Prevalence and Spectrum of DICER1 Mutations in Adult-onset Thyroid Nodules with Indeterminate Cytology

Context: DICER1 mutations are found in multinodular goiter and differentiated thyroid carcinoma in children, and can be a manifestation of DICER1 syndrome, but the prevalence of DICER1 mutations and their significance in adult-onset thyroid nodules is unknown.

Objective: Determine (1) the prevalence of DICER1 hotspot mutations in thyroid nodules; (2) the frequency of a second DICER1 pathogenic variant in thyroid nodules with DICER1 hotspot mutations; (3) the prevalence of other thyroid cancer driver mutations in thyroid nodules with and without DICER1 hotspot mutations.

Methods: Population-based study of 14 993 consecutive fine needle aspiration biopsies of thyroid nodules evaluated by ThyroSeq v3. From 214 DICER1 hotspot-positive cases, we selected 61, matched to DICER1 hotspot-negative nodules. We performed full sequencing of all exons and exon-intron boundaries of DICER1.

Setting: Commercial and university-based laboratories in the United States and Canada.

Results: Among 14 993 thyroid nodules, 214 (1.4%) revealed a DICER1 hotspot mutation. A second pathogenic/likely pathogenic variant in DICER1 was found in 45/59 (76%) DICER1 hotspot-positive nodules studied while no other DICER1 variant was identified in the DICER1 hotspot-negative group by full DICER1 sequencing. Other alterations in thyroid-related genes were significantly more frequent in DICER1 hotspot-negative nodules (32/61) than in DICER1 hotspot--positive nodules (4/59) (P < .0001).

Conclusion: DICER1 alterations occur in a proportion of adult thyroid nodules and appear mutually exclusive with alterations in other thyroid cancer-related genes. DICER1 hotspot mutations occur with a second hit in most cases and could suggest occult DICER1 syndrome in adults with thyroid nodules.