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

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.

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

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.

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.

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.