀ hormone-responsive BC cells and found a widespread effect of this ER subtype on the expression pattern of these non-coding RNAs. More importantly, the expression pattern of 67 miRNAs, including 10 regulated by ERb in BC cells, clearly distinguishes ERb þ , node-negative, from ERbÀ, metastatic, mammary tumors. Molecular dissection of miRNA biogenesis revealed multiple mechanisms for direct regulation of this process by ERb þ in BC cell nuclei. In particular, ERb downregulates miR-30a by binding to two specific sites proximal to the gene and thereby inhibiting pri-miR synthesis. On the other hand, the receptor promotes miR-23b, -27b and 24-1 accumulation in the cell by binding in close proximity of the corresponding gene cluster and preventing in situ the inhibitory effects of ERa on pri-miR maturation by the p68/DDX5-Drosha microprocessor complex. These results indicate that cell autonomous regulation of miRNA expression is part of the mechanism of action of ERb in BC cells and could contribute to establishment or maintenance of a less aggressive tumor phenotype mediated by this nuclear receptor.

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“…Initial wurde es aufgrund seiner Beschreibung im Kontext pleuropulmonaler Blastome und assoziierter Tumoren/Dysplasien [61] auch "pleuropulmonales Blastom, familiäres Tumor-und Dysplasie-Syndrom" genannt.…”

Section: Dicer1-syndromunclassified

Seltene Tumordispositionssyndrome mit Manifestation im Kindesalter

Ripperger

Wimmer

Kratz

2017

Medizinische Genetik

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Zusammenfassung Bei etwa 7–10 % der pädiatrischen Krebspatienten werden zugrunde liegende Tumordispositionssyndrome (TDS) vermutet. Das Erkennen von TDS hat klinische Implikationen für die Krebsprävention und -früherkennung, die Krebstherapie und -nachsorge, die psychosoziale Unterstützung sowie die Beratung von Angehörigen und Identifizierung weiterer Anlageträger in den betroffenen Familien. Hinweise auf das Vorliegen eines TDS anhand von Eigen- und Familienanamnese, Untersuchungsbefund sowie gegebenenfalls Tumorhistologie und -genetik müssen daher möglichst früh erkannt werden, um bei Verdacht auf Vorliegen eines TDS eine humangenetische Beratung und gegebenenfalls genetische Diagnostik zu veranlassen. Wissenschaftliche Untersuchungen zu TDS liefern Einblicke in die Biologie der Gewebe- und Tumorentwicklung und weisen auf mögliche Ansatzpunkte zielgerichteter Therapien hin. Die vorliegende Arbeit gibt eine Übersicht über TDS mit erhöhtem Risiko für Wilms-Tumoren (Nephroblastome), Neuroblastome oder Medulloblastome. Zusätzlich werden zwei vergleichsweise neu beschriebene Syndrome mit breitem Neoplasiespektrum erläutert: die konstitutionelle Mismatch-Reparatur-Defizienz (CMMRD) und das DICER1-Syndrom. Neben der Erläuterung der klinischen Charakteristika und der genetischen Grundlagen werden für die tägliche Praxis Hinweise zur Indikation von genetischen Untersuchungen und Früherkennung bei TDS aufgeführt. Die Betreuung der Betroffenen und ihrer Angehörigen sollte möglichst interdisziplinär erfolgen. Forschung zu TDS, zum Beispiel im Rahmen von Registern für TDS, ist essenziell, um langfristig die medizinische Versorgung von Menschen zu verbessern, die bedingt durch konstitutionelle genetische Veränderungen ein erhöhtes Krebsrisiko haben.

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DICER1 Mutations in Familial Pleuropulmonary Blastoma

Abstract: A rare form of lung cancer in children is associated with mutational disruption of an enzyme that generates small noncoding RNAs.

Cited by 621 publications

References 6 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

Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer

Seltene Tumordispositionssyndrome mit Manifestation im Kindesalter

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