| Autor: |
Condello, Vincenzo, Poma, Anello M, Macerola, Elisabetta, Vignali, Paola, Paulsson, Johan O, Zedenius, Jan, Basolo, Fulvio, Juhlin, C Christofer |
| Předmět: |
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| Zdroj: |
Journal of Clinical Endocrinology & Metabolism; Jul2024, Vol. 109 Issue 7, p1733-1744, 12p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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