Tracing the molecular route to progression in miRNA-biogenesis-defective thyroid lesions
Por:
Chong AS, Roca C, Morales-Sánchez P, Dorca E, Barea V, Ruz-Caracuel I, Valderrabano P, Rovira-Zurriaga C, Jou-Munoz C, Bouron-Dal Soglio D, Chernock RD, Torrezan GT, Pusztaszeri M, Cameselle-Teijeiro JM, Matias-Guiu X, Alvarez CV, Salvador-Hernandez H, Wasserman JD, Leandro-García LJ, Foulkes WD, Andrés-León E, Casano-Sancho P and Rivera B
Publicada:
9 feb 2026
Ahead of Print:
9 feb 2026
Resumen:
Germline and somatic changes in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignanttransformation 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.
Filiaciones:
Chong AS:
Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
Genetics Program, Faculty of Biology, and
Roca C:
Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
Morales-Sánchez P:
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
Dorca E:
Pathology Department, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain
Barea V:
Genetics and Genomics, Faculty of Biology, University of Barcelona, Barcelona, Spain
Ruz-Caracuel I:
Ramón y Cajal Health Research Institute (IRYCIS), Ramón y Cajal University Hospital, CIBERONC, Madrid, Spain
Department of Pathology, Ramón y Cajal University Hospital, Madrid, Spain
Valderrabano P:
Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain
Rovira-Zurriaga C:
Department of Pathology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Jou-Munoz C:
Department of Pathology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Bouron-Dal Soglio D:
Centre Hospitalier Universitaire Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, Canada
Chernock RD:
Department of Pathology and Immunology, and
Department of Otolaryngology Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
Torrezan GT:
Clinical and Functional Genomics Group, International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, Brazil
Pusztaszeri M:
Department of Pathology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
Cameselle-Teijeiro JM:
Department of Pathology, Clinical University Hospital of Santiago de Compostela, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain
Matias-Guiu X:
Department of Pathology, Hospital Universitari Arnau de Vilanova, Universitat de Lleida, IRBLLEIDA, Lleida, Spain
Alvarez CV:
Neoplasia & Endocrine Differentiation P0L5, Centre for Research in Molecular Medicine and Chronic Disease (CIMUS), Santiago de Compostela, Spain
Salvador-Hernandez H:
Department of Oncology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Wasserman JD:
Division of Endocrinology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Leandro-García LJ:
Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Foulkes WD:
Department of Human Genetics, and
Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
Andrés-León E:
Bioinformatics Unit, Institute of Parasitology and Biomedicine López-Neyra (IPBLN), CSIC, Granada, Spain
Casano-Sancho P:
Pediatric Endocrinology Department, Institut de Recerca Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
Rivera B:
Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
Green Submitted, gold
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