Tracing the molecular route to progression in miRNA biogenesis-defective thyroid lesions [miRNA_profiling_data]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE301150 | GEO | 2025/12/10
REPOSITORIES: GEO
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Project description:Germline and somatic alterations in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignant transformation remain unclear. We trace the molecular trajectories from benignity to malignancy in DICER1/DGCR8-mutated thyroid lesions using multi-omic profiling on 27 DICER1/DGCR8-mutated samples. Our findings reveal a progressive, specific, and linear accumulation of genetic alterations, which when combined with enhanced downregulation of miRNAs distinguished DICER1/DGCR8-malignant lesions from their benign counterparts. Compensatory hypomethylation of miRNA encoding genes characterised DICER1/DGCR8-benign lesions, but as the tumors progressed to malignancy, methylation was partly reimposed, reversing the attempts to activate miRNA-encoded genes and further compromising miRNA production. Transcriptomic analyses revealed mutation-specific effects on the microenvironment, whereby DICER1 mutations activated canonical thyroid cancer progression pathways, whereas altered DGCR8 associated with immune-related alterations. This work unveils specific molecular events underlying malignant progression of miRNA-biogenesis related thyroid tumors and identifies potential biomarkers and disease etiology mechanisms.
2025-12-10 | GSE300956 | GEO
Project description:Germline and somatic alterations in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignant transformation remain unclear. We trace the molecular trajectories from benignity to malignancy in DICER1/DGCR8-mutated thyroid lesions using multi-omic profiling on 27 DICER1/DGCR8-mutated samples. Our findings reveal a progressive, specific, and linear accumulation of genetic alterations, which when combined with enhanced downregulation of miRNAs distinguished DICER1/DGCR8-malignant lesions from their benign counterparts. Compensatory hypomethylation of miRNA encoding genes characterised DICER1/DGCR8-benign lesions, but as the tumors progressed to malignancy, methylation was partly reimposed, reversing the attempts to activate miRNA-encoded genes and further compromising miRNA production. Transcriptomic analyses revealed mutation-specific effects on the microenvironment, whereby DICER1 mutations activated canonical thyroid cancer progression pathways, whereas altered DGCR8 associated with immune-related alterations. This work unveils specific molecular events underlying malignant progression of miRNA-biogenesis related thyroid tumors and identifies potential biomarkers and disease etiology mechanisms.
2025-12-10 | GSE301163 | GEO
Project description:Background: Fine needle aspiration biopsy (FNAB) is the gold-standard procedure for diagnosing malignant thyroid nodules. Indeterminate cytology is identified in 10-40% of cases and molecular testing may guide management in this setting. Current commercial options are expensive, and are either sensitive or specific. The aim of this study was to utilize next generation sequencing (NGS) technology to identify informative diversities in the microRNA (miRNA) expression profile of benign versus malignant thyroid nodules. Methods: Ex-vivo FNAB samples were obtained from thyroid specimens of patients that underwent thyroidectomy at a referral center. miRNA levels were determined using NGS and multiplexing technologies. Statistical analyses identified differences between normal and malignant samples and miRNA expression profiles that associate with malignancy were established. The accuracy of the miRNA signature in predicting histological malignancy was validated using a group of patient specimens with indeterminate cytology results. Results: 274 samples were obtained from 102 patients undergoing thyroidectomy. Of these samples, 71% were benign and 29% were malignant. Nineteen miRNAs were identified as statistically different between benign and malignant samples and were used to classify 35 additional nodules with indeterminate cytology (validation). The miRNA panel’s sensitivity, specificity, negative and positive predictive values and overall accuracy were 91%, 100%, 87%, 100% and 94%, respectively. Conclusion: Using NGS technology we identified a panel of 19 miRNAs that may be utilized to distinguish benign from malignant thyroid nodules with indeterminate cytology. Impact: Our panel may classify indeterminate thyroid nodules at higher accuracy than commercially available molecular tests.
2018-12-21 | GSE116196 | GEO
Project description:Thyroid cancer is a common endocrine malignancy; however, its diagnosis is not straightforward. The current gold standard for diagnosing thyroid cancer is fine needle aspiration biopsy (FNAB), but when cytological analysis does not provide viable results or samples belong to less defined categories of diagnosis, patients are often referred to diagnostic surgery. Given that not all these nodules require removal, nor all of them are malignant, patients would not necessarily require surgery had the initial FNAB diagnosis been more conclusive. There is therefore a lack of reliable and specific biomarkers for thyroid cancer malignancy, that can complement and improve the current diagnosing methods. “Omics” approaches have gained much attention in the last decade in the field of biomarker discovery for diagnostic and prognostic characterization of various pathophysiological conditions. In this project, proteomics and metabolomics approaches were applied to the same thyroid nodules from patients with benign and malignant lesions. Tissue analysis provided several interesting biomarkers by both proteomics and metabolomics. The combination of these results demonstrated the high energetic and biomass demand of cancer cells, as well as a biomarker panel including 2 free peptides and 2 proteins with high sensitivity and specificity. Together, these results have contributed to increasing the knowledge of thyroid cancer phenotype and corresponding biochemical profiles, as well as providing potential biomarkers for malignancy, and improving diagnostic methodologies.
2023-10-24 | PXD035583 | Pride
Project description:Although most thyroid tumours are benign, thyroid cancer represents the most common malignancy of the endocrine system, comprising mainly follicular and papillary thyroid carcinomas (FTC and PTC, respectively). Previous studies have shed some light on the molecular pathogenesis of thyroid cancer but there have not been any comprehensive mass spectrometry-based proteomic studies to reveal protein expression differences between thyroid tumours and the molecular alterations associated with tumour malignancy. We applied a label-free quantitative mass spectrometry analysis to compare normal thyroid tissue with the three most common tumours of the thyroid gland: follicular adenoma, follicular carcinoma and papillary carcinoma.
2017-05-03 | PXD002732 | Pride
Project description:Well-differentiated tumours (WDT) of the thyroid gland can be difficult to diagnose. Focal nuclear clearing can be suggestive of a papillary thyroid carcinoma (PTC), while questionable vascular or capsular penetration may raise the possibility of diagnosis of a follicular thyroid carcinoma (FTC). The recently proposed term “thyroid tumours of uncertain malignant potential” (TT-UMP) defines cases showing inconclusive morphological evidence of malignancy. We use microRNA (miRNA) expression profiling to analyze 42 well differentiated thyroid tumours including 7 follicular tumours of uncertain malignant potential (FT-UMP), 6 well differentiated tumours of uncertain malignant potential (WDT-UMP), 7 follicular thyroid adenomas (FTA), 5 follicular variant of papillary thyroid carcinoma (FV-PTC) 6 follicular thyroid carcinoma (FTC), and 11 conventional papillary thyroid carcinoma (C-PTC) with 6 C-PTC mutated for BRAFV600E (C-PTC-mut) and 5 not mutated: wild type (C-PTC-wt). Comparison of these 13 tumours of uncertain malignant potential (7 FT-UMP and 6 WDT-UMP) with those obtained from 16 PTC (11 C-PTC and 5 FV-PTC), 6 FTC and 7 FTA is performed in order to clarify the relationships between TT-UMP and the morphologically well characterized categories of thyroid tumours (i.e. C-PTC, FV-PTC, FTC and FTA). In first, each pathological sample (“L” for Lesional tissue) is compared with its matched control (“S” for Safe tissue) for the 42 patients (84 miRNA microarray slides). This control was taken from the same patient at a large distance from the tumour. Secondly, the perilesional tissue from the same patients but 2 (1 PTC and 1 adenoma, without enough RNA left) is compared to normal thyroid tissue (safe tissue reference) obtained from a patient who underwent total thyroidectomy for a laryngeal carcinoma that partially invaded the thyroid gland, to search for microRNA signatures of perilesional tissues (80 miRNA microarray slides).Experiments is performed with a miRNA microarray, referenced in GEO under the accession number GPL4717 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GPL4717). 42 Patients: 7 FT-UMP, 6 WDT-UMP, 7 FTA (+1 duplicate sample), 5 FV-PTC, 6 FTC (+ 2 duplicate samples), and 11 C-PTC. 44 dye-swap pairs and 1 with no dye swap pair for a total of 89 samples.
2011-08-21 | E-GEOD-15740 | biostudies-arrayexpress
Project description:Well-differentiated tumours (WDT) of the thyroid gland can be difficult to diagnose. Focal nuclear clearing can be suggestive of a papillary thyroid carcinoma (PTC), while questionable vascular or capsular penetration may raise the possibility of diagnosis of a follicular thyroid carcinoma (FTC). The recently proposed term “thyroid tumours of uncertain malignant potential” (TT-UMP) defines cases showing inconclusive morphological evidence of malignancy. We use microRNA (miRNA) expression profiling to analyze 42 well differentiated thyroid tumours including 7 follicular tumours of uncertain malignant potential (FT-UMP), 6 well differentiated tumours of uncertain malignant potential (WDT-UMP), 7 follicular thyroid adenomas (FTA), 5 follicular variant of papillary thyroid carcinoma (FV-PTC) 6 follicular thyroid carcinoma (FTC), and 11 conventional papillary thyroid carcinoma (C-PTC) with 6 C-PTC mutated for BRAFV600E (C-PTC-mut) and 5 not mutated: wild type (C-PTC-wt). Comparison of these 13 tumours of uncertain malignant potential (7 FT-UMP and 6 WDT-UMP) with those obtained from 16 PTC (11 C-PTC and 5 FV-PTC), 6 FTC and 7 FTA is performed in order to clarify the relationships between TT-UMP and the morphologically well characterized categories of thyroid tumours (i.e. C-PTC, FV-PTC, FTC and FTA). In first, each pathological sample (“L” for Lesional tissue) is compared with its matched control (“S” for Safe tissue) for the 42 patients (84 miRNA microarray slides). This control was taken from the same patient at a large distance from the tumour. Secondly, the perilesional tissue from the same patients but 2 (1 PTC and 1 adenoma, without enough RNA left) is compared to normal thyroid tissue (safe tissue reference) obtained from a patient who underwent total thyroidectomy for a laryngeal carcinoma that partially invaded the thyroid gland, to search for microRNA signatures of perilesional tissues (80 miRNA microarray slides).Experiments is performed with a miRNA microarray, referenced in GEO under the accession number GPL4717 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GPL4717).
2011-08-22 | GSE15740 | GEO
Project description:PURPOSE: Thyroid cancer is frequently difficult to diagnose due to an overlap of cytological features between malignant and benign nodules. This overlap leads to unnecessary removal of the thyroid in patients without cancer. While providing some improvement over cytopathologic diagnostics, molecular methods frequently fail to provide a correct diagnosis for thyroid nodules. These approaches are based on the difference between malignant nodules and normal adjacent thyroid tissue and assume that normal thyroid tissues are the same as benign nodules. However, in contrast to normal thyroid tissues, benign thyroid nodules can contain genetic alterations that can be found in cancerous nodules. PATIENTS AND METHODS: For the development of a new molecular diagnostic test for thyroid cancer, we evaluated DNA methylation in 109 thyroid tissues by using genome wide single base resolution DNA methylation analysis (Reduced Representation Bisulfite Sequencing). The test was validated in the retrospective cohort containing 64 thyroid nodules. RESULTS: By conducting Reduced Representation Bisulfite Sequencing in 109 thyroid specimens, we found significant differences between normal tissue, benign nodules, and cancer. Based on tissue-specific epigenetic signatures for benign and malignant nodules, we developed a new epigenetic approach for thyroid diagnostics. According to the validation cohort, our test has an estimated specificity of 97% (95% CI, 80 to 100), sensitivity of 100% (95% CI, 86 to 100), PPV of 97% (95% CI, 82-100), NPV of 100% (95%, 85 to 100). CONCLUSION: These data show that epigenetic testing can provide outstanding diagnostic accuracy for thyroid nodules by evaluating tissue specific DNA methylation.
2018-11-30 | GSE107738 | GEO
Project description:BACKGROUND: Following fine needle aspiration, 15-30% of thyroid nodules are not clearly benign or malignant. These cytologically indeterminate nodules are often referred for diagnostic surgery, though most prove benign. A novel diagnostic test measuring the expression of 167 genes has shown promise in improving pre-operative risk assessment. We evaluated this test in a prospective, multicenter study. METHODS: Over 19 months, we performed a prospective study at 49 clinical sites enrolling 3,789 patients and collecting 4,812 samples from thyroid nodules >1cm requiring evaluation. We obtained 577 cytologically indeterminate aspirates with corresponding histopathology of excised lesions on 413. Central blinded histopathologic review served as the reference (“gold”) standard. After applying inclusion criteria, gene expression classifier results were obtained for 265 indeterminate nodules used in this analysis, and performance was calculated. RESULTS: 85 of 265 indeterminate nodules were malignant. The gene expression classifier correctly identified 78 of 85 as ‘suspicious’ (92% sensitivity, [84%-97%] 95% CI). Specificity was 52%, [44%-59%]. The negative predictive value was 95%, 94%, and 85%, respectively, for aspirates with AUS/FLUS, FN/SFN, or ‘suspicious’ cytology. Analysis of 7 false negative cases revealed 6 with a paucity of thyroid follicular cells, suggesting that insufficient sampling of the nodule had occurred. CONCLUSIONS: Though individualized clinical care is recommended, these data support consideration of a conservative approach for most patients with indeterminate FNA cytology and benign gene expression classifier results. 265 cytologically indetermine samples, 47 cytologically benign and 55 cytologically malignant samples
2012-06-24 | E-GEOD-34289 | biostudies-arrayexpress
Project description:DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and attenuating aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its miRNA-processing activity, which is mediated by its C-terminal domains. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1 Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathologically and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA processing-independent role for DGCR8 in maintaining heterochromatin organization and attenuating senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
2019-05-28 | PXD013856 | Pride