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.

DICER1‐associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing

“…Studies have shown that a great proportion of human protein‐coding genes contain microRNA‐binding sites 24 and consequently, microRNA dysregulation is associated with many human diseases, particularly cancer 25,26 . Not only are microRNA expression patterns altered in many tumor types, but also genetic alterations of the key miRNA biogenesis factors (ie, DICER1, DROSHA, and DGCR8) have been found 27‐30 …”

Mice Hypomorphic forKeap1, a Negative Regulator of the Nrf2 Antioxidant Response, Show Age-Dependent Diffuse Goiter with Elevated Thyrotropin Levels

“…Familial nontoxic multinodular goiter (MNG) is a rare disease that is characterized by Mendelian inheritance (mostly in an autosomal dominant pattern), nodular enlargement of the thyroid gland, normal thyroid function, and absence of thyroidal inflammation ( 1 ). Several associated genes and loci have been identified, including DICER1 (MNG-1, Online Mendelian Inheritance in Man [OMIM] #138800) ( 2 ), Xp22 (MNG-2, OMIM #300273) ( 3 ), 3q26.1-q26.3 (MNG-3, OMIM #606082) ( 4 ), and others ( 5 , 6 ). One of the genes more recently associated with familial nontoxic MNG is KEAP1 , encoding Kelch-like ECH-associated protein 1, an adaptor protein tethered to the actin cytoskeleton as well as to the cytoplasmic surface of mitochondria ( 7 , 8 ).…”

Genetic Mutations and Variants in the Susceptibility of Familial Non-Medullary Thyroid Cancer

“…Then, DICER acts in the next step in the cytoplasm and cleaves the precursor miRNA to form mature functional miRNAs. In a similar extent to DICER1 mutations, DGCR8 mutations were also detected in familial cases of MNG and are associated with schwannoma [ 82 ]. Altogether, these studies indicate the essential role of proper miRNA processing and expression for thyroid gland physiology.…”