Abstract IA003: DICER1-related tumor predisposition: genotypes, phenotypes and mechanisms
DICER1 is an endoribonuclease that plays a critical role in microRNA (miRNA) biogenesis. DICER1 contains two catalytic ribonuclease domains: RNase IIIa and RNase IIIb, which cleave the bound precursor miRNA to generate 3p and 5p strands, respectively, of the miRNA. One strand is loaded into the RNA-induced silencing complex to mediate gene silencing. Germline loss-of-function (LOF) mutations in DICER1 are associated with DICER1-related tumor predisposition (DRTP), a rare hereditary tumour predisposition syndrome affecting mainly children and young adults. DRTP is associated with a broad spectrum of benign and malignant tumors, including pleuropulmonary blastoma (PPB), Sertoli-Leydig cell tumors, and aggressive sarcomas at multiple sites, the most common being gynecological and intra-cranial. Unlike the classical Knudson two-hit model involving biallelic inactivation, DRTP tumors typically carry a germline LOF mutation with a hotspot somatic missense mutation in the RNase IIIb catalytic domain. These somatic mutations affecting residues (e.g. D1709, E1813) selectively disrupt cleavage of 5p miRNAs, while preserving most 3p miRNA production. This creates an miRNA imbalance marked by depletion of 5p miRNAs, including tumor suppressors such as the let-7 family, which contributes to oncogenesis. We examined the effects of two of these variants using Dicer1-floxed mouse mesenchymal stem cells: the canonical RNase IIIb mutant E1813K and the non-canonical RNase IIIa mutant S1344L, which also impairs RNase IIIb activity. We show that while both variants impair 5p miRNA production and enhance 3p miRNA levels, S1344L affects only a subset of 5p miRNAs. Consistent with their differential effects on 5p miRNA production, E1813K and S1344L induce partially overlapping gene expression changes relative to wild-type DICER1 cells. When compared with a DICER1 mutant–initiated pituitary blastoma, we identify a discrete set of stabilized mRNAs, many of which promote cell proliferation. Conversely, several mRNAs encoding pro-apoptotic factors exhibit reduced stability in DICER1 mutant cells. One of the most aggressive DRTP cancers is primary intracranial sarcoma (PIS), which lacks effective therapies. Using a longitudinal primary and recurrent DRTP PIS patient tumour pair, we characterize elevated expression of myogenic transcription factor MYOD1 and concomitant downregulation of neural gene signatures in recurrent PIS. We also establish patient-derived xenograft (PDX) and primary cell models of DRTP PIS, that recapitulate human tumor biology. We demonstrate that inhibitors of MEK and CDK4/6 strongly suppressed tumour growth of DRTP PIS PDXs and induced upregulation of genes associated with neuronal differentiation. Our results suggest that disrupted neural differentiation program is associated with DRTP PIS progression and inhibition of MEK and CDK4/6 can be used to induce neural differentiation and suppress growth of DRTP PIS. Taken together, these studies have begun to identify the key pathways and vulnerabilities that characterise tumors that arise in DRTP. William D. Foulkes, Anne-Laure Chong, Hannah D. Hosein, Anais Gagne, Sidong Huang, Marc R. Fabian. DICER1-related tumor predisposition: genotypes, phenotypes and mechanisms [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr IA003.