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

Abstract

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. Design 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<0.0001). Conclusions 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.

Whole-genome Sequencing of Follicular Thyroid Carcinomas Reveal Recurrent Mutations in MicroRNA Processing Subunit DGCR8

“…Therefore, it is possible that the DGCR8 mutation found in these tumors influenced the tumor progression or invasive behavior without driving the tumor formation per se. However, recent studies have found recurrent DICER1 mutations in various forms of thyroid cancer, of which most cases did not display established driver-gene alterations, vaguely suggesting that aberrant miRNA expressional patterns could be at play even at the level of tumor initiation ( 58 , 59 ).…”

Circulating microRNAs and Clinicopathological Findings of Papillary Thyroid Cancer: A Systematic Review

“…The DICER1 mutated thyroid tumors in both adult and pediatric patients have been shown by several groups to be mutually exclusive of any of the well-known driver mutations of thyroid cancer (including BRAF and RAS among others). This provides evidence that DICER1 mutation can be a driver of thyroid tumor development (76,77) and establishes another link between miRNA dysregulation and thyroid cancer. Furthermore, the role of DICER1 down-regulation and subsequently miRNA dysregulation has been shown in vitro.…”

Molecular testing in fine‐needle aspiration of thyroid nodules

“…100 In adults, DICER1 alterations are found in approximately 1% of indeterminate thyroid nodules. 101 2.9.1 | MicroRNA alterations MicroRNAs (miRNAs) are small, single-stranded, and noncoding RNA molecules. These molecules regulate genes at the posttranscriptional level and are part of the RNA-induced silencing complex; downregulating the expression of other genes by increasing degradation of the target transcript or inhibiting translation.…”

“…In a cohort of 15 patients with FTC less than 20 years old, 8 patients had DICER1 mutations; DICER1 alterations were found in co‐occurring nodular hyperplasia and follicular adenomas 100 . In adults, DICER1 alterations are found in approximately 1% of indeterminate thyroid nodules 101 …”