Genomic characterization of DICER1-associated neoplasms uncovers molecular classes

Kommoss, Felix K.F.; Chong, Anne‐Sophie; Chong, Anne‐Laure; Pfaff, Elke; Jones, David; Hiemcke-Jiwa, Laura S.; Kester, Lennart; Flucke, Uta; Gessler, Manfred; Schrimpf, Daniel; Sahm, Felix; Clarke, Blaise; Stewart, Colin J.R.; Wang, Yemin; Gilks, C Blake; Kommoss, Friedrich; Huntsman, David G.; Schüller, Ulrich; Koelsche, Christian; McCluggage, W. Glenn; Deimling, Andreas von; Foulkes, William D.

doi:10.1038/s41467-023-37092-w

Cited by 16 publications

(14 citation statements)

References 82 publications

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“…Regarding the nosology that should be used to classify our case, some authors have proposed to use a broad term of “ DICER1 ‐mutated sarcomas” 13,27 as these tumors commonly combine rhabdomyosarcomatous and spindle cell features and share a similar molecular signature 28 . Some morphological features seem recurrent if not constant, including the presence of foci of cartilage, 14,18,20 of teratoid glandular/epithelial elements as highlighted in our case.…”

Section: Discussionmentioning

confidence: 79%

DICER1‐mutated rhabdomyosarcoma of the ovary with teratoid features

Lethongsavarn,

Vieille,

Kikweta Makhama

et al. 2023

Genes Chromosomes & Cancer

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DICER1‐mutated rhabdomyosarcoma is a rare, emerging entity with a predilection for the gynecologic and genitourinary tracts. We report here a case of DICER1‐mutated rhabdomyosarcoma of the ovary in a 14 years old girl which displayed interspersed mature teratoid glands, neuroectodermal rosettes and immature blastematous‐like tubes. Morphologically the sarcomatous component predominated, corresponding to a high grade spindle cell rhabdomyosarcoma with botryoid features. Islets of cartilage were present. The sarcomatous proliferation encased the teratoid glands, forming cambium layer‐like arrangements. The sarcoma cells were Myogenin and MYOD1 positive, the neuroectodermal rosettes expressed SALL4 along with cytokeratins and EMA and were negative for Inhibin; immature blastematous‐like tubes were negative for SALL4 and Inhibin. Whole RNA‐ and targeted DNA‐sequencing revealed two DICER1 mutations in exon 26: c.5113G>A: p.(Glu1705Lys) and exon 12: c.1642C>T: p.(Gln548X). The sarcomatous component harbored a complex genetic profile while the teratoid component was diploid, none of the above displayed abnormality of 12p. DICER1‐mutated sarcomas display pathological features similar to embryonal rhabdomyosarcomas, botryoid type. They also display heterogeneous features combining cartilage foci, teratoid mature glands, immature blastematous‐like tubes and/or neuroectodermal components. Molecular testing remains necessary to confirm the diagnosis. Further studies need to clarify the nosology of DICER1‐mutated sarcomas and devise specific therapeutic strategies.

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Section: Discussionmentioning

confidence: 79%

DICER1‐mutated rhabdomyosarcoma of the ovary with teratoid features

Lethongsavarn,

Vieille,

Kikweta Makhama

et al. 2023

Genes Chromosomes & Cancer

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“…S4E). Alternatively, human tumors may harness other oncogenic signaling pathways or growth factors, such as RAS/MAP kinase; indeed, RAS pathway genes are the most frequently mutated genes in DICER1-related tumors after TP53 [87][88][89]. Future studies will be needed to identify the mitogenic signaling pathways used in human pineoblastomas.…”

Section: Discussionmentioning

confidence: 99%

An imbalance between proliferation and differentiation underlies the development of microRNA-defective pineoblastoma

Fraire,

Desai,

Obalapuram

et al. 2024

Preprint

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Mutations in the microRNA processing genes DICER1 and DROSHA drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated Drosha or Dicer1 in the developing pineal gland to emulate the pathogenesis of pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. Accordingly, these mice develop pineal tumors marked by loss of microRNAs, including the let-7/miR-98-5p family, and de-repression of microRNA target genes. Pineal tumors driven by loss of Drosha or Dicer1 mimic tumors driven by Rb1 loss, as they exhibit upregulation of S-phase genes and homeobox transcription factors that regulate pineal development. Blocking proliferation of these tumors facilitates expression of pinealocyte maturation markers, with a concomitant reduction in embryonic markers. Select embryonic markers remain elevated, however, as the microRNAs that normally repress these target genes remain absent. One such microRNA target gene is the oncofetal transcription factor Plagl2, which regulates expression of pro-growth genes, and inhibiting their signaling impairs tumor growth. Thus, we demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.

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“…D ICER1 syndrome is a pleiotropic cancer predisposition syndrome caused by germline pathogenic variants (GPVs) in DICER1. 1,2 The phenotype includes a diverse type of tumors (eg, pleuropulmonary blastoma (PPB), cystic nephroma, Sertoli-Leydig cell tumor, and embryonic rhabdomyosarcoma), but many of them appear to share unifying pathologic features, 3,4 which is further supported by methylation data showing that DIC-ER1-associated sarcomas arising from different sites cluster together 5 . For the most part, DICER1-associated tumors are characterized by a loss of function (LOF) variant on 1 allele and an acquired somatic mutation on the other allele that affects nucleotides encoding for the catalytic RNase IIIb domain of DICER1.…”

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confidence: 93%

Fetal Type Morphologies Suggest the Presence of DICER1 Hotspot Mutations in Non–small Cell Lung Cancer

Chong,

Thorner,

Ellis

et al. 2023

American Journal of Surgical Pathology

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Germline and somatic pathogenic variants (PVs) in DICER1, encoding a miRNA biogenesis protein, are associated with a wide variety of highly specific pathologic entities. The lung tumors pleuropulmonary blastoma, pulmonary blastoma (PB), and well-differentiated fetal lung adenocarcinoma (WDFLAC) are all known to harbor DICER1 biallelic variants (loss of function and/or somatic hotspot missense mutations), and all share pathologic features reminiscent of the immature lung. However, the role of DICER1 PVs in non–small cell lung cancer (NSCLC) is relatively unknown. Here, we aimed to establish the spectrum of lung pathologies associated with DICER1 hotspot PVs and to compare the mutational landscape of DICER1-mutated NSCLC with and without hotspots. We queried DNA sequencing data from 12,146 NSCLCs featuring somatic DICER1 variants. 235 (1.9%) cases harboring ≥ 1 DICER1 PV were found and 9/235 (3.8%) were DICER1 hotspot-positive cases. Histologic review of DICER1 hotspot-positive cases showed that all but one tumor were classified as within the histologic spectrum of PB/WDFLAC, whereas all the DICER1 non-hotspot double variants were classified as lung adenocarcinomas, not otherwise specified. Comparison between the mutational landscape of DICER1 hotspot-positive and hotspot-negative cases revealed a higher frequency of CTNNB1 mutations in the hotspot-positive cases (5/9 vs. 2/225; P<0.00001). We conclude that DICER1 somatic hotspots are not implicated in the most common forms of NSCLC but rather select for morphologic features of lung tumor types such as PB and WDFLAC. As a corollary, cases showing this tumor morphology should undergo testing for DICER1 variants, and if positive, genetic counseling should be considered.

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Genomic characterization of DICER1-associated neoplasms uncovers molecular classes

Cited by 16 publications

References 82 publications

DICER1‐mutated rhabdomyosarcoma of the ovary with teratoid features

DICER1‐mutated rhabdomyosarcoma of the ovary with teratoid features

An imbalance between proliferation and differentiation underlies the development of microRNA-defective pineoblastoma

Fetal Type Morphologies Suggest the Presence of DICER1 Hotspot Mutations in Non–small Cell Lung Cancer

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