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

## TL;DR

This study traces how genetic and epigenetic changes drive the progression from benign to malignant thyroid tumors in patients with mutations in DICER1 or DGCR8.

## Contribution

The study reveals a linear accumulation of genetic changes and epigenetic shifts that distinguish malignant from benign miRNA-biogenesis-defective thyroid lesions.

## Key findings

- DICER1-/DGCR8-malignant lesions show progressive genetic changes and enhanced miRNA downregulation.
- Compensatory hypomethylation in benign lesions reverses as tumors progress to malignancy.
- DICER1 mutations affect thyroid cancer pathways, while DGCR8 mutations influence immune-related changes.

## 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.

Multiomic analysis in DICER1/DGCR8-thyroid lesions depicts the benign to malignant progression route at the genomic, miRNAomic, and transcriptional levels and identify an epi-signature of DICER1-cancers.