Prevalence, Molecular Landscape, and Clinical Impact of DICER1 and DGCR8 Mutated Follicular-Patterned Thyroid Nodules.
J Clin Endocrinol Metab
; 109(7): 1733-1744, 2024 Jun 17.
Article
em En
| MEDLINE
| ID: mdl-38252873
ABSTRACT
BACKGROUND:
Mutations in micro-RNA (miRNA) regulators DICER1 and DGCR8 have recently been uncovered, revealing a potential novel mechanism driving thyroid tumor development. However, the true frequency of these hotspot mutations in follicular-patterned thyroid tumors (FTs) and their relation to established driver gene events remain elusive.METHODS:
A total of 440 FTs from 2 institutions were interrogated for DICER1, DGCR8, and RAS family hotspot mutations using Sanger sequencing. Whole-exome sequencing was also performed to identify additional driver gene aberrations in DICER1/DGCR8-mutant cases. Subsets of cases were further analyzed using miRNA expression profiling, and key dysregulated miRNAs were validated as markers of DICER1 mutations using quantitative RT-PCR analysis. The Cancer Genome Atlas (TCGA) database was also probed for DICER1/DGCR8 mutations and miRNA dysregulation.RESULTS:
Fourteen (3.2%) and 4 (1%) FTs harbored DICER1 and DGCR8 hotspot mutations, respectively, in the combined cohort, and no cases with normal tissue available were found to exhibit a constitutional variant. Two DGCR8-mutant cases also harbored oncogenic RAS mutations. Whole-exome sequencing analysis did not identify additional driver gene events in DICER1/DGCR8-positive cases. Comprehensive miRNA expression profiling revealed a unique pattern of dysregulated miRNAs in DICER1/DGCR8-mutant cases compared with wild-type lesions. Moreover, DICER1-mutant cases showed a remarkable reduction of 5' arm miRNAs, findings corroborated in the TCGA cohort.CONCLUSION:
DICER1 and DGCR8 hotspot mutations are rare in unselected cohorts of FTs, and mutated cases exhibit a specific miRNA profile. Although DGCR8 mutations may coexist with established RAS gene alterations, FTs with DICER1 variants were devoid of other driver gene events.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Nódulo da Glândula Tireoide
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Proteínas de Ligação a RNA
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MicroRNAs
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Ribonuclease III
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RNA Helicases DEAD-box
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Mutação
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article