title: DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Program in Cancer Genetics, Department of Oncology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rio Frio
authors.forename: Amin
authors.initials: A
authors.lastname: Bahubeshi
authors.forename: Chryssa
authors.initials: C
authors.lastname: Kanellopoulou
authors.forename: Nancy
authors.initials: N
authors.lastname: Hamel
authors.forename: Marek
authors.initials: M
authors.lastname: Niedziela
authors.forename: Nelly
authors.initials: N
authors.lastname: Sabbaghian
authors.forename: Carly
authors.initials: C
authors.lastname: Pouchet
authors.forename: Lucy
authors.initials: L
authors.lastname: Gilbert
authors.forename: Paul K
authors.initials: PK
authors.lastname: O'Brien
authors.forename: Kim
authors.initials: K
authors.lastname: Serfas
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lesueur
authors.forename: Elena
authors.initials: E
authors.lastname: Bonora
authors.forename: Stefan
authors.initials: S
authors.lastname: Muljo
authors.forename: R Neil
authors.initials: RN
authors.lastname: Schimke
authors.forename: Dorothée
authors.initials: D
authors.lastname: Bouron-Dal Soglio
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Arseneau
authors.forename: Kris Ann
authors.initials: KA
authors.lastname: Schultz
authors.forename: John R
authors.initials: JR
authors.lastname: Priest
authors.forename: Van-Hung
authors.initials: VH
authors.lastname: Nguyen
authors.forename: H Rubén
authors.initials: HR
authors.lastname: Harach
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006044:Goiter, Nodular / Q000150:complications / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000150:complications / Q000235:genetics*; D018202:Pulmonary Blastoma / Q000150:complications / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics*; D018310:Sertoli-Leydig Cell Tumor / Q000150:complications / Q000235:genetics; D055815:Young Adult
chemical_list: D035683:MicroRNAs; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases