Mesenchymal Hamartoma of the Liver and DICER1 Syndrome

Apellaniz-Ruiz, María; Segni, Maria; Kettwig, Matthias; Glüer, S.; Pelletier, Dylan; Nguyễn, Văn Hùng; Wagener, Rabea; López, Cristina; Muchantef, Karl; Soglio, Dorothée Bouron‐Dal; Sabbaghian, Nelly; Wu, Mona; Zannella, Stefano; Fabian, Marc R.; Siebert, Reiner; Menke, Jan; Priest, John R.; Foulkes, William D.

doi:10.1056/nejmoa1812169

Cited by 42 publications

(32 citation statements)

References 21 publications

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“…Together with earlier findings that ETMRs could present with a pineoblastoma-like histology this opens the possibility that the type of aberration affecting DICER1 could influence what type of tumor develops. Mesenchymal hamartomas of the liver also show DICER1 mutations affecting the RNase IIIb domain, which are, interestingly, again mutually exclusive with C19MC aberrations [ 4 ], in line to what is observed in ETMRs [ 80 ]. ETMRs were found to be molecularly similar regardless of C19MC amplification, suggesting that DICER1 mutations affecting the RNase III domains and C19MC may have common downstream mechanisms.…”

Section: Genetic Aberrations In Etmrmentioning

confidence: 99%

ETMR: a tumor entity in its infancy

et al. 2020

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Embryonal tumor with Multilayered Rosettes (ETMR) is a relatively rare but typically deadly type of brain tumor that occurs mostly in infants. Since the discovery of the characteristic chromosome 19 miRNA cluster (C19MC) amplification a decade ago, the methods for diagnosing this entity have improved and many new insights in the molecular landscape of ETMRs have been acquired. All ETMRs, despite their highly heterogeneous histology, are characterized by specific high expression of the RNA-binding protein LIN28A, which is, therefore, often used as a diagnostic marker for these tumors. ETMRs have few recurrent genetic aberrations, mainly affecting the miRNA pathway and including amplification of C19MC (embryonal tumor with multilayered rosettes, C19MC-altered) and mutually exclusive biallelic DICER1 mutations of which the first hit is typically inherited through the germline (embryonal tumor with multilayered rosettes, DICER1-altered). Identification of downstream pathways affected by the deregulated miRNA machinery has led to several proposed potential therapeutical vulnerabilities including targeting the WNT, SHH, or mTOR pathways, MYCN or chromosomal instability. However, despite those findings, treatment outcomes have only marginally improved, since the initial description of this tumor entity. Many patients do not survive longer than a year after diagnosis and the 5-year overall survival rate is still lower than 30%. Thus, there is an urgent need to translate the new insights in ETMR biology into more effective treatments. Here, we present an overview of clinical and molecular characteristics of ETMRs and the current progress on potential targeted therapies.

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Section: Genetic Aberrations In Etmrmentioning

confidence: 99%

ETMR: a tumor entity in its infancy

et al. 2020

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“…This lowers the odds of all events coinciding and could explain the low penetrance of DICER1 syndrome 34 . Exceptions to this model include pineoblastomas, where loss‐of‐heterozygosity (LOH) is frequently found in the second allele, 40,41 individuals with de novo germline DICER1 variants 42 or with large germline deletions 43‐46 and DICER1 mosaics 34,47,48 …”

Section: Dicer1 Function Dicer1 Syndrome and Molecular Geneticsmentioning

confidence: 99%

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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“…From the matched sequencing cohort, we noted several additional possibly pathogenic somatic mutations including singleton mutations in 3 different JAK-STAT pathway genes, though none other than TP53 that were recurrent at the gene level (S2 Table). Given recent reports of an association of DICER1 syndrome with mesenchymal hamartoma of the liver [40], we specifically analyzed somatic and germline sequencing data for evidence inactivating mutation in DICER1 but found none in our cohort.…”

Section: Plos Geneticsmentioning

confidence: 99%

“…These prior reports of UESL, however, did not identify that the functional consequence of these fusion events is to lead to extreme overexpression of C19MC. Additionally, while individual C19MC miRNAs have been demonstrated to be overexpressed in MHL [40,47], to our knowledge a comprehensive evaluation of C19MC miRNA expression in either MHL or UESL has not previously been performed. Furthermore, we find it striking that all UESL tumors in our study that demonstrated C19MC overexpression also had evidence of TP53 mutation or copy number loss.…”

Section: Plos Geneticsmentioning

confidence: 99%

The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with TP53 mutation or loss

et al. 2020

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Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy. Though the molecular underpinnings of this cancer have been largely unexplored, recurrent chromosomal breakpoints affecting a noncoding region on chr19q13, which includes the chromosome 19 microRNA cluster (C19MC), have been reported in several cases. We performed comprehensive molecular profiling on samples from 14 patients diagnosed with UESL. Congruent with prior reports, we identified structural variants in chr19q13 in 10 of 13 evaluable tumors. From whole transcriptome sequencing, we observed striking expressional activity of the entire C19MC region. Concordantly, in 7 of 7 samples undergoing miRNAseq, we observed hyperexpression of the miRNAs within this cluster to levels >100 fold compared to matched normal tissue or a non-C19MC amplified cancer cell line. Concurrent TP53 mutation or copy number loss was identified in all evaluable tumors with evidence of C19MC overexpression. We find that C19MC miRNAs exhibit significant negative correlation to TP53 regulatory miRNAs and K-Ras regulatory miRNAs. Using RNA-seq we identified that pathways relevant to cellular differentiation as well as mRNA translation machinery are transcriptionally enriched in UESL. In summary, utilizing a combination of next-generation sequencing and high-density arrays we identify the combination of C19MC

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Mesenchymal Hamartoma of the Liver and DICER1 Syndrome

Cited by 42 publications

References 21 publications

ETMR: a tumor entity in its infancy

ETMR: a tumor entity in its infancy

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

The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with TP53 mutation or loss

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