JCI insight · 2026
Tracing the molecular route to progression in miRNA-biogenesis-defective thyroid lesions.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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 D, Torrezan Giovana T, Pusztaszeri Marc, Cameselle-Teijeiro José M, Matias-Guiu Xavier, Alvarez Clara V, Salvador Héctor, Wasserman Jonathan D, Leandro-García Luis Javier, Foulkes William D, Andrés-León Eduardo, Casano-Sancho Paula, Rivera Barbara
Аннотация
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.