DICER1 Syndrome Research Articles

Relevance of Molecular Pathology for the Diagnosis of Sex Cord-Stromal Tumors of the Ovary: A Narrative Review.

Ovarian sex cord-stromal tumors (SCSTs) account for 8% of all primary ovarian neo-plasms. Accurate diagnosis is crucial since each subtype has a specific prognostic and treatment. Apart from fibrosarcomas, stromal tumors are benign while sex cord tumors may recur, sometimes with a significant time to relapse. Although the diagnosis based on morphology is straightforward, in some cases the distinction between stromal tumors and sex cord tumors may be tricky. Indeed, the immunophenotype is usually nonspecific between stromal tumors and sex cord tumors. Therefore, molecular pathology plays an important role in the diagnosis of such entities, with pathognomonic or recurrent alterations, such as FOXL2 variants in adult granulosa cell tumors. In addition, these neoplasms may be associated with genetic syndromes, such as Peutz-Jeghers syndrome for sex cord tumors with annular tubules, and DICER1 syndrome for Sertoli-Leydig cell tumors (SLCTs), for which the pathologist may be in the front line of syndromic suspicion. Molecular pathology of SCST is also relevant for patient prognosis and management. For instance, the DICER1 variant is associated with moderately to poorly differentiated SLCTS and a poorer prognosis. The present review summarizes the histomolecular criteria useful for the diagnosis of SCST, using recent molecular data from the literature.

DICER1-Mutant Thyroid Carcinoma of Unusual Morphology: A Follicular Carcinoma with Bizarre Nuclei or a Novel Entity?

Abstract Introduction/Objective DICER1 mutations are associated with a host of benign and malignant neoplasms, of which the thyroid ranks among those with the highest prevalence. We present a case of a DICER1-mutant thyroid carcinoma with unusual morphologic features not described in the existing literature. Methods/Case Report A 29-year old 33 weeks pregnant female presented with swelling of the left neck. The patient subsequently underwent an ultrasound, which revealed a thyroid lesion measuring 6.2cm in greatest dimension. Labs including TSH and free T4 wree within normal 3rd trimester limits. Following an unremarkable delivery, FNA revealed loosely clustered cells with marked hyperchromasia and nuclear pleomorphism and variable microfollicular architecture in a colloid-containing background. Though definitively malignant, the anomalous cytomorphology of this neoplasm prompted molecular testing by Afirma Genomic Sequencing Classifier and Xpression Atlas next-generation sequencing, which was significant for a DICER1 hotspot mutation (p.E1705K c.5113G>A). Follow-up total thyroidectomy was pertinent for a tan-red, nodular mass involving 95% of the thyroid. Histomorphology revealed a neoplasm of primarily macrofollicular architecture with scattered microfollicles and intervening zones that appeared poorly-to-undifferentiated. Cells demonstrated bizarre hyperchromatic, pleomorphic nuclei with multinucleation and Azzopardi effect. Capsular invasion was identified. Inconsistent with a poorly-differentiated or anaplastic carcinoma, the mitotic rate and Ki-67 index were low at < 1/2mm2 and 1-2%, respectively. The tumor was consequently theorized to represent a follicular carcinoma with bizarre nuclei or other entity associated with DICER1 mutations not previously described. To date, no recurrence or metastasis has occurred. Results (if a Case Study enter NA) NA Conclusion We report an enigmatic morphology of a thyroid cancer associated with a DICER1 mutation. DICER1 mutations have been hitherto described in follicular carcinoma, papillary carcinoma, poorly-differentiated carcinoma and thyroblastoma, none of which are consistent with the present case. Thus, we conjecture that this morphomolecular profile may constitute a "follicular carcinoma with bizarre nuclei" or other novel entity not previously reported. Further investigation should be pursued to determine the nature of this entity, its pathophysiology, epidemiology, possible association with germline DICER1 syndrome, and relationship between morphology and prognosis in patients with DICER1 mutations.

Pediatric Sertoli-Leydig Cell Tumors of the Ovary: An Integrated Study of Clinicopathological Features, Pan-cancer-Targeted Next-generation Sequencing and Chromosomal Microarray Analysis From a Single Institution.

Sertoli-Leydig cell tumors (SLCTs) are currently classified into 3 molecular subtypes: DICER1 -mutant (younger patient age), FOXL2 -mutant, and DICER1/FOXL2 -wildtype. However, it is not clear whether all pediatric SLCTs are DICER1 -mutant molecular subtypes and whether other molecular genetic aberrations besides DICER1 are involved in the pathogenesis and prognosis of these tumors. We studied comprehensive data for 8 cases of pediatric SLCTs, including clinicopathological features, pan-cancer-targeted next-generation sequencing/OncoKids panel, and chromosomal microarray analysis, to further analyze the correlation among clinicopathological features, molecular genetic aberrations, and prognosis. The ages of the patients ranged from 4 to 16 years (median, 14y). Seven cases were moderately differentiated, and one was poorly differentiated with heterologous mesenchymal elements. Two cases had heterologous epithelium or retiform elements. Follow-up was available for all 8 patients (median, 49.5mo). Seven patients were alive without evidence of recurrence or metastasis, and only case 5 developed metastases (synchronous bilateral pulmonary tumors with rhabdomyosarcomatous differentiation). All 8 tumors were found to harbor somatic hotspot DICER1 mutations, and 5 patients carried germline DICER1 mutations (2 of them had the phenotype of DICER1 syndrome). Together with recent studies, the DICER1 mutation frequency is 100% in pediatric SLCTs (n=27, age≤16y). Copy number alterations were detected in 3 tumors; the only recurrent copy number alterations was the gain of whole chromosome 6 in case 5 and case 8. This is the first report describing clinicopathological features and molecular alterations in pediatric SLCTs. Our results demonstrate that all pediatric SLCTs belong to the DICER1 -mutant molecular subtype, highlighting that somatic hotspot DICER1 mutation detection has high sensitivity (100%) for the auxiliary diagnosis of pediatric SLCTs (age ≤16y). Some pediatric SLCTs harbor molecular genetic aberrations other than DICER1 mutation, and their significance needs further study.

Newly Recognized Genetic Tumor Syndromes of the CNS in the 5th WHO Classification: Imaging Overview with Genetic Updates.

The nervous system is commonly involved in a wide range of genetic tumor-predisposition syndromes. The classification of genetic tumor syndromes has evolved during the past years; however, it has now become clear that these syndromes can be categorized into a relatively small number of major mechanisms, which form the basis of the new 5th edition of the World Health Organization book (beta online version) on genetic tumor syndromes. For the first time, the World Health Organization has also included a separate chapter on genetic tumor syndromes in the latest edition of all the multisystem tumor series, including the 5th edition of CNS tumors. Our understanding of these syndromes has evolved rapidly since the previous edition (4th edition, 2016) with recognition of 8 new syndromes, including the following: Elongator protein complex-medulloblastoma syndrome, BRCA1-associated protein 1 tumor-predisposition syndrome, DICER1 syndrome, familial paraganglioma syndrome, melanoma-astrocytoma syndrome, Carney complex, Fanconi anemia, and familial retinoblastoma. This review provides a description of these new CNS tumor syndromes with a focus on imaging and genetic characteristics.

A young girl with papillary thyroid cancer, could it be DICER1 Syndrome?

A young girl with papillary thyroid cancer, could it be DICER1 Syndrome?

DICER1 syndrome: clinical variety endocrine manifestations and features of diagnostics

DICER1 syndrome is a rare genetic disorder with the progressive development of malignant and non-malignant diseases in childhood. The cause of this syndrome is a dusfunction of the endoribonuclease DICER, which plays an important role in the processing of microRNAs with subsequent regulation of the control of the expression of oncogenes and tumor suppressor genes. Clinical manifestations of dyseropathies is very different and may include both endocrine manifestations - multinodular goiter, differentiated thyroid cancers, ovarian stromal tumors, pituitary blastoma, and non-endocrine formations - pleuropulmonary blastoma, cystic nephroma, pineoblastoma. The presence of somatic mutations of the DICER1 gene is a resultant stage in the pathogenesis of dyseropathies, determining the further path of oncogenesis. At present, DICER1 syndrome is diagnosed extremely rarely, which leads to late detection of the components of the disease in the patient, late diagnosis of neoplasms, lack of family counseling. Diagnosis at the early stages of the disease, the development of screening programs for the management of these patients allows minimizing the risks of developing more malignant, aggressive forms of the disease.

SAT508 Siblings With Heterozygous DICER1 c.322C>T, pGln108* Variant: A Novel Genetic Variant for DICER1 Syndrome

Abstract Disclosure: N.L. Yamashita: None. J. Austin: Consulting Fee; Self; Ascendis, Vertice. Research Investigator; Self; IBSA Pharmaceuticals. Background: Several genetic variants are implicated in DICER1 syndrome - a neoplasm predisposition syndrome with a spectrum of presentations with both benign and malignant tumors. DICER1 c.322C>T, pGln108* variant is a new mutation that was found in this case of two siblings presenting with thyroid cancers. Clinical case: Sibling A is a 10-year-old female who presented to the emergency department (ED) with a rapidly progressing right neck mass. She underwent fine needle aspiration (FNA) that returned as Follicular Lesion of Undetermined Significance (FLUS), Bethesda III. Subsequently, she had a right lobectomy, and pathology results revealed multiple follicular adenomatous nodules with focal papillary hyperplasia. Approximately one year later, she re-presented with a new left sided neck swelling with ultrasound revealing three new nodules. She underwent left lobectomy and pathology showed follicular variant papillary thyroid carcinoma (FVPTC). She was started on levothyroxine replacement daily. Her surveillance regimen included I-123 thyroid uptake scans which showed uptake in the neck. Her TSH-stimulated thyroglobulin was as high as 4.3 ng/mL with negative thyroglobulin antibody titer. She did not receive radioactive iodine ablation (RAI). Since then, routine thyroglobulin levels have remained low and neck ultrasounds have been reassuring. She is currently 19 years old. Approximately three years after Sibling A’s second lobectomy, her sister, Sibling B, presented as an 11-year-old female to the ED with neck swelling. Thyroid ultrasound showed multiple solid and cystic nodules on both right and left thyroid lobes. FNA returned with Bethesda Category IV (suspicious for follicular neoplasm) on the left lower nodule and Bethesda II (benign follicular nodule) on other nodules. She underwent total thyroidectomy and was found to have follicular thyroid carcinoma (FTC). TSH-stimulated thyroglobulin was as high as 8.9 ng/mL. Her surveillance thyroid scan showed uptake in the right thyroidectomy bed and 1.6 cm nodule was found on ultrasound. FNA of this lesion was benign with stable repeat thyroid scans with downtrending TSH-stimulated thyroglobulin. This patient is currently 15 years old. Soon after the Sibling B was diagnosed with FTC, the decision was made to pursue genetic analysis. Both siblings underwent mutation analysis which were both positive for heterozygous DICER1 c.322C>T, pGln108* variant.Conclusion: This case introduces a novel variant to DICER1 syndrome: DICER1 c.322C>T, pGln108* variant. Without a family history of multinodular goiter (MNG), thyroid cancers, or other associated tumors to this syndrome, these siblings had unusual presentations of a germline DICER1 syndrome variant. This case highlights the expressive variability in DICER1 syndrome and this variant may be of consideration when children present without other predisposing tumors. Presentation Date: Saturday, June 17, 2023

DICER1 Mutations Do Not Always Indicate Dismal Prognosis in Pediatric Poorly Differentiated Thyroid Carcinomas.

Progress in the field of pediatric thyroid pathology has linked DICER1 mutations to benign follicular cell-derived thyroid tumors (e.g., follicular adenoma with papillary architecture, follicular nodular disease), low-risk follicular cell-derived differentiated thyroid carcinomas and PDTCs enriched in fatal or recurrent/progressive disease. The dismal outcome of DICER1-harboring pediatric PDTCs stems from a limited number of reported patients' data given the rarity of pediatric PDTCs. In light of the former observations, the current study assessed clinicopathological variables of a series of 5 pediatric (≤ 18 years old) PDTCs using the Turin criteria (WHO 2022) and also examined the status of DICER1 and TERT promoter mutations. Five PDTCs (3 males, 2 females) were included in the study. The mean age at the time of diagnosis was 15.4 years. No patients had a history of DICER1 syndrome-related tumors or other clinicopathological diagnostic features of DICER1 syndrome. The mean tumor size was 3.9 cm. All tumors were completely submitted for microscopic examination. There was increased mitotic activity ranging from 3 to 10 mitoses per 2 mm2. Tumor necrosis was present in two cases. No PDTC harbored TERT promoter mutation. DICER1 hot spot mutation was identified in one (20%) tumor. The DICER1-mutant tumor had neither associated differentiated thyroid carcinoma component nor other pathological findings in the adjacent thyroid parenchyma. The DICER1-mutant PDTC showed widely invasive growth confined to the thyroid parenchyma. Despite the widely invasive growth, the tumor lacked vascular invasion. Two DICER1 wild-type PDTCs had lymphocytic thyroiditis and another one had underlying follicular nodular disease and/or follicular adenomas. Three DICER1 wild-type PDTCs also had an associated differentiated thyroid carcinoma component with no high-grade features. No abnormal p53 expression (overexpression or global loss) was recorded in all tested tumors. Four patients had follow-up data with a mean follow-up time of 60.25 months (range: 18-86 months). One patient with no evidence of disease recurrence died of anunrelated cause after 18 months of the initial surgery, all remaining patients were alive with no distant metastasis at their last visit. Of the 4 patients with lymph node (LN) dissection, one DICER1 wild-type PDTC had recurrent nodal disease. During the follow-up period (72 months), no local recurrence or distant metastases was detected in the DICER1-mutant PDTC. Taken together all reported findings from earlier series, DICER1 mutations alone may not necessarily indicate dismal outcome in a subset of pediatric PDTCs. The occurrence of additional genomic alterations as discussed in some earlier reports may be contributing to tumor progression or aggressivity of pediatric PDTCs. The lack of vascular invasion in the current DICER1-mutant pediatric PDTC may also explain an indolent biologic outcome. The risk escalation of DICER1 mutations should integrate the status of additional genetic events and well-established pathologic variables in order to ensure predictive dynamic risk stratification in DICER1-mutant pediatric PDTCs. Additional studiesare needed to corroborate the findings of this study and advance our knowledge in pediatric thyroid neoplasia.

Bi-allelic Dicer1 mutations in the gynecologic tract of mice drive lineage-specific development of DICER1 syndrome-associated cancer.

DICER1 is an RNase III enzyme essential for microRNA (miRNA) biogenesis through cleaving pre-miRNA hairpins. Germline loss-of-function DICER1 mutations underlie the development of DICER1 syndrome, a rare genetic disorder that predisposes children to cancer development in organs such as lung, gynecologic tract, kidney, and brain. Unlike classical tumor suppressors, the somatic "second hit" in DICER1 syndrome-associated cancers does not fully inactivate DICER1 but impairs its RNase IIIb activity only, suggesting a noncanonical two-hit hypothesis. Here, we developed a genetically engineered conditional compound heterozygous Dicer1 mutant mouse strain that fully recapitulates the bi-allelic DICER1 mutations in DICER1 syndrome-associated human cancers. Crossing this tool strain with tissue-specific Cre strains that activate Dicer1 mutations in gynecologic tract cells at two distinct developmental stages revealed that embryonic bi-allelic Dicer1 mutations caused infertility in females by disrupting oviduct and endometrium development and ultimately drove cancer development. These multicystic tubal and intra-uterine tumors histologically resembled a subset of DICER1 syndrome-associated human cancers. Molecular analysis uncovered accumulation of additional oncogenic events (e.g. aberrant p53 expression, Kras mutation, and Myc activation) in murine Dicer1 mutant tumors and validated miRNA biogenesis defects in 5P miRNA strand production, of which loss of let-7 family miRNAs was identified as a putative key player in transcriptomic rewiring and tumor development. Thus, this DICER1 syndrome-associated cancer model recapitulates the biology of human cancer and provides a unique tool for future investigation and therapeutic development.

DICER1 Syndrome: A Multicenter Surgical Experience and Systematic Review.

DICER1 syndrome is a rare genetic disorder that predisposes patients to the development of malignant and non-malignant diseases. Presently, DICER1 syndrome diagnosis still occurs late, usually following surgical operations, affecting patients' outcomes, especially for further neoplasms, which are entailed in this syndrome. For this reason, herein we present a multicenter report of DICER1 syndrome, with the prospective aim of enhancing post-surgical surveillance. A cohort of seven patients was collected among the surgical registries of Pediatric Surgery at the University of Pisa with the General and Oncologic Surgery of Federico II, University of Naples, and the Pediatric Surgery, Regina Margherita Hospital, University of Turin. In each case, the following data were analyzed: sex, age at diagnosis, age at first surgery, clinical features, familial, genetic investigations, and follow-up. A comprehensive literature review of DICER1 cases, including case reports and multicenter studies published from 1996 to June 2022, was performed. Eventually, the retrieved data from the literature were compared with the data emerging from our cohort of patients.

Amyloid goiter secondary to familial Mediterranean fever with E148Q mutation: A unique case.

Amyloid goiter secondary to familial Mediterranean fever with E148Q mutation: A unique case.

Reclassification of two germline DICER1 splicing variants leads to DICER1 syndrome diagnosis

DICER1 syndrome is an inherited condition associated with an increased risk of developing hamartomatous and neoplastic lesions in diverse organs, mainly at early ages. Germline pathogenic variants in DICER1 cause this condition. Detecting a variant of uncertain significance in DICER1 or finding uncommon phenotypes complicate the diagnosis and can negatively impact patient care. We present two unrelated patients suspected to have DICER1 syndrome. Both females (aged 13 and 15 years) presented with multinodular goiter (thyroid follicular nodular disease) and ovarian tumours. One was diagnosed with an ovarian Sertoli-Leydig cell tumour (SLCT) and the other, with an ovarian juvenile granulosa cell tumour, later reclassified as a retiform variant of SLCT. Genetic screening showed no germline pathogenic variants in DICER1. However, two potentially splicing variants were found, DICER1 c.5365-4A>G and c.5527+3A>G. Also, typical somatic DICER1 RNase IIIb hotspot mutations were detected in the thyroid and ovarian tissues. In silico splicing algorithms predicted altered splicing for both germline variants and skipping of exon 25 was confirmed by RNA assays for both variants. The reclassification of the ovarian tumour, leading to recognition of the association with DICER1 syndrome and the characterization of the germline intronic variants were all applied to recently described DICER1 variant classification rules. This ultimately resulted in confirmation of DICER1 syndrome in the two teenage girls.

Thyroid Nodules and Follicular Cell-Derived Thyroid Carcinomas in Children.

Although pediatric thyroid tumors have many similarities to those occurring in adults, significant differences are also recognized. For example, although thyroid nodules in children are much less common than in adults, a higher percentage is malignant. Moreover, while pediatric papillary thyroid carcinoma (PTC) is associated with more advanced disease, death due to disease in children and adolescents is very rare, even when distant metastases are present. Some subtypes of thyroid carcinoma, like diffuse sclerosing variant, are especially common in children and adolescents. Moreover, certain histologic findings, such as a tall cell morphology or increased mitotic activity, may not carry the same prognostic significance in children as in adults. Recent studies exploring the molecular underpinnings of pediatric thyroid carcinoma indicate that while driver alterations of thyroid tumorigenesis in children and adults are essentially the same, they occur at very different frequencies, with translocation-associated tumors (most commonly harboring RET and NTRK fusions) comprising a sizable and distinct group of pediatric PTC. DICER1 mutations, an infrequent mutation in adult thyroid tumors, are relatively frequent in pediatric encapsulated follicular-patterned thyroid tumors (with or without invasion or nuclear features of PTC). Additionally, tumor predisposition syndromes (most notably DICER1 syndrome and PTEN hamartoma tumor syndromes such as Cowden syndrome) should be considered in children with thyroid tumors, especially follicular-patterned thyroid tumors and poorly differentiated thyroid carcinoma. This review will explore the current state of knowledge of thyroid nodules and carcinomas in children and adolescents.

Comparative Biochemical Studies of Disease-Associated Human Dicer Mutations on Processing of a Pre-microRNA and snoRNA.

Dicer is an RNase III enzyme that is responsible for the maturation of small RNAs such as microRNAs. As Dicer's cleavage products play key roles in promoting cellular homeostasis through the fine-tuning of gene expression, dysregulation of Dicer activity can lead to several human diseases, including cancers. Mutations in Dicer have been found to induce tumorigenesis and lead to the development of a rare pleiotropic tumor predisposition syndrome found in children and young adults called DICER1 syndrome. These patients harbor germline and somatic mutations in Dicer that lead to defective microRNA processing and activity. While most mutations occur within Dicer's catalytic RNase III domains, alterations within the Platform-PAZ (Piwi-Argonaute-Zwille) domain also cause loss of microRNA production. Using a combination of in vitro biochemical and cellular studies, we characterized the effect of disease-relevant Platform-PAZ-associated mutations on the processing of a well-studied oncogenic microRNA, pre-microRNA-21. We then compared these results to those of a representative from another Dicer substrate class, the small nucleolar RNA, snord37. From this analysis, we provide evidence that mutations within the Platform-PAZ domain result in differential impacts on RNA binding and processing, adding new insights into the complexities of Dicer processing of small RNA substrates.

Abstract 3522: DICER1 Platform domain missense variants led to tumor susceptibility via failure of precursor miRNA binding

Abstract DICER1 is a key protein in the micro(mi)RNA biogenesis pathway responsible for cleaving precursor (pre)-miRNA stemloops with its RNase IIIa and IIIb domains into mature single stranded miRNAs. DICER1 syndrome is a pleiotropic tumor predisposition syndrome in which clinical manifestations are normally first seen during childhood. This genetic disorder is defined by the presence of inherited or de novo germline pathogenic variants (GPVs) in the DICER1 gene. While many germline loss of function variants fail to generate DICER1 protein, a subset of patients has germline missense variants that are predicted to produce full-length DICER1 protein that cluster in the DICER1 Platform domain, a region that plays a role in binding to the 5’ phosphate of pre-miRNA stemloops. Due to the uncertainty surrounding the pathogenicity of missense variants in DICER1 syndrome, clinical actionability can be limited. To determine how Platform mutations predispose to DICER1 syndrome we characterized a number of these variants using in vitro pre-miRNA binding and cleavage assays. Interestingly, four of these variants displayed impaired pre-miRNA binding and processing, with three of them localizing to a hydrophobic pocket in the Platform domain. In keeping with in vitro results, DICER1 mutants displayed impaired miRNA processing when introduced into mesenchymal stem cells. Furthermore, we identified a second somatic hit in the RNase IIIb domain of DICER1 in thyroid nodular hyperplasia DNA from a patient affected by one of these variants. Taken together, these results identify a key region in the DICER1 protein that is essential for pre-miRNA processing and help the classification of these germline variants as pathogenic to ensure proper clinical management of affected patients. Additionally, these results provide insight on the molecular basis involved in DICER1 syndrome predisposition. Citation Format: Dylan Pelletier, Anne-Laure Chong, Sophie Albert, Marc Fabian, William Foulkes. DICER1 Platform domain missense variants led to tumor susceptibility via failure of precursor miRNA binding. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3522.

Abstract 23: Development of a biallelicDicer1mutant mouse strain for studying the pathogenesis of DICER1 syndrome-associated cancer

Abstract DICER1 encodes a RNase III enzyme that post-transcriptionally controls gene expression through governing microRNA (miRNA) biogenesis. We and others have demonstrated that somatic mutations of DICER1 at its RNase IIIb domain metal binding sites, impairing its capability to produce mature miRNAs from the 5P strand of miRNA precursors, occur recurrently in a broad spectrum of cancers associated with the DICER1 syndrome that affects children and youths predominantly. The biallelic DICER1 mutations in these cancers challenge the two-hit hypothesis theory of traditional tumour suppressors, but it remains unproven whether these mutations are sufficient to drive tumorigenesis. The lack of biology relevant preclinical models has also hindered the understanding the pathogenesis. Here, we developed a genetically engineered mouse strain that expresses an inducible knockin Dicer1 missense mutation (Dicer1+/fl-D1693N), equivalent to the DICER1 RNase IIIb hotspot mutation D1709N in human cancers. This conditional strain behaves as a null allele due to an aberrant splicing event without Cre-mediated recombination. When crossed with a well-characterized conditional null Dicer1 strain (Dicer1fl/fl), the resulting compound heterozygous strain (Dicer1fl/fl-D1693N), acts as a hemizygous wildtype allele that is converted to a hemizygous missense mutation allele upon Cre-mediated recombination, reflecting the genetic status of DICER1 in DICER1 syndrome-associated cancer. When crossing with the anti-Mullerian hormone receptor 2 (Amhr2) driven cre strain (Amhr2+/cre), the biallelic Dicer1 mutation resulted in infertility in females by impairing the development of oviduct and endometrium and ultimately drove the development of multicystic tubal and intra-uterine tumours. Histologically, these murine tumors resemble human Müllerian adenosarcoma and other DICER1 syndrome-associated sarcomas. Molecular analysis of these murine tumours validated the miRNA biogenesis defects in 5P-miRNA production, uncovered the activation of the myc signaling and identified that loss of let-7 family miRNAs may drive the transcriptomic rewiring and malignant transformation. Thus, this first DICER1 syndrome-associated murine cancer model faithfully recapitulates the biology of human cancer and provides a unique tool for future investigation and therapeutic development. Citation Format: Yemin Wang, Shary Chen, Janine Senz, Maxwell Douglas, Shelby Thornton, Yana Moscovitz, C. Blake Gilks, David Huntsman, Gregg Morin. Development of a biallelicDicer1mutant mouse strain for studying the pathogenesis of DICER1 syndrome-associated cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 23.

Genomic characterization of DICER1-associated neoplasms uncovers molecular classes

DICER1 syndrome is a tumor predisposition syndrome that is associated with up to 30 different neoplastic lesions, usually affecting children and adolescents. Here we identify a group of mesenchymal tumors which is highly associated with DICER1 syndrome, and molecularly distinct from other DICER1-associated tumors. This group of DICER1-associated mesenchymal tumors encompasses multiple well-established clinicopathological tumor entities and can be further divided into three clinically meaningful classes designated “low-grade mesenchymal tumor with DICER1 alteration” (LGMT DICER1), “sarcoma with DICER1 alteration” (SARC DICER1), and primary intracranial sarcoma with DICER1 alteration (PIS DICER1). Our study not only provides a combined approach to classify DICER1-associated neoplasms for improved clinical management but also suggests a role for global hypomethylation and other recurrent molecular events in sarcomatous differentiation in mesenchymal tumors with DICER1 alteration. Our results will facilitate future investigations into prognostication and therapeutic approaches for affected patients.

Congenital pleuropulmonary blastoma in a newborn with a variant of uncertain significance in DICER1 evaluated by RNA-sequencing

BackgroundPleuropulmonary blastoma (PPB) is a rare mesenchymal malignancy of the lung and is the most common pulmonary malignancy in infants and children. Cystic PPB, the earliest form of PPB occurring from birth to approximately two years of age, is often mistaken for a congenital pulmonary airway malformation, as the two entities can be difficult to distinguish on imaging and pathology. Diagnosis of PPB should prompt workup for DICER1 syndrome, an autosomal dominant tumor predisposition syndrome. We report a newborn with a congenital PPB presenting with tachypnea and hypoxia, who was found to have variant of uncertain clinical significance (VUS) in DICER1.Case presentationA term female infant developed respiratory distress shortly after birth. Initial imaging was concerning for a congenital pulmonary airway malformation versus congenital diaphragmatic hernia, and she was transferred to a quaternary neonatal intensive care unit for management and workup. Chest CT angiography demonstrated a macrocytic multicystic lesion within the right lower lobe without systemic arterial supply. The pediatric surgery team was consulted, and the neonate underwent right lower lobectomy. Pathology revealed a type I PPB. Oncology and genetics consultants recommended observation without chemotherapy and single gene sequencing of DICER1, which identified a germline VUS in DICER1 predicted to alter splicing. RNA-sequencing from blood demonstrated that the variant resulted in an in-frame deletion of 29 amino acids in a majority of transcripts from the affected allele. Due to the patient’s young age at presentation and high clinical suspicion for DICER1 syndrome, tumor surveillance was initiated. Renal and pelvic ultrasonography were unremarkable.ConclusionWe present the case of a term neonate with respiratory distress and cystic lung mass, found to have a type I PPB with a germline VUS in DICER1 that likely increased her risk of DICER1-related tumors. Nearly 70% of patients with PPB demonstrate germline mutations in DICER1. Review of RNA sequencing data demonstrates the difficulty in classifying splice variants such as this. Penetrance is low, and many patients with pathogenic DICER1 variants do not develop a malignancy. Best practice surgical and oncologic recommendations include an individualized approach and tumor board discussion. This case highlights the importance of a multidisciplinary team approach and the utility of international registries for patients with rare diagnoses.

A Korean child with DICER1 syndrome presenting with thyroid manifestations accompanied by other types of neoplasms: a case report and literature review.

We experienced a rare case of an 8-year-old girl with a diagnosis of DICER1 syndrome. The patient exhibited renal and thyroid symptoms. On family history, the patient's maternal grandmother and aunt had a diagnosis of multinodular goiter. The patient underwent whole exome sequencing (WES) to examine whether she had cancer predisposition syndrome, including DICER1 syndrome. This showed a heterozygous missense mutation, c.3506C>G (p.S1169*), in exon 21 of the DICER1 gene. Sanger sequencing was performed to confirm the DICER1 variant detected by WES and to examine whether the patient's family members had a mutation in the same DICER1 exon. Two siblings and father of the patient were negative for genetic test, but the patient's mother was positive for DICER1 pathogenic variant. At the age of 16, the patient had a polypoid mass in the right nasal cavity. On histopathology, the patient was found to have nasal chondromesenchymal hamartoma. Our case showed the longitudinal time course of DICER1 syndrome, which has not been described in the Korean literature. In conclusion, our case highlights the importance of thyroid diagnostic work-up; clinicians should consider the possibility of DICER1 syndrome in a child or an adolescent who present with thyroid diseases accompanied by common type of neoplasms.

A Rare Adult Primary Intracranial Sarcoma, DICER1-Mutant Identified by Epigenomic Profiling: A Case Report

Diagnoses of primary malignant mesenchymal brain tumors are a challenge for pathologists. Here, we report the case of a 52-year-old man with a primary brain tumor, histologically diagnosed as a high-grade glioma, not otherwise specified (NOS). The patient underwent two neurosurgeries in several months, followed by radiotherapy and chemotherapy. We re-examined the tumor samples by methylome profiling. Methylome analysis revealed an epi-signature typical of a primary intracranial sarcoma, DICER1-mutant, an extremely rare tumor. The diagnosis was confirmed by DNA sequencing that revealed a mutation in DICER1 exon 25. DICER1 mutations were not found in the patient's blood cells, thus excluding an inherited DICER1 syndrome. The methylome profile of the DICER1 mutant sarcoma was then compared with that of a high-grade glioma, a morphologically similar tumor type. We found that several relevant regions were differentially methylated. Taken together, we report the morphological, epigenetic, and genetic characterization of the sixth described case of an adult primary intracranial sarcoma, DICER1-mutant to-date. Furthermore, this case report underscores the importance of methylome analysis to refine primary brain tumor diagnosis and to avoid misdiagnosis among morphologically similar subtypes.