ETA2024 Oral Presentations Oral Session 9: Basic thyroid cancer research (5 abstracts)
Tracing the molecular route to progression in defective mirna biogenesis benign vs malignant thyroid lesions
Anne-Sophie Chong 1 , Paula Morales 2 , Carla Roca 3 , Eduard Dorca 4 , Luis Javier Leandro-Garcia 5 , Jonathan Wasserman 6 , Marc Pusztaszeri 7 , Pablo Valderrabano Herrero 8 , Giovana Tardin Torrezan 9 , Xavier Matias-Guiu 10 , Clara Álvarez Villamarín 11 , William Foulkes 12 , Eduardo Andrés 13 , Paula Casano 14 & Barbara Rivera 3
1Idibell, Hereditary Cancer Program, L’hospitalet de Llobregat, Barcelona, Spain; 2University of Barcelona, Department of Biomedicine, Faculty of Medicine, Barcelona, Spain; 3Bellvitge Biomedical Research Institute (Idibell), Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), and Hereditary Cancer Program at Ico-Idibell, L’hospitalet de Llobregat, Barcelona, Spain; 4Bellvitge Universitary Hospital, Pathology Department, L’hospitalet de Llobregat, Barcelona, Spain; 5Spanish National Cancer Research Centre (Cnio), Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Madrid, Spain; 6Hospital for Sick Children, University of Toronto, Division of Endocrinology, Department of Pediatrics, Toronto, Ontario, Canada; 7Jewish General Hospital, McGill University, Department of Pathology, Montreal, Quebec, Canada; 8Hospital Universitario Ramón Y Cajal, Irycis, Department of Endocrinology and Nutrition, Madrid, Spain; 9A.C. Camargo Cancer Center, Clinical and Functional Genomics Group, International Research Center/Cipe, São Paulo, Brazil; 10Hereditary Cancer Program, Catalan Institute of Oncology, Idibell-Igtp-Idibgi, L’hospitalet de Llobregat, Badalona, Girona, Spain, Spain; 11Centro de Investigación En Medicina Molecular Y Enfermedades Crónicas (Cimus), University of Santiago de Compostela, Instituto de Investigación Sanitaria (Idis), Neoplasia & Endocrine Differentiation, Santiago de Compostela, Spain; 12McGill University, Montreal, Quebec, Canada; 13Instituto de Parasitología Y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas, Pts Granada and Ciberonc (Instituto de Salud Carlos Iii), Granada, Spain; 14Pediatric Research Institute Sant Joan de Déu, University of Barcelona, Endocrinology Department, Barcelona, Spain
Alterations in DICER1 and DGCR8 have been observed in benign thyroid manifestations, well-differentiated and recently reported in poorly-differentiated thyroid cancers (PDTC). The involvement of 2 miRNA biogenesis genes in benign and malignant thyroid tumors highlights the key role of miRNAs in the thyroid gland.
Objectives: To determine the deregulated miRNAs involved in benign and malignant thyroid tumors associated with miRNA biogenesis defects and pinpoint key effectors in tumor progression.
Methods: We genotyped hotspot mutations in 4 miRNA-processing genes in 66 pediatric and 385 adult thyroid lesions. Combining newly identified cases with previous in-house cases, whole exome sequencing (WES) (n = 18), miRNA profiling (n = 38) and/or methylome was performed in benign and malignant DICER1-/DGCR8-mutated cases. Shared miRNA profiles of DICER1- and DGCR8-mutated cases were interrogated and profiles unique to benign or malignant samples were determined. The spatial transcriptome of 1 DICER1 and 1 DGCR8 case with different histological components was profiled.
Results: We found DICER1 mutations in 9 samples (1 adult, 8 pediatric). No alteration in other miRNA biogenesis genes was detected. WES of DICER1-/DGCR8-mutated samples denoted the classical mutually exclusive pattern with alterations in canonical thyroid cancer (TC) driver genes while demonstrating a putative mutational route to progression. Interrogation of miRNA expression profiles across DICER1-/DGCR8-mutated and control cases encompassing 5 histological subtypes revealed 36 differentially expressed (DE) miRNAs shared by DICER1-/DGCR8-mutated TCs and 2 DE miRNAs shared by benign thyroid lesions highlighting 34 miRNAs unique to the malignant status. Pathway analyses of the predicted miRNA targets of DICER1-/DGCR8-mutated TCs showed an association with known cancer signaling (MAPK, TGFβ) and cell cycle pathways, which were not observed in DICER1-/DGCR8-mutated benign lesions. Spatial transcriptomics analysis showed larger differences in the stroma of the mutated cases than in the thyroid follicular cells. Pathways associated with angiogenesis, dedifferentiation and Notch and Hedgehog signaling were upregulated in DICER1-PDTC stroma. DGCR8-FND and DGCR8-microPTC showed less remarkable differences between their stromal and epithelial components.
Conclusion: DICER1 alterations were more prevalent in children and seen in a wide variety of histological subtypes, highlighting the importance of uncovering DICER1 syndrome patients. DGCR8 mutations are rare in both pediatric and adult cohorts. Moreover, a novel mutational landscape of progression was observed in DGCR8 cases. DICER1-/DGCR8-mutated TCs showed an effect on known TC signaling (despite the lack of MAPK alterations in DICER1-mutated cases) and cell cycle pathways, DICER1-/DGCR8-mutated benign lesions did not. Spatial transcriptomics analysis showed larger differences in the stroma of the mutated cases than in the thyroid follicular cells.
Volume 101
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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