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DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis.

ABSTRACT: BACKGROUNDDICER1 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.METHODSWhole-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.RESULTSWe 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.CONCLUSIONWe identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDINGCanadian Institutes of Health Research, Compute Canada, Alex's Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d'Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen.

SUBMITTER: Rivera B

PROVIDER: S-EPMC7269565 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Project description:CONTEXT:Nontoxic multinodular goiter (MNG) is frequently observed in the general population, but little is known about the underlying genetic susceptibility to this disease. Familial cases of MNG have been reported, and published reports describe 5 families that also contain at least 1 individual with a Sertoli-Leydig cell tumor of the ovary (SLCT). Germline mutations in DICER1, a gene that codes for an RNase III endoribonuclease, have been identified in families affected by pleuropulmonary blastoma (PPB), some of whom include cases of MNG and gonadal tumors such as SLCTs. OBJECTIVE:To determine whether familial MNG with or without SLCT in the absence of PPB was associated with mutations in DICER1. DESIGN, SETTING, AND PATIENTS:From September 2009 to September 2010, we screened 53 individuals from 2 MNG and 3 MNG/SLCT families at McGill University for mutations in DICER1. We investigated blood lymphocytes and MNG and SLCT tissue from family members for loss of the wild-type DICER1 allele (loss of heterozygosity), DICER1 expression, and microRNA (miRNA) dysregulation. MAIN OUTCOME MEASURE:Detection of germline DICER1 gene mutations in familial MNG with and without SLCT. RESULTS:We identified and characterized germline DICER1 mutations in 37 individuals from 5 families. Two mutations were predicted to be protein truncating, 2 resulted in in-frame deletions, and 1 was a missense mutation. Molecular analysis of the 3 SLCTs showed no loss of heterozygosity of DICER1, and immunohistochemical analysis in 2 samples showed strong expression of DICER1 in Sertoli cells but weak staining of Leydig cells. miRNA profiling of RNA from lymphoblastoid cell lines from both affected and unaffected members of the familial MNG cases revealed miRNA perturbations in DICER1 mutation carriers. CONCLUSIONS:DICER1 mutations are associated with both familial MNG and MNG with SLCT, independent of PPB. These germline DICER1 mutations are associated with dysregulation of miRNA expression patterns.

Project description:BackgroundThe most appropriate surgical procedure for multinodular goiter (MNG) remains under debate. Incidental thyroid carcinoma (ITC) is often identified on histopathological examination after thyroidectomy performed for presumed benign MNG.Aim of the studyThe aim of the study was to determine the value of radical surgery for MNG patients considering the prevalence of ITC diagnosed postoperatively.Materials and methodsWe conducted retrospective analysis of the medical records of 2,306 patients surgically treated for MNG between 2008 and 2013 at one center. None of the patients presented with any suspicion of malignancy, history of familial thyroid cancer, multiple endocrine neoplasia syndrome or previous head or neck radiation exposure.ResultsAmong the 2,306 MNG patients, ITC was detected in 49 (2.12%) (44 women and 5 men, with average ages of 52.2 (21-79) and 55.6 (52-62), respectively). Papillary thyroid carcinoma was significantly more frequently observed than other types of ITC (p<0.00001). Among the MNG patients, 866 (37.5%) underwent total/near total surgery, 464 (20.1%) received subtotal thyroidectomy, and 701 (30.3%) received the Dunhill operation. The remaining 275 (11.9%) patients underwent a less radical procedure and were classified as "others." Among the 49 (100%) patients with ITC, 28 (57.1%) underwent radical surgery. Another 21 (42.9%) patients required completion surgery due to an insufficient primary surgical procedure. A total of 21 (2.42%) patients in the total/near total surgery group were diagnosed with ITC, as well as 16 (2.48%) in the subtotal thyroidectomy group and 12 (1.71%) in the Dunhill operation group; 21 (100%), 4 (25%) and 3 (25%) of these patients, respectively, underwent radical surgery; thus, 0 (0%), 12 (75%) and 9 (75%) required completion surgery. The prevalence rates of ITC were comparable between the radical and subtotal surgery groups (2.42% and 3.44%, respectively, p = 0.4046), and the prevalence was higher in the radical surgery group than in the Dunhill operation group (2.42% and 1.71%, respectively, p = 0.0873). A significant difference was observed between the group of patients who underwent total/near total surgery, among whom all of the patients with ITC (100%) received primary radical surgery, and the groups of patients who received the subtotal and Dunhill operations, among whom only 25% of the patients with ITC in each group received primary radical surgery (p<0.0001).ConclusionsMore radical procedures for MNG result in a lower risk of reoperation for ITC. The prevalence of ITC on postoperative histopathological examination should determine the extent of surgery in MNG patients. In the future, total/near total thyroidectomy should be considered for MNG patients due to the increased prevalence of ITC to avoid the necessity for reoperation.

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DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis.

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