Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis

Vedanayagam, Jeffrey; Chatila, Walid K.; Aksoy, Bülent Arman; Majumdar, Sonali; Skanderup, Anders Jacobsen; Demir, Emek; Schultz, Nikolaus; Sander, Chris; Lai, Eric C.

doi:10.1038/s41467-019-11610-1

Cited by 59 publications

(90 citation statements)

References 73 publications

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“…Interestingly, one of the latter cutaneous melanomas from the MSK‐IMPACT study harbored an additional loss‐of‐function DICER1 alteration, but it is not known whether the two alterations existed in trans . These data are supported and extended by a recent publication from Dr Eric Lai's laboratory (Vedanayagam et al, ).…”

Section: Variant Impact and Clinical Relevancesupporting

confidence: 81%

Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes

2019

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DICER1 syndrome is a pleiotropic tumor predisposition syndrome characterized by a distinctive constellation of neoplastic and dysplastic lesions, which are generally rare and affect children and young adults. Germline pathogenic variants in the DICER1 gene are the underlying cause of the syndrome; variants are typically inherited in an autosomal dominant pattern but may arise de novo in the germline or in a somatic mosaic distribution. The encoded DICER1 protein is a key component of the microRNA processing pathway. In this Mutation Update, we present a comprehensive review of all DICER1 genetic alterations reported in articles published before January 31st, 2019. A total of 1,136 DICER1 alterations were catalogued from 808 individuals and the tumors that occurred in these persons. We provide an inventory of these DICER1 alterations and discuss them with respect to their provenance, distribution across the gene, associated phenotypes and ages of onset, and penetrance. We also address approaches to classification of DICER1 variants of uncertain significance and discuss the clinical significance of DICER1 variant identification.

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Section: Variant Impact and Clinical Relevancesupporting

confidence: 81%

Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes

2019

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“…Because DICER1 mutations are frequently found in ultramutant tumors, DICER1 mutations in endometrial adenocarcinoma were thought to be passenger mutations. However, recent genomic profiling of tumors through TCGA PanCancer and MSK-IMPACT showed enrichment of biallelic DICER1 hotspot mutations in endometrial but not other cancers (8). Importantly, this analysis removed hypermutated tumors and the POLE subclass of endometrial cancers (8).…”

Section: Discussionmentioning

confidence: 85%

“…In vitro studies showed that hotspot mutations in the RNase IIIb domain resulted in altered miRNA processing (11)(12)(13)(14)(15). Independent studies not only validated the effects of hotspot biallelic mutations in the RNase IIIb domain resulting in miRNA biogenesis defects in human endometrial cancers but also showed that hotspot mutations in the RNase IIIa domain had similar functional effects in human endometrial cancers (8). Further, downregulation of DICER1 expression was associated with features of more aggressive endometrial adenocarcinoma, including myometrial invasion, high FIGO grade tumors, and disease recurrence (16)(17)(18).…”

Section: Introductionmentioning

confidence: 93%

“…Human DICER1-mutant TCGA endometrial cancers were enriched in miRNAtarget genes from five miRNA families: let-7-5p, miR-17-5p, miR-16-5p, miR-29-3p, and miR-101-3p (8). Mature miRNAs from each of these five miRNA families were significantly downregulated in the small RNA sequencing datasets from human Ishikawa Table S5).…”

Section: Unique Transcriptomic Profile With Loss Of Two Alleles Of DImentioning

confidence: 99%

“…In endometrial cancer, DICER1 is a prominent cancer-driver gene (7). Hotspot biallelic mutations in DICER1, the endoribonuclease responsible for miRNA genesis, are enriched in endometrial adenocarcinomas over other cancers profiled in both TCGA (The Cancer Genome Atlas) PanCancer and MSK-IMPACT (Memorial Sloan-Kettering Integrated Mutation Profiling and Actionable Cancer Targets) studies (8). DICER1 contains two RNase III domains -RNase IIIa and RNase IIIb.…”

Section: Introductionmentioning

confidence: 99%

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PtenandDicer1loss causes poorly-differentiated endometrial adenocarcinoma in mice

Wang

Wendel

Emerson

et al. 2020

Preprint

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Endometrial cancer remains the most common gynecological malignancy in the UnitedStates. While the loss of the tumor suppressor, PTEN (phosphatase and tensin homolog), is well studied in endometrial cancer, recent studies suggest that DICER1, the endoribonuclease responsible for miRNA genesis, also plays a significant role in endometrial adenocarcinoma. In an endometrial adenocarcinoma mouse model, which has a conditional uterine deletion of Pten, Dicer1 was also conditionally deleted.Conditional uterine deletion of Dicer1 and Pten resulted in high-penetrance, poorlydifferentiated endometrial adenocarcinomas. Poorly-differentiated endometrial adenocarcinomas expressed known markers of clear-cell adenocarcinoma, including Napsin A and HNF1B (hepatocyte nuclear factor 1 homeobox B). Adenocarcinomas were hormone-independent, and treatment with long-term progesterone did not mitigate poorly-differentiated adenocarcinoma, nor did it affect adnexal metastasis.Transcriptomic analyses of uteri or Ishikawa cells with deletion of DICER1 revealed unique transcriptomic profiles and global downregulation of miRNAs. Integration of downregulated miRNAs with upregulated mRNA targets revealed deregulated let-7 and miR-16 target genes, similar to published human DICER1-mutant endometrial cancers from TCGA (The Cancer Genome Atlas). Importantly, these miRNA-target genes, involved in ephrin-receptor and transforming growth factor-beta signaling, represent potential clinical targets for rare, yet deadly, poorly-differentiated endometrial adenocarcinomas in women. This mouse model represents poorly-differentiated endometrial adenocarcinoma and will allow for the discovery of novel mechanisms of hormone-independent endometrial adenocarcinoma from atrophic endometrium. Significance StatementEndometrial cancer is one of the few cancers with an increasing death rate in the United States. The most significant risk factor associated with death is high tumor grade, which occurs most frequently in postmenopausal women, where it develops within an atrophic endometrium. Here, we present a mouse model with conditional deletion of Dicer1, a key enzyme in miRNA genesis, and Pten, a tumor suppressor, that develops poorlydifferentiated, steroid hormone-independent, endometrial adenocarcinoma with adnexal metastasis. These high-grade adenocarcinomas develop from an atrophic endometrium and share molecular features with DICER1-mutant human endometrial adenocarcinomas. We anticipate that this preclinical model represents a move toward the discovery of novel mechanisms of hormone-independent development of endometrial adenocarcinoma from atrophic endometrium.

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DICER1‐associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing

Apellaniz-Ruiz

McCluggage

Foulkes

2020

Genes Chromosomes & Cancer

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Gynecologic sarcomas are uncommon neoplasms, the majority occurring in the uterus. Due to the diverse nature of these, the description of “new” morphological types and the rarity of some of them, pathological diagnosis and treatment is often challenging. Finding genetic alterations specific to, and frequently occurring, in a certain type can aid in the diagnosis. DICER1 is a highly conserved ribonuclease crucial in the biogenesis of microRNAs and mutations in DICER1 (either somatic or germline) have been detected in a wide range of sarcomas including genitourinary embryonal rhabdomyosarcomas (ERMS) and adenosarcomas. Importantly, DICER1‐associated sarcomas share morphological features irrespective of the site of origin such that the pathologist can strongly suspect a DICER1 association. A review of the literature shows that almost all gynecologic ERMS reported (outside of the vagina) harbor DICER1 alterations, while approximately 20% of adenosarcomas also do so. These two tumor types exhibit significant morphological overlap and DICER1 tumor testing may be helpful in distinguishing between them, because a negative result makes ERMS unlikely. Given that germline pathogenic DICER1 variants are frequent in uterine (corpus and cervix) ERMS and pathogenic germline variants in this gene cause a hereditary cancer predisposition syndrome (DICER1 syndrome), patients diagnosed with these neoplasms should be referred to medical genetic services. Cooperation between pathologists and geneticists is crucial and will help in improving the diagnosis and management of these uncommon sarcomas.

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Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis

Cited by 59 publications

References 73 publications

Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes

Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes

PtenandDicer1loss causes poorly-differentiated endometrial adenocarcinoma in mice

DICER1‐associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing

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