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
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
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Research Article Endocrinology Genetics Oncology

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

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.

Authors

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

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Figure 1

Landscape of DICER1- and DGCR8-mutated thyroid lesions.

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Landscape of DICER1- and DGCR8-mutated thyroid lesions. (A) Molecular la...
(A) Molecular landscape of DICER1- and DGCR8-altered thyroid lesions showing MAPK pathway– or thyroid cancer progression–associated changes and recurrent copy number changes. Benign thyroid lesions (BTLs) harbored DICER1 or DGCR8 changes. In well-differentiated thyroid cancers (WDTCs) and poorly differentiated thyroid carcinomas (PDTCs), DICER1 mutations were mutually exclusive from MAPK gene changes, occasionally co-occurring with TP53 mutations. DGCR8-altered cancers co-occurred with MAPK pathway mutations. Both DICER1- and DGCR8-mutated thyroid cancers lacked TERT promoter changes as well as the most prevalent RET fusions (RET-PTC1 and RET-PTC3). All FVPTCs are invasive encapsulated FVPTCs (IEFVPTC) with the exception of TCGA-EL-A3D5-01, which showed follicular-patterned areas, but could not be classified as IEFVPTC or infiltrative FVPTC due to limited histological material. LoF, loss-of-function; LOH, loss of heterozygosity; VUS, variant of uncertain significance, TFND, follicular nodular disease; FTA, follicular adenoma; FTC, follicular thyroid cancer; FVPTC, follicular variant of papillary thyroid cancer; CPTC, classic papillary thyroid cancer. ‡, †, and § show sets of 2 different lesions from a single patient; #TFND with incidental microPTC; *Case IDs from Chernock et al. (12). (B) In the germline DICER1 context, a truncating variant is followed by a somatic RNase IIIb hotspot mutation, leading to BTL formation. In sporadic cases, a somatic RNase IIIb hotspot occurs first, followed by loss of the WT allele (truncating or LOH), sufficient for BTL development. In both contexts, BTLs progress to cancer in the absence of other changes and may progress to more aggressive cancer types (PDTC) via (a) TP53 mutation or (b) without further changes. (C) In the germline DGCR8 context, a missense c.1552G>A, p.E518K hotspot mutation is followed by LOH or truncation of the WT allele, forming a BTL. This BTL may acquire MAPK (BRAF, RAS) or PI3K (PIK3CA) mutations for malignant transformation. In sporadic cases, the same sequence of DGCR8 events occurs, followed by MAPK/PI3K changes during progression to cancer.