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 patients 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.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology