ICEECE2012 Symposia New familial endocrine cancer syndromes: pathophysiology and counselling (3 abstracts)
DICER1 mutations characterize a novel syndrome with endocrine features
M. Wu 1, , J. Priest 5 , N. Hamel 1, , N. Sabbaghian 1, , B. Xu 1, , M. Tischkowitz 1, , C. Choong 6, , C. Deal 8 , S. Albrecht 1, , A. Charles 6 , P. Goodyer 1 & W. Foulkes 1,
1McGill University, Montreal, Quebec, Canada; 2Lady Davis Institute, Montreal, Quebec, Canada; 3Research Institute, McGill University Health Centre, Montreal, Quebec, Canada; 4University of Cambridge, Cambridge, UK; 5Minneapolis, MN; 6University of Western Australia, Perth, Western Australia, Australia; 7Princess Margaret Hospital for Children, Perth, Western Australia, Australia; 8Université de Montréal, Montreal, Quebec, Canada; 9Montreal Children’s Hospital, Montreal, Quebec, Canada.
DICER1 is a microRNA processing-RNase III-type endoribonuclease and is crucial for embryogenesis and early development. Nearly 50 different heterozygous germ-line DICER1 mutations have been reported world-wide in individuals who developed, as children or young adults, pleuropulmonary blastoma, cystic nephroma, ovarian sex cord stromal tumors (especially Sertoli–Leydig cell tumor), multi-nodular goiter, embryonal rhabdomyosarcoma (of cervix and other typical sites), Wilms Tumor (WT) and other rare phenotypes, including pituitary blastoma. The latter is a very rare tumor with an apparently specific presentation: infants less than age 24 months with Cushing’s syndrome or diabetes insipidus; the three investigated to date all carry DICER1 mutations.
In addition, single cases of primitive neuroectodermal tumor, pulmonary sequestration, juvenile intestinal polyps, adult-onset pleomorphic sarcoma, ciliary-body medulloepithelioma and pineoblastoma have been reported in DICER1 mutation carriers.
More recently, somatic mutations in DICER1 have been identified in nearly 30% of non-epithelial ovarian tumor, notably 60% in Sertoli–Leydig cell tumors, including 4/4 from individuals with germline DICER1 mutations. Somatic mutations involved codons encoding metal-binding sites within the RNase IIIb catalytic centers, critical for microRNA interaction and cleavage. Mutations were also found in non-seminomatous testicular germ-cell tumor (1/14), embryonal rhabdomyosarcomas (2/5), and ovarian/endometrial carcinoma (1/266). The mutant DICER1 proteins showed reduced RNase IIIb activity but retained RNase IIIa activity.
In an extension of this work, we have recently identified somatic DICER1 mutations, both within and outside the RNaseIIIb domain, in a small percentage of apparently sporadic WT. Notably, all three WT with germ-line DICER1 mutations possessed likely pathogenic somatic mutations. Since these mutations do not obliterate DICER1 function but alter it in specific cell types, the traditional two-hit model of carcinogenesis does not seem to apply.
The prevalence of endocrine presentations (goitre, androgenisation in young women and infants with pituitary dysfunction, especially Cushing syndrome) indicates that endocrinologists should consider germ-line DICER1 mutations when evaluating children and adolescents with these distinctive clinical presentations.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.
Volume 29
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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