Tracing the molecular route to progression in miRNA-biogenesis-defective thyroid lesions.
Anne-Sophie Chong, Carla Roca, Paula Morales-Sánchez, Eduard Dorca, Verónica Barea, Ignacio Ruz-Caracuel, Pablo Valderrabano, Carlota Rovira, Cristina Jou, Dorothée Bouron-Dal Soglio, Rebecca D Chernock, Giovana T Torrezan, Marc Pusztaszeri, José M Cameselle-Teijeiro, Xavier Matias-Guiu, Clara V Alvarez, Héctor Salvador, Jonathan D Wasserman, Luis Javier Leandro-García, William D Foulkes, Eduardo Andrés-León, Paula Casano-Sancho, Barbara Rivera
Journal: JCI insight
2026;11(3):
PMID: 41657311
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.
Address:
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.; 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.; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.; Pathology Department, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain.; Genetics and Genomics, Faculty of Biology, University of Barcelona, Barcelona, Spain.; 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.; Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.; Department of Pathology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.; Centre Hospitalier Universitaire Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, Canada.; Department of Pathology and Immunology, and.; Department of Otolaryngology Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.; Clinical and Functional Genomics Group, International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, Brazil.; Department of Pathology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.; 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.; Department of Pathology, Hospital Universitari Arnau de Vilanova, Universitat de Lleida, IRBLLEIDA, Lleida, Spain.; Neoplasia & Endocrine Differentiation P0L5, Centre for Research in Molecular Medicine and Chronic Disease (CIMUS), Santiago de Compostela, Spain.; Department of Oncology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.; Division of Endocrinology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Department of Human Genetics, and.; Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada.; Bioinformatics Unit, Institute of Parasitology and Biomedicine López-Neyra (IPBLN), CSIC, Granada, Spain.; 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.; 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.
MeSH Terms:
Ribonuclease III,
MicroRNAs,
Humans,
DEAD-box RNA Helicases,
Thyroid Neoplasms,
RNA-Binding Proteins,
Disease Progression,
Gene Expression Regulation, Neoplastic,
Mutation,
Thyroid Gland,
Female,
Gene Expression Profiling,
DNA Methylation,
Male
