Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

Kock, Leanne de; Rivera, Bárbara; Revil, Timothée; Thorner, Paul; Goudie, Catherine; Soglio, Dorothée Bouron‐Dal; Choong, Catherine S.; Priest, John R.; Diest, Paul J. van; Tanboon, Jantima; Wagner, Anja; Ragoussis, Jiannis; Choong, Peter; Foulkes, William D.

doi:10.1038/bjc.2017.147

Cited by 31 publications

(21 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During the validation phase, 24 CPTs (8 CPPs, 8 aCPPs, and 8 CPCs) were also studied by WES (following the protocol described above). Tumor DNA from 50 sporadic CPTs, 67 schwannomas (66 primary tumors and 1 recurrence), and germline DNA from 18 MNGs of suspected hereditary origin was sequenced using a custom Fluidigm Access Array (Fluidigm), which targets all exons and exon-intron boundaries of DGCR8 following the same methodology as for the DICER1 Fluidigm Access Array previously published (42).…”

Section: Dgcr8 Screening Methods In Schwannomas Cpts Mngs and Thyrmentioning

confidence: 99%

DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis

Rivera¹,

Nadaf²,

Fahiminiya³

et al. 2020

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

BACKGROUND. DICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist. METHODS. Whole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K. RESULTS. We identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p. E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons. CONCLUSION. We identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.

show abstract

Section: Dgcr8 Screening Methods In Schwannomas Cpts Mngs and Thyrmentioning

confidence: 99%

DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis

Rivera¹,

Nadaf²,

Fahiminiya³

et al. 2020

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…The presence of a DICER1 VUS in trans with an RNase IIIb hotspot mutation is supportive of the VUS being pathogenic, although not conclusive. Careful sequencing of the full DICER1 coding sequence in tumor‐derived DNA should be performed in such cases to screen for a potential somatically acquired loss‐of‐function alteration occurring in trans with the RNase IIIb hotspot mutation, which together, would outweigh the VUS (de Kock, Rivera, et al, ). The recurrent observation of a variant in population databases [either in individuals who have (e.g., TCGA) or have not developed tumors (e.g., ExAC and gnomAD)], may assist with its interpretation.…”

Section: Variant Impact and Clinical Relevancementioning

confidence: 99%

“…Although we do not think these features constitute a distinct syndrome, such pleiotropic presentations of RNase IIIb mosaic mutations have been considered to represent “GLOW (global delay, lung cysts, overgrowth and Wilms) syndrome” (Klein et al, ). A small subset of patients have a single tumor harboring tumor‐specific biallelic DICER1 pathogenic variants (typically one loss‐of‐function and one involving an RNase IIIb hotpot; Brenneman et al, ; de Kock, Rivera, et al, ). These patients represent sporadic instances of DICER1 ‐related disease and are not at risk of future DICER1 ‐related tumors, although mosaicism for the loss‐of‐function mutation could remain a possibility (Brenneman et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Time is represented on the x-axis and the typical ages of diagnosis are provided in brackets below each lesion (although risk may extend beyond the stipulated ages; see Figure 2; Foulkes et al, 2014). CNS, central nervous system; pathogenic variants (typically one loss-of-function and one involving an RNase IIIb hotpot; Brenneman et al, 2015;de Kock, Rivera, et al, 2017).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

2019

View full text Add to dashboard Cite

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.

show abstract

“…allele is inactivated by a germline mutation in DICER1 and the other allele has a somatic missense mutation that affects one of the RNase IIIb metal ion-binding sites (Doros et al 2014). Several publications in the literature report sarcomas arising from germline and somatic mutations in DICER1, including urogenital ERMS cases (Doros et al 2012;de Kock et al 2017). In this case, however, no germline mutations were found in DICER1, and the expression of DICER1 (198.53 TPM) was not decreased compared to the normal cohort of skeletal muscles from the GTEx project (median TPM, 14.03).…”

Section: Molecular Case Studiesmentioning

confidence: 99%

Defining an embryonal rhabdomyosarcoma endotype

Ricker

Crawford

Matlock

et al. 2020

Cold Spring Harb Mol Case Stud

View full text Add to dashboard Cite

Rhabdomyosarcoma (RMS) is the most common childhood soft-tissue sarcoma. The largest subtype of RMS is embryonal rhabdomyosarcoma (ERMS) and accounts for 53% of all RMS. ERMS typically occurs in the head and neck region, bladder, or reproductive organs and portends a promising prognosis when localized; however, when metastatic the 5-yr overall survival rate is ∼43%. The genomic landscape of ERMS demonstrates a range of putative driver mutations, and thus the recognition of the pathological mechanisms driving tumor maintenance should be critical for identifying effective targeted treatments at the level of the individual patients. Here, we report genomic, phenotypic, and bioinformatic analyses for a case of a 3-yr-old male who presented with bladder ERMS. Additionally, we use an unsupervised agglomerative clustering analysis of RNA and whole-exome sequencing data across ERMS and undifferentiated pleomorphic sarcoma (UPS) tumor samples to determine several major endotypes inferring potential targeted treatments for a spectrum of pediatric ERMS patient cases.

show abstract

Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

Cited by 31 publications

References 27 publications

DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis

DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis

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

Defining an embryonal rhabdomyosarcoma endotype

Contact Info

Product

Resources

About