Somatic DICER1 Mutations in Benign Adult Thyroid Nodules: Persistent Follicular Growth

Overview

Somatic DICER1 hotspot mutations were identified in 13 benign thyroid nodules among 931 adult-onset cases, all classified as thyroid follicular nodular disease (TFND). These DICER1-mutant nodules demonstrated continuous growth, with longer duration nodules showing significant enlargement and increased follicular activity in organoid cultures.

Background

DICER1 encodes an endoribonuclease critical for microRNA maturation, with germline mutations linked to familial multinodular goiter (MNG) and differentiated thyroid carcinoma. While somatic DICER1 mutations have been reported in pediatric and adult thyroid nodules, their prevalence and characteristics in non-MNG benign nodules remain unclear. Understanding the molecular and pathological features of these mutations is important for elucidating their role in thyroid follicular cell biology and nodule behavior.

Data Highlights

Key Findings

• Somatic DICER1 hotspot mutations combined with truncating variants were found in benign thyroid nodules classified as TFND.
• 38.5% of DICER1-mutant nodules exhibited significant growth, with nodules present for over 2 years showing greater enlargement.
• DICER1-mutant TFND nodules grew faster than wild-type DICER1 nodules.
• Organoid cultures from DICER1-mutant nodules showed increased active follicular formation.
• Transcriptomic analysis revealed higher MAPK pathway activity and lower epithelial-mesenchymal transition scores compared to normal thyroid tissue.
• Genes related to follicular polarity and thyroid function (CDH16, SLC5A5, TSHR, TPO) were downregulated in DICER1-mutant nodules.

Clinical Implications

Somatic DICER1 mutations define a subset of benign thyroid nodules with persistent growth and distinct molecular features, suggesting these nodules represent a unique follicular nodular condition. Recognition of this mutation pattern may inform surveillance strategies, as these nodules can enlarge over time despite benign pathology. Molecular testing for DICER1 mutations could aid in risk stratification and management decisions in adult patients with thyroid nodules.

Conclusion

Somatic DICER1 2-hit mutations are present in a notable fraction of adult benign thyroid nodules, characterized by continuous growth and altered follicular biology. These findings expand understanding of thyroid nodule pathogenesis and highlight the importance of molecular profiling in benign thyroid disease.

References

1. Foulkes et al. 2011 -- DICER1 mutations linked to familial multinodular goiter
2. WHO Classification of Thyroid Neoplasms 2022
3. Study Source -- Somatic Mutations in DICER1 Found in Benign Thyroid Nodules of Adults