DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies

Abstract

Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations. In addition to conferring increased cancer risks for pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors, particularly Sertoli–Leydig cell tumor, individuals with pathogenic germline DICER1 variants may also develop lung cysts, cystic nephroma, renal sarcoma and Wilms tumor, nodular hyperplasia of the thyroid, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, genitourinary embryonal rhabdomyosarcoma and brain tumors including pineoblastoma and pituitary blastoma. In May 2016, the International PPB Registry convened the inaugural International DICER1 Symposium to develop consensus testing, surveillance and treatment recommendations. Attendees from North America, Europe and Russia provided expert representation from the disciplines of pediatric oncology, endocrinology, genetics, genetic counseling, radiology, pediatric surgery, pathology and clinical research. Recommendations are provided for genetic testing, prenatal management, and surveillance for DICER1-associated pulmonary, renal, gynecologic, thyroid, ophthalmologic, otolaryngologic, central nervous system tumors and gastrointestinal polyps. Risk for most DICER1-associated neoplasms is highest in early childhood and decreases in adulthood. Individual and caregiver education and judicious imaging-based surveillance are the primary recommended approaches. These testing and surveillance recommendations reflect a consensus of expert opinion and current literature. As DICER1 research expands, guidelines for screening and treatment will continue to be updated.

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

“…In families afflicted with tumor predisposition syndromes, determining the specific genetic defect in affected individuals and then screening for additional at‐risk family members is key to timely implementation of appropriate surveillance and treatment protocols. Standardized screening regimens are still being developed for DICER1 syndrome, but recommended strategies are emerging (Schultz et al, ). Some of the considerations for such strategies include the risk for development of DICER1 tumors being highest in early childhood and waning into adulthood, and that the DICER1 phenotypes vary widely in terms of rarity, age range of onset, severity, rapidity of development, means of detection, and effectiveness of early detection.…”

“…PPB, which is most often diagnosed before age 6 years, is plausibly the greatest threat to patient well‐being, particularly Types II and III which have 5‐year overall survival rates of 71% and 53%, respectively (Messinger et al, ). As such, and given the possible progression of some of the tumor types to fulminant disease (including cystic PPB to the solid variants, and possibly, more rarely, MNG to DTC, and pCN to anaplastic sarcoma of the kidney), it is advised that identification and screening of DICER1 pathogenic variant heterozygotes be implemented as early as possible with the aim of detecting precancerous or lower‐stage lesions that may be more amendable to treatment (Schultz et al, ; van Engelen et al, ). Timely counseling, genetic testing, and accurate variant classification are therefore of significant clinical importance.…”

Germline DICER1‐mutant intracranial sarcoma with dual chondroid and spindle cell morphology and pulmonary metastases treated with multimodal therapy

“…Another series has reported pleomorphic differentiation with prominent eosinophilic cytoplasmic globules . Interestingly, among two infants with posterior‐fossa embryonal tumors, one had chondroid differentiation, which has been described in DICER1‐associated extracranial tumors such as nasal chondromesenchymal hamartoma, RMS, and renal anaplastic sarcoma …”

“…To the Editor: Pediatric intracranial sarcomas are rare tumors with poor prognoses . Mutations in the DICER1 gene on chromosome 4, which encodes a RNase‐IIIb endonuclease involved in microRNA processing and thereby controlling gene expression, has recently been reported to be associated with intracranial spindle‐cell sarcomas with rhabdomyosarcoma (RMS)‐like features . We describe the multimodal management of a case with germline DICER1 mutation and pulmonary metastases.…”

“…DICER1 syndrome, classically associated with pleuropulmonary blastoma, is an autosomal‐dominant condition with reduced penetrance, increasingly being recognized as predisposing to benign and malignant neoplasms, including CNS tumors such as pinealoblastoma, pituitary blastoma, and ciliary‐body medulloepithelioma, and genitourinary sarcomas . Recently, a group of DICER1‐mutant pediatric intracranial sarcomas were described, which are histologically heterogeneous, but homogeneous at the molecular level, with a characteristic methylation profile .…”