Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes

Abstract

DICER1 syndrome is a pleiotropic tumor predisposition syndrome characterized by a distinctive constellation of neoplastic and dysplastic lesions, which are generally rare and affect children and young adults. Germline pathogenic variants in the DICER1 gene are the underlying cause of the syndrome; variants are typically inherited in an autosomal dominant pattern but may arise de novo in the germline or in a somatic mosaic distribution. The encoded DICER1 protein is a key component of the microRNA processing pathway. In this Mutation Update, we present a comprehensive review of all DICER1 genetic alterations reported in articles published before January 31st, 2019. A total of 1,136 DICER1 alterations were catalogued from 808 individuals and the tumors that occurred in these persons. We provide an inventory of these DICER1 alterations and discuss them with respect to their provenance, distribution across the gene, associated phenotypes and ages of onset, and penetrance. We also address approaches to classification of DICER1 variants of uncertain significance and discuss the clinical significance of DICER1 variant identification.

Somatic tumour testing establishes that bilateral DICER1‐associated ovarian Sertoli–Leydig cell tumours represent independent primary neoplasms

“…There have been considerable advances in recent years regarding discovery of the underlying molecular events in rare non‐epithelial ovarian neoplasms, such as the common occurrence of FOXL2 mutations in adult granulosa cell tumour and SMARCA4 mutations in small‐cell carcinoma of the ovary of hypercalcaemic type 1–11 . Sertoli–Leydig cell tumour (SLCT) is a rare ovarian neoplasm that, especially when of the moderately or poorly differentiated type, is commonly associated with somatic and/or germline DICER1 mutations 12–14 . Patients with germline mutations have DICER1 syndrome.…”

“…Patients with germline mutations have DICER1 syndrome. As well as SLCT, these patients are also predisposed to develop a wide range of other ‘hyperplastic’ disorders and uncommon neoplasms; these include lung cysts, thyroid multinodular goitre, various benign and malignant thyroid neoplasms, pleuropulmonary blastoma, cystic nephroma, anaplastic sarcoma of the kidney, ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, pituitary blastoma, pineoblastoma, and embryonal rhabdomyosarcoma of the cervix, ovary, fallopian tube, and genitourinary tract 9,12–20 …”

DICER1-associated metastatic abdominopelvic primitive neuroectodermal tumor with an EWSR1 rearrangement in a 16-yr-old female

“…Initially described in familial pleuropulmonary blastoma (Hill et al 2009;Slade et al 2011), in which 70% of cases harbor a germline heterozygous DICER1 loss-of-function mutation, DICER1 syndrome has since been associated with a variety of additional benign and malignant conditions including lung cysts, cystic nephroma (Bahubeshi et al 2010;Faure et al 2016), Wilms tumor (Foulkes et al 2014), multinodular goiter (Rio Frio et al 2011;Schultz 2018), thyroid adenoma, juvenile-type intestinal polyps, ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, pituitary blastoma, pinealoblastoma (Schultz 2018), cervical embryonal rhabdomyosarcoma (Doros et al 2012), Sertoli-Leydig tumors (Fremerey et al 2017), and malignant sacrococcygeal tumors (Nakano et al 2019;Warren et al 2020). DICER1 syndrome exhibits incomplete penetrance, and up to 95% of DICER1 carriers do not develop any significant clinical features by the age of 10 (Doros et al 1993;Wormald et al 2018;de Kock et al 2019;Stewart et al 2019).…”

Cancer genetics—one family at a time

“…More information on DICER1 syndrome c a n b e f o u n d o n o u r m u l t i -l i n g u a l w e b s i t e , www.dicer1syndrome.ca. Our work, and the work of many others, has recently been summarized in a 10-year review of DICER1 syndrome [23].…”