DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis.

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

Journal: The Journal of clinical investigation 2020;130(3):1479-1490

PMID: 31805011

Free Full Text on American Society for Clinical Investigation View on PubMed

Abstract

BACKGROUNDDICER1 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.METHODSWhole-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.RESULTSWe 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.CONCLUSIONWe identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDINGCanadian 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.

Address: Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada.; Lady Davis Institute for Medical Research and.; Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada.; Cancer Research Program, McGill University Health Centre, Montreal, Quebec, Canada.; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.; Division of Medical Genetics, Department of Medicine, McGill University Health Centre and Jewish General Hospital, Montreal, Quebec, Canada.; Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada.; Institute of Human Genetics, University of Ulm and University of Ulm Medical Center, Ulm, Germany.; Génome Québec Innovation Centre, McGill University, Montreal, Quebec, Canada.; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.; Department of Diagnostic Radiology, McGill University, Montreal, Quebec, Canada.; Pediatric Radiology, Montreal Children's Hospital, Montreal, Quebec, Canada.; Institute of Neuropathology, University Hospital Muenster, Muenster, Germany.; Department of Neurosurgery, McGill University Health Centre, Montreal, Quebec, Canada.; Department of Biochemistry, McGill University, Montreal, Quebec, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Department of Pathology, University Health Network, Toronto, Ontario, Canada.; Department of Medicine.; Department of Oncology.; Department of Pathology.; Biochemistry and Molecular Biology Institute, and.; Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.; Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada.; Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.; Division of Orthopedic Surgery (Experimental Surgery), McGill University, Montreal, Quebec, Canada.; Department of Surgical Oncology, McGill University Health Centre, Montreal, Quebec, Canada.

DOI: 10.1172/JCI130206

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MeSH Terms: Amino Acid Substitution, Child, Chromosomes, Human, Pair 22, Female, Gene Dosage, Genetic Predisposition to Disease, Genome-Wide Association Study, Goiter, Nodular, HEK293 Cells, Humans, Male, Mutation, Missense, Neoplasm Proteins, Neurilemmoma, Neurofibromatoses, RNA-Binding Proteins, Skin Neoplasms, Exome Sequencing