Somatic DICER1-Mutant Benign Thyroid Nodules in Adults: A Group of Follicular Nodular Disease With Continuous Growth.

Context: Germline DICER1 mutations cause familial multinodular goiter (MNG). However, the prevalence of somatic DICER1 mutations in non-MNG benign thyroid nodules and their characteristics remain unknown.

Objective: To determine the prevalence of somatic DICER1-mutant non-MNG benign thyroid nodules and their clinicopathological, molecular, behavioral and transcriptional characteristics.

Methods: Adult-onset thyroid nodules with a pathological diagnosis were genotyped via targeted sequencing. DICER1-mutant nodules were assessed clinically and pathologically. Organoids were established to investigate follicular formation and growth. Transcriptomic analysis was conducted to evaluate transcriptional features, which were validated by immunofluorescence.

Results: Among 931 adult-onset thyroid nodules, we identified 13 benign thyroid nodules with DICER1 hotspot mutations. The majority harbored a somatic DICER1 hotspot mutation with a somatic DICER1 truncating variant. Clinically, 38.5% of the DICER1-mutant nodules exhibited substantial growth. DICER1-mutant nodules with durations longer than 2 years were substantially enlarged (P = .0448). Pathologically, all DICER1-mutant nodules were defined as thyroid follicular nodular disease (TFND). The TFND nodules with DICER1 mutations grew faster than those with wild-type DICER1. Organoid culture of a DICER1-mutant nodule revealed increased active follicular formation. Compared with the normal thyroid tissues, the DICER1-mutant nodules had similar thyroid differentiation scores, significantly higher extracellular signal-related kinase scores (P = .0141) and lower epithelial-mesenchymal transition scores (P = .0001). Moreover, the expression of genes related to follicular polarity, such as CDH16, SLC5A5, TSHR, and TPO, was downregulated in the DICER1-mutant nodules.

Conclusion: Somatic DICER1 2-hit mutations represent a notable percentage in adult patients with TFND, and DICER1-mutant benign thyroid nodules were characterized by continuous growth.