DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis
Barbara Rivera, … , Marc R. Fabian, William D. Foulkes
Barbara Rivera, … , Marc R. Fabian, William D. Foulkes
Published March 2, 2020; First published December 5, 2019
Citation Information: J Clin Invest. 2020;130(3):1479-1490. https://doi.org/10.1172/JCI130206.
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Clinical Medicine Genetics Oncology

DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis

Abstract

BACKGROUND DICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.METHODS Whole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K–positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K.RESULTS We identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.CONCLUSION We identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDING Canadian Institutes of Health Research, Compute Canada, Alex’s Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d’Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen.

Authors

Barbara Rivera, Javad Nadaf, Somayyeh Fahiminiya, Maria Apellaniz-Ruiz, Avi Saskin, Anne-Sophie Chong, Sahil Sharma, Rabea Wagener, Timothée Revil, Vincenzo Condello, Zineb Harra, Nancy Hamel, Nelly Sabbaghian, Karl Muchantef, Christian Thomas, Leanne de Kock, Marie-Noëlle Hébert-Blouin, Angelia V. Bassenden, Hannah Rabenstein, Ozgur Mete, Ralf Paschke, Marc P. Pusztaszeri, Werner Paulus, Albert Berghuis, Jiannis Ragoussis, Yuri E. Nikiforov, Reiner Siebert, Steffen Albrecht, Robert Turcotte, Martin Hasselblatt, Marc R. Fabian, William D. Foulkes

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Figure 3

Clustering of miRNA expression in DGCR8-c.1552G>A;p.E518K mutated tumors and their WT counterparts.

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Clustering of miRNA expression in DGCR8-c.1552G>A;p.E518K mutated tum...
(A) Clustering of miRNA expression in 4 DGCR8-E518K mutated schwannomas, 5 DGCR8-WT schwannomas, 4 DGCR8-E518K mutated, and 20 DGCR8-WT Wilms tumors analyzed by the TARGET initiative (7). Heatmap shows sample-by-sample correlation matrix, based on Pearson correlation coefficients, using normalized values for 300 most variable miRNA expression across all samples. The DGCR8-E518K mutated tumors clustered together in the same consensus cluster. DGCR8 denotes which cases harbor the DGCR8-c.1552G>A;p.E518K variant (mut) and which are DGCR8-WT. See also Supplemental Figures 8 and 9 and ref. 7. (B) Unsupervised clustering of the top 50 most variably expressed miRNAs based on NanoString data of 8 MNG samples (5 DGCR8-E518K mutated and 3 WT cases), 4 follicular variant papillary thyroid cancers (PTC) (2 DGCR8-E518K mutated and 2 WT), and 11 schwannomas (5 DGCR8-E518K mutated; 1 with the VUS c.1147A>G;p.S383G case [*]; 1 with germline variant c.1763A>G;p.K588R previously described in Wilms tumors [#]; and 4 WT for DGCR8). DGCR8-E518K mutated samples clustered together independently of the tissue of origin. Both c.1147A>G;p.S383G and c.1763A>G;p.K588R variants clustered with WT tumors, suggesting the variants do not disturb the miRNA processing role of DGCR8. While tissue types are distributed randomly among DGCR8-E518K, WT samples clustered by tissue of origin (thyroid vs. schwannoma cells), highlighting the particularity of the c.1552G>A;p.E518K profile in miRNA processing.