Tracing the molecular route to progression in miRNA-biogenesis-defective thyroid lesions

Abstract

Germline and somatic changes in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignant transformation remain unclear. We trace the molecular trajectories from benignity to malignancy in DICER1- and DGCR8-mutated thyroid lesions using multiomic profiling on over 30 DICER1-/DGCR8-mutated samples. Our findings reveal a progressive, specific, and linear accumulation of genetic changes, which when combined with enhanced downregulation of miRNAs distinguished DICER1-/DGCR8-malignant lesions from their benign counterparts. Compensatory hypomethylation of miRNA-encoding genes characterized DICER1-/DGCR8-benign lesions, but as the tumors progressed to malignancy, methylation was partly reimposed, reversing the attempts to activate miRNA-encoded genes and further compromising miRNA production. Transcriptomic analyses revealed mutation-specific effects on the microenvironment, whereby DICER1 mutations activated canonical thyroid cancer progression pathways, whereas altered DGCR8 associated with immune-related changes. This work unveils specific molecular events underlying malignant progression of miRNA-biogenesis-related thyroid tumors and identifies potential biomarkers and disease etiology mechanisms.

Fundación Científica Asociación Española Contra el Cáncer (AECC) (grant LABAE235269RIVE) to BR. • Fundación Mutua Madrileña (grant AP173972020) to BR. • Fundación La Marató de TV3 (grant 202031-10) to BR. • Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (grant 2021 SGR 01066) to BR. • Instituto de Salud Carlos III (ISCIII) and the European Social Fund: Investing in Your Future (grant CP21/00038) to BR. • “La Caixa” Foundation (ID 100010434) fellowship LCF/BQ/DI21/11860051 to ASC. • Agencia Estatal de Investigación (grant PID2022-140149OB-I00) to CVA and to the TIROCHUS collection [Rnb code: ISCIII-BIO-2012/000026]). • ISCIII (grant PI23/00722) to JMCT. • Fundação de Amparo à Pesquisa do Estado de São Paulo (grants 2018/06269-5 and 2020/00870-9) to GTT. • Comunidad de Madrid (funding for the iTIRONET Consortium [P2022/BMD7379], of which LJLG, PV, and IRC are members).