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Prevalence, Molecular Landscape, and Clinical Impact of DICER1 and DGCR8 Mutated Follicular-Patterned Thyroid Nodules
Vincenzo Condello1, Anello M Poma2, Elisabetta Macerola2
1Department of Oncology-Pathology, Karolinska Institutet, 171 64 Stockholm, Sweden.
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.
Insights
Mutations in micro-RNA (miRNA) regulators DICER1 and DGCR8 are rare in follicular thyroid tumors (FTs). DICER1-mutant FTs showed a distinct miRNA profile and lacked other driver events, unlike DGCR8 mutations which can co-occur with RAS mutations.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- Mutations in micro-RNA (miRNA) regulators DICER1 and DGCR8 are implicated in thyroid tumor development.
- The frequency and impact of these mutations in follicular thyroid tumors (FTs) remain unclear.
Purpose of the Study:
- To determine the frequency of DICER1 and DGCR8 hotspot mutations in FTs.
- To investigate the relationship between these mutations and other driver gene events.
- To characterize the miRNA expression profile in mutant FTs.
Main Methods:
- Sanger sequencing of 440 FTs for DICER1, DGCR8, and RAS mutations.
- Whole-exome sequencing for additional driver gene identification in mutant cases.
- miRNA expression profiling and quantitative RT-PCR validation.
- Analysis of The Cancer Genome Atlas (TCGA) database.
Main Results:
- DICER1 and DGCR8 hotspot mutations were found in 3.2% and 1% of FTs, respectively.
- Two DGCR8-mutant cases also had RAS mutations; no other driver events were found in DICER1/DGCR8-mutant cases.
- Mutant cases exhibited a unique miRNA dysregulation pattern, with DICER1-mutant tumors showing reduced 5' arm miRNAs.
Conclusions:
- DICER1 and DGCR8 hotspot mutations are infrequent in unselected FTs.
- Mutated cases display a specific miRNA signature.
- DICER1 variants are associated with distinct molecular features, while DGCR8 mutations can coexist with RAS alterations.
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