Multinodular Goiter Progression Toward Malignancy in a Case of DICER1 Syndrome

Gullo, Irene; Batısta, Rui; Rodrigues-Pereira, Pedro; Soares, Paula; Barroca, Helena; Bom-Sucesso, Maria; Sobrinho-Simões, Manuel

doi:10.1093/ajcp/aqy004

Cited by 23 publications

(14 citation statements)

References 14 publications

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“…Our results are consistent with a previous study showing that multiple DICER1 somatic pathogenic variants were present in both benign and malignant nodules . This suggests that thyroid carcinogenesis related to the DICER1 syndrome is distinct from the classical pathways towards PTC or FTC as BRAF, RAS and RET alterations …”

Section: Discussionsupporting

confidence: 93%

Multinodular goitre is a gateway for molecular testing of DICER1 syndrome

Oliver‐Petit¹,

Bertozzi

Grunenwald

et al. 2019

Clinical Endocrinology

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Background DICER1 syndrome is an autosomal dominant disorder that predisposes individuals to develop benign or malignant tumours from infancy to adulthood. There is low‐to‐moderate penetrance of tumour development, which is sex‐ and age‐dependent. Multinodular goitre (MNG) is among the most highly penetrant phenotype of the disorder, especially in females. Patients and Methods We report a series of eight families referred for childhood‐onset of MNG or DICER1‐related tumours with familial history of MNG in relatives. No additional families with these criteria stated were identified during the same date. We screened DNA samples from the probands and members of their family (40) for constitutional DICER1 variants using Next Generation Sequencing tools. Results Germline pathogenic DICER1 gene variants were identified in all probands and several of their relatives: 64% presented with MNG/thyroidectomy as the phenotypic expression of the syndrome. DICER1 gene variants were identified in the RNAseIII and the PAZ domains. All tumour tissues studied presented clonal pathogenic variants in hotspot regions. Early identification of DICER1 variant carriers has permitted diagnosis and therapeutic scheme correction for two patients and cascade testing in relatives. Conclusions Multinodular goitre is uncommon in children. Childhood‐onset MNG, multiple occurrences of the disease within the same family, or its association with rare benign or malignant tumours should raise suspicions of anomalies in the DICER1 gene, as proposed by recent international recommendations. Early detection of DICER1 pathogenic variants has important consequences in terms of therapeutic strategy, early tumour screening, and genetic counselling.

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Section: Discussionsupporting

confidence: 93%

Multinodular goitre is a gateway for molecular testing of DICER1 syndrome

Oliver‐Petit¹,

Bertozzi

Grunenwald

et al. 2019

Clinical Endocrinology

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“…Outside of DICER1 syndrome, DICER1 mutations are rare in thyroid neoplasms and, to date, have been found nearly exclusively in well-differentiated tumors (papillary thyroid carcinoma, follicular carcinoma and follicular adenoma) 41 , 44 - 48 . Of note, somatic “hotspot” DICER1 mutations may be more common in pediatric compared to adult differentiated thyroid tumors, seen in 10% of pediatric papillary thyroid carcinomas in one series 47 .…”

Section: Discussionmentioning

confidence: 99%

Poorly differentiated thyroid carcinoma of childhood and adolescence: a distinct entity characterized by DICER1 mutations

et al. 2020

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Poorly differentiated thyroid carcinomas (PDTC) in young individuals are rare and their clinical and histopathologic features, genetic mechanisms, and outcomes remain largely unknown. Here, we report a detailed characterization of a series of 6 PDTC in patients ≤ 21 years old defined by Turin diagnostic criteria studied for mutations and gene fusions characteristic of thyroid cancer using targeted next-generation sequencing (NGS) and whole exome sequencing (WES). All tumors had solid, insular or trabecular growth pattern and high mitotic rate, and 5 out of 6 tumors showed tumor necrosis. Targeted NGS assay identified somatic mutations in the DICER1 gene in 5 of 6 (83%) tumors, all of which were “hotspot” mutations encoding the metal-ion binding sites of the RNase IIIb domain of DICER1 . WES was performed in 5 cases which confirmed all hotspot mutations and detected 2 tumors with additional inactivating DICER1 alterations. Of these two, one was a germline pathogenic DICER1 variant and the other had loss of heterozygosity for DICER1 . No other mutations or gene fusions characteristic of adult well-differentiated thyroid cancer and PDTC ( BRAF , RAS , TERT , RET/PTC and other) were detected. On follow-up, available for 5 patients, 3 patients died of disease 8-24 months after diagnosis, whereas 2 were alive with no disease. The results of our study demonstrate that childhood- and adolescent-onset PDTC are genetically distinct from adult-onset PDTC in that they are strongly associated with DICER1 mutations and may herald DICER1 syndrome in a minority. As such, all young persons with PDTC may benefit from genetic counselling. Furthermore, their clinically aggressive behavior contrasts sharply with the indolent nature of the great majority of thyroid tumors with DICER1 mutations reported to date.

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“…DICER1 mutations were associated with MNG with relatively high penetrance, and DICER1-asociated thyroid cancer (PTC and FC) was reported in increasing numbers. 15,[19][20][21][22][23][24][25][26][27][28] Notably, a large number of neoplasms developed in children who had received chemotherapy for a DICER1-related tumor. Thyroid FNA cytology is a critical diagnostic tool for the evaluation of thyroid gland Cancer Cytopathology October 2020…”

Section: Discussionmentioning

confidence: 99%

Cytomorphologic features of thyroid disease in patients with DICER1 mutations: A report of cytology–histopathology correlation in 7 patients

Darbinyan

Morotti

Cai

et al. 2020

Cancer Cytopathology

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BACKGROUND: Germline and somatic mutations of DICER1 have been identified in various types of neoplastic lesions, with germline DICER1 mutation being linked to autosomal dominant hereditary pleiotropic tumor syndrome (DICER1 syndrome). Patients with DICER1 syndrome are at increased risk of developing thyroid disease, including thyroid cancer. The goal of this study was to identify diagnostic cytologic features in thyroid fine-needle aspiration (FNA) samples from patients with DICER1 mutation. METHODS: Cytology cases of thyroid FNA from 7 patients with DICER1 mutation were identified. Clinical, imaging, cytomorphologic, and molecular data were analyzed. RESULTS: Cytologic preparations from reviewed cases showed thyroid lesions of follicular derivation with scant colloid, moderate cellularity, uniform follicular cells with round nuclei and inconspicuous nucleoli arranged in small crowded groups and microfollicles. Follicular neoplasm was diagnosed in 4 cases and follicular lesion of undetermined significance in 3 cases, based on the Bethesda System for Reporting Thyroid Cytopathology. Histopathological analysis of thyroid tissue confirmed neoplastic process in 6 out of 7 cases: follicular carcinoma (FC, 3 cases), papillary thyroid carcinoma (2 cases), poorly differentiated thyroid carcinoma (PDTC, 1 case). Genetic studies identified 3 different somatic variants of DICER1 gene, including transcript consequence c.5428G>T, which was detected in FC and PDTC (and has been described previously in multinodular goiter). CONCLUSION: DICER1 mutation in all analyzed patients was identified as a result of thyroid FNA evaluation, emphasizing the critical role of FNA in the screening of patients with thyroid nodules, proper diagnosis of thyroid disease, and monitoring of patients with DICER1 mutation. Cancer

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Multinodular Goiter Progression Toward Malignancy in a Case of DICER1 Syndrome

Cited by 23 publications

References 14 publications

Multinodular goitre is a gateway for molecular testing of DICER1 syndrome

Multinodular goitre is a gateway for molecular testing of DICER1 syndrome

Poorly differentiated thyroid carcinoma of childhood and adolescence: a distinct entity characterized by DICER1 mutations

Cytomorphologic features of thyroid disease in patients with DICER1 mutations: A report of cytology–histopathology correlation in 7 patients

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