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

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 thy...

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Detalles Bibliográficos
Autores: Chong, Anne Sophie, Roca, Carla, Morales Sánchez, Paula, Dorca, Eduard, Barea, Verónica, Ruz Caracuel, Ignacio, Valderrabano, Pablo, Rovira, Carlota, Jou, Cristina, Bouron Dal Soglio, Dorothée, Chernock, Rebecca, Torrezan, Giovana, Pusztaszeri, Marc, Cameselle Teijeiro, José, Matias-Guiu, Xavier, Alvarez, Clara, Salvador, Héctor, Wasserman, Jonathan, Leandro García, Luis Javier, Foulkes, William, Andrés León, Eduardo, Casano Sancho, Paula, Rivera, Barbara
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2026
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/469745
Acceso en línea:https://doi.org/10.1172/jci.insight.198338
https://hdl.handle.net/10459.1/469745
Access Level:acceso abierto
Palabra clave:Endocrinology
Genetics
Oncology
RNA processing
Thyroid disease
Transcriptomics
Descripción
Sumario: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.

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