Publications

Deep sequencing reveals spatially distributed distinct hotspot mutations in DICER1-related multinodular goiter

de Kock, L., Bah, I., Revil, T. et al.

Context:
Nontoxic multinodular goiter (MNG) occurs frequently, but its genetic etiology is not well-established. Familial MNG and MNG occurring with ovarian Sertoli-Leydig cell tumor are associated with germ-line DICER1 mutations. We recently identified second somatic DICER1 RNase IIIb mutations in two MNGs.

Objective:
To investigate the occurrence of somatic DICER1 mutations and mutational clonality in MNG.

Patients:
MNGs from 15 patients (10 with and 5 without germ-line DICER1 mutations) were selected based on tissue availability.

Design:
Core biopsies/scrapings (n = 70) were obtained, sampling areas of follicular hyperplasia (FH), hyperplasia within colloid pools (HC), unremarkable thyroid parenchyma (UTP), and/or areas of thyroid parenchyma, not classified (TPNC). Following capture with a Fluidigm Access Array®, the coding sequence of DICER1 was deep-sequenced using DNA from each core/scraping.

Results:
All germ-line DICER1-mutated cases were found to harbor at least one RNase III mutation. Specifically, we identified 12 individually-distinct DICER1 RNase IIIb hotspot mutations in 32 of the FH or HC cores/scrapings. These mutations are predicted to affect the metal-ion binding residues at positions p.Glu1705, p.Asp1709, p.Gly1809, p.Asp1810 and p.Glu1813. Somatic RNase IIIb mutations were identified in the 10 DICER1 germ-line mutated MNGs as follows: 2 cases contained 1 somatic mutation, 5 cases contained 2 mutations, and 3 cases contained 3 distinct somatic hotspot mutations. No RNase IIIb mutations were identified in the MNGs from individuals without germline DICER1 mutations.

Citation

de Kock, L., Bah, I., Revil, T. et al. "Deep sequencing reveals spatially distributed distinct hotspot mutations in DICER1-related multinodular goiter" Journal of Clinical Endocrinology and Metabolism (2016): 3,637–45