• Thomas Rio Frio, Amin Bahubeshi, Chryssa Kanellopoulou, Nancy Hamel, Marek Niedziela, Nelly Sabbaghian, Carly Pouchet, Lucy Gilbert, Paul K O'Brien, Kim Serfas, Peter Broderick, Richard S Houlston, Fabienne Lesueur, Elena Bonora, Stefan Muljo, R Neil Schimke, Dorothée Bouron-Dal Soglio, Jocelyne Arseneau, Kris Ann Schultz, John R Priest, Van-Hung Nguyen, H Rubén Harach, David M Livingston, William D Foulkes, and Marc Tischkowitz.
• Program in Cancer Genetics, Department of Oncology, McGill University Health Centre, Montreal, Quebec, Canada.
• JAMA. 2011 Jan 5; 305 (1): 68-77.

ContextNontoxic 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.ObjectiveTo determine whether familial MNG with or without SLCT in the absence of PPB was associated with mutations in DICER1.Design, Setting, And PatientsFrom 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 MeasureDetection of germline DICER1 gene mutations in familial MNG with and without SLCT.ResultsWe 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.ConclusionsDICER1 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.

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