The following is a summary of “Prevalence, Molecular Landscape, and Clinical Impact of DICER1 and DGCR8 Mutated Follicular-Patterned Thyroid Nodules,” published in the July 2024 issue of Endocrinology by Condello, et al.

Recent studies have identified mutations in the micro-RNA (miRNA) regulators DICER1 and DGCR8 as potential novel mechanisms driving the development of thyroid tumors. However, the actual prevalence of these hotspot mutations in follicular-patterned thyroid tumors (FTs) and their relationship with established driver gene mutations remain unclear.

A total of 440 FTs from two institutions were examined for hotspot mutations in DICER1, DGCR8, and the RAS family through Sanger sequencing. Additionally, whole-exome sequencing was utilized to uncover further driver gene mutations in cases with DICER1/DGCR8 mutations. Subsets of these cases underwent miRNA expression profiling, with key dysregulated miRNAs validated as markers of DICER1 mutations using quantitative RT-PCR. The Cancer Genome Atlas (TCGA) database was also explored for mutations in DICER1/DGCR8 and associated miRNA dysregulation.

Among the 440 FTs studied, 14 cases (3.2%) had DICER1 hotspot mutations, and 4 cases (1%) had DGCR8 hotspot mutations. Notably, none of the cases with available normal tissue showed a constitutional variant. Two DGCR8-mutant FTs also contained oncogenic RAS mutations. Whole-exome sequencing revealed no additional driver gene mutations in DICER1/DGCR8-positive tumors. Comprehensive miRNA expression profiling disclosed a distinct pattern of dysregulated miRNAs in DICER1/DGCR8-mutant FTs compared to wild-type FTs. DICER1-mutant cases exhibited a significant reduction in 5′ arm miRNAs, a finding that was consistent with observations from the TCGA cohort.

DICER1 and DGCR8 hotspot mutations are infrequent in unselected cohorts of follicular-patterned thyroid tumors, with DICER1 and DGCR8 mutations presenting a unique miRNA expression profile. While DGCR8 mutations may occur alongside RAS gene mutations, tumors with DICER1 mutations do not show other driver gene alterations.

Reference: academic.oup.com/jcem/article/109/7/1733/7585177