Spectrum of DICER1 Germline Pathogenic Variants in Ovarian Sertoli–Leydig Cell Tumor

Abstract

Sertoli–Leydig Cell Tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms, which predominantly affect adolescents and young female adults. The SLCTs clinical diagnosis and treatment remains challenging due to the rarity and the varied presentation. A large majority of SLCTs are unilateral, but also bilateral neoplasms have been reported, sometimes in the context of DICER1 syndrome. In fact, the most significant discovery regarding the molecular genetics basis of SLCTs was the finding of somatic and germline pathogenic variants in the DICER1 gene. The DICER1 protein is a key component of the micro-RNA processing pathway. Germline DICER1 pathogenic variants are typically inherited in an autosomal dominant pattern and are most often loss-of-function variants dispersed along the length of the gene. Contrarily, DICER1-related tumors harbor a characteristic missense “RNase IIIb hotspot” mutation occurring in trans, or, less frequently, loss of heterozygosity (LOH) event involving the wild-type allele. While DICER1 mutations have been identified in approximately 60% of SLCTs, especially in the moderately or poorly differentiated types, there are only a few case reports of ovarian SLCT with underlying germline DICER1 mutations. In this review, we focus on the molecular genetic features of SLCT, performing an extensive survey of all germline pathogenic variants modifying the whole sequence of the DICER1 gene. We point out that DICER1 genetic testing, coupled with an accurate variants classification and timely counseling, is of crucial importance in the clinical management of ovarian SLCT-affected patients.

Three-Dimensional Modelling of Ovarian Cancer: From Cell Lines to Organoids for Discovery and Personalized Medicine

“…Mutations in the RAS/MAPK pathway are also observed in EnOC ( Hollis et al, 2020 ), OCCC ( Kim et al, 2018 ), and MOC ( Cheasley et al, 2021 ). Adult ovarian GCTs are characterized predominantly by mutation of FOXL2 , and Sertoli-Leydig Cell Tumors (SLCTs) harbor mutations in DICER1 ( Fuller et al, 2017 ; De Paolis et al, 2021 ). Epithelial and stromal cell ovarian cancer histotypes and associated genes known to be mutated are summarized in Figure 1 .…”

Comparative Biochemical Studies of Disease-Associated Human Dicer Mutations on Processing of a Pre-microRNA and snoRNA

“…Although rarer than RNase III domain mutations, alterations within the Platform-PAZ domain are observed in cancer patients and, in some cases, are associated with disease. Select examples are highlighted in Figure A, which provides an overview of Dicer alterations found within the Platform-PAZ domain, their related disease phenotype, and the likelihood of pathogenicity based upon the proposed impact on Dicer structure and, thus, activity. ,,, While frame shift and deletion mutants would have an obvious impact in altering Platform-PAZ integrity and Dicer activity through loss of amino acids or a shift in the amino acid sequence in sections of the domain (Figure B), the effects of the disease-associated point mutations shown are less clear.…”

15-Year-Old Patient with an Unusual Alpha-Fetoprotein-Producing Sertoli-Leydig Cell Tumor of Ovary

“…DICER1 mutations can be of germline or somatic type. In the case of germline mutations, called DICER1 syndrome, significant clinical relapse and morbidity occur in patients at young age [ 28 ].…”