ESPE Abstracts (2016) 86 RFC11.3

Germline and Somatic DICER1 Mutations in Familial Papillary Thyroid Carcinoma and Multinodular Goiter

César Lumbrerasa, María Jesús Chuecab, Laura Arribasa, Rajdee de Randamiea, Ángel Alonsoc, Pilar Fernándezd, Sara Berradeb, Emma Andae, Rita María Regojof, Marta Mendiolag & José Carlos Morenoa

aThyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain; bPediatric Endocrinology Service, Navarra Hospital Center, Pamplona, Spain; cGenetics Service, Navarra Hospital Center, Pamplona, Spain; dAnatomic Pathology Service, Navarra Hospital Center, Pamplona, Spain; eEndocrinology and Nutrition Service, Navarra Hospital Center, Pamplona, Spain; fAnatomic Pathology Service, La Paz University Hospital, Madrid, Spain; gMolecular Pathology of Cancer and Translational Oncology Laboratory, La Paz University Hospital Research Institute (IdiPAZ), Madrid, Spain

Background: The inheritable component of familial Papillary Thyroid Cancer (fPTC) was recently attributed to monogenic defects in a reduced number of genes including DICER1. DICER1 codes for a ribonuclease of the RNaseIII family essential for the biogenesis of microRNAs.

Objective and hypotheses: We aimed to identify germline and/or somatic mutations in DICER1 in a familial pedigree with PTC, multinodular goiter (MNG) and other tumours consistent with the DICER1 Syndrome.

Patients and methods: The index patient, an 11-year-old girl, was diagnosed with cystic nephroblastoma (CN) as an infant, MNG at age 8 and follicular variant PTC at age 10 (fvPTC1). Her mother presented MNG at age 9 and fvPTC at age 11 (fvPTC2), and her maternal aunt was thyroidectomized for compressive MNG (MNG1) at age 30. The patient’s father and maternal grandparents were healthy. Germline DICER1 mutations were screened in peripheral blood lymphocyte DNA from 6 members (affected and non-affected) of the kindred. Somatic DICER1 mutations were studied in DNA from all paraffin-embedded tissues available by PCR amplification of mutational “hotspots”, T-A cloning and Sanger sequencing. “Hotspots” for BRAF in fvPTC1/2 and H/K/N-RAS in fvPTC1 were also analyzed.

Results: The proband, her mother, and maternal aunt and grandfather carry a novel germline heterozygous pathogenic DICER1 2-bp deletion (c.1440_1441delTG), which prematurely truncates the functional RNase IIIa and IIIb domains of the protein (p.Gly481ThrfsTer25). Tissue samples showed three different heterozygous DICER1 missense mutations affecting the RNase IIIb domain: c.5438A>G (p.Glu1813Gly) in fvPTC1, c.5113G>A (p.Glu1705Lys) in fvPTC2 and CN, and c.5432T>A (p.Ile1811Asn) in MNG1. BRAF and RAS mutations were absent in the studied tissues.

Conclusion: A novel monoallelic germline mutation in DICER1 increases the susceptibility to develop MNG and subsequently PTC. Phenotype segregation analyses suggests that additional tissue-specific mutations in the RNase IIIb domain, unreported to date in PTC, are necessary for the efficient neoplastic or hyperplastic transformation of the thyroid tissue.