Integration of miRNA, mRNA and methylation profiling reveals genes aberrantly regulated associated to RETM918T mutation in Medullary Thyroid Carcinoma
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ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE72730 | GEO | 2016/12/31
SECONDARY ACCESSION(S): PRJNA294771
REPOSITORIES: GEO
Similar Datasets
Project description:Medullary thyroid carcinoma (MTC) accounts for 1-2% of thyroid malignancies. It is a disease of few genetic drivers, and the etiology specifically associated with each mutation remains unknown. Here, we investigated the role of aberrant DNA methylation in the MTC development. We performed genome-wide DNA methylation profiling assessing >27,000 CpGs in the largest MTC series reported to date, comprising 48 molecularly characterized tumors. We observed significant differences between the methylation patterns among the samples bearing the RETM918T, RETC634 mutation and “wild-type” (WT) tumors, but not those RAS-related. In detail, the RETM918T –related tumors had a larger number of hypomethylation events when compared to RETC634 – positive and WT ones. Moreover, through the integration of methylation with mRNA and miRNA expression data of the same tumors, we identified genes whose expression is negatively correlated with the methylation status of their promoters. For PLCB2, DKK4, MMP20 as well as miR-10a, -30a and -200c, the impact of promoter methylation levels on expression of these genes in MZ-CRC-1 and TT cell lines was assessed. Finally, the aberrant methylation validation of three of the genes in an independent set of 25 MTCs by bisulfite pyrosequencing suggests their role as MTC methylation markers.
2016-12-31 | GSE72728 | GEO
Project description:Medullary thyroid carcinoma (MTC) accounts for 1-2% of thyroid malignancies. It is a disease of few genetic drivers, and the etiology specifically associated with each mutation remains unknown. Here, we investigated the role of aberrant DNA methylation in the MTC development. We performed genome-wide DNA methylation profiling assessing >27,000 CpGs in the largest MTC series reported to date, comprising 48 molecularly characterized tumors. We observed significant differences between the methylation patterns among the samples bearing the RETM918T, RETC634 mutation and “wild-type” (WT) tumors, but not those RAS-related. In detail, the RETM918T –related tumors had a larger number of hypomethylation events when compared to RETC634 – positive and WT ones. Moreover, through the integration of methylation with mRNA and miRNA expression data of the same tumors, we identified genes whose expression is negatively correlated with the methylation status of their promoters. For PLCB2, DKK4, MMP20 as well as miR-10a, -30a and -200c, the impact of promoter methylation levels on expression of these genes in MZ-CRC-1 and TT cell lines was assessed. Finally, the aberrant methylation validation of three of the genes in an independent set of 25 MTCs by bisulfite pyrosequencing suggests their role as MTC methylation markers.
2016-12-31 | GSE72729 | GEO
Project description:Integration of miRNA, mRNA and methylation profiling reveals genes aberrantly regulated associated to RETM918T mutation in Medullary Thyroid Carcinoma
| PRJNA294771 | ENA
Project description:Multiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The RETK666N DNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown.The clinical features, genetic data, and family information of eight index MTC patients with a germline RETK666N variant were assessed.Four probands presented with MTC and extensive nodal metastasis, one with biopsy-confirmed distant metastasis. Two additional probands presented with localized disease. However, nodal status was not available. Of the final two probands, one had an incidental 1.5?mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had two foci of MTC (largest dimension 2.3?cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (aged 5-90 years), 11 of whom have documented evaluation for MTC. Of these, only two were found to have elevated basal serum calcitonin upon screening, and the remaining patients had calcitonin levels within the reference range. One patient who elected to have a thyroidectomy at 70 years of age was confirmed to have MTC. The other subject, 57 years old, elected surveillance. Four prophylactic thyroidectomies were performed, with one case of C-cell hyperplasia at 20 years and three cases that revealed normal pathology at ages 21, 30, and 30 years. None of the K666N DNA variant carriers had evidence of primary hyperparathyroidism or pheochromocytoma.From this case series, the largest such experience to date, it is concluded that the RETK666N variant is likely pathogenic and associated with low penetrance of MTC. However, the findings are insufficient to define its pathogenicity clearly and make firm recommendations for screening and treatment. Given the potential benefit associated with early detection of aberrant C-cell growth, and the noninvasive nature of genetic testing, "at risk" individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.
| S-EPMC5175438 | biostudies-literature
Project description:This study aims to investigate the microRNA profile in human medullary carcinoma tissue by microarray analysis and RT-qPCR. Matched tumor and adjacent normal tissue were obtained from 24 patients and analysed using human microRNA Microarray Kit Agilent, Differentially expressed miRNAs were validated by RT-qPCR using 37 other tumors samples (validation set), Associations of microRNA expression with clinicopathological items were studied
2014-12-15 | GSE40807 | GEO
Project description:This study aims to investigate the microRNA profile in human medullary carcinoma tissue by microarray analysis and RT-qPCR. Matched tumor and adjacent normal tissue were obtained from 24 patients and analysed using human microRNA Microarray Kit Agilent, Differentially expressed miRNAs were validated by RT-qPCR using 37 other tumors samples (validation set), Associations of microRNA expression with clinicopathological items were studied Matched tumor and adjacent normal frozen tissues were obtained from thyroid of 40 patients. Normal tissue (name with suffix S) and lesionnal tissue (name with suffix L) were hybridized on microarray.
2014-12-15 | E-GEOD-40807 | biostudies-arrayexpress
Project description:The current focus in the treatment of papillary thyroid carcinoma (PTC) is tumor progression. The aim of this study was to build RNA-based classifiers and develop a comprehensive model to provide progression-free interval (PFI) risk prediction for PTC. The RNAseq data, miRNAseq data, and clinical information of PTC were downloaded from The Cancer Genome Atlas database. Based on the differently expressed RNAs, the least absolute shrinkage and selection operator (LASSO) Cox regression model was utilized to build the RNA-based classifiers for PFI of the patients with PTC. A 6-messenger RNA (mRNA)-based classifier, a 5-long non-coding RNA (lncRNA)-based classifier, and a 4-microRNA (miRNA)-based classifier were constructed to predict the PFI. Patients with high risk based on the constructed RNA-based classifiers had worse prognosis in Kaplan-Meier curve analysis with log-rank test. The areas under the curves of the first, third, and fifth years in the training and testing set were 0.83, 0.82, and 0.82 and 0.67, 0.72, and 0.73 for the 6-mRNA-based classifier, respectively; 0.75, 0.84, and 0.85 and 0.71, 0.67, and 0.71 for the 5-lncRNA-based classifier, respectively; and 0.70, 0.77, and 0.79 and 0.74, 0.67, and 0.66 for the 4-miRNA-based classifier, respectively. The prediction capability of the three RNA-based classifiers was superior to the TNM stage system. Furthermore, a nomogram based on the verified independent prognostic factors was established for the prognostic prediction. The C-index and calibration plots indicated good predictive accuracy of the nomogram. In summary, the 6-mRNA-based classifier and 5-lncRNA-based classifier constructed in this study were independent prognostic factors for PTC.
| S-EPMC7417634 | biostudies-literature
Project description:Pycnodysostosis is a rare autosomal recessive skeletal dysplasia caused by a mutation in the cathepsin K encoded by cathepsin K gene (CTSK). Medullary thyroid carcinoma (MTC) is also a relatively rare type of primary thyroid carcinoma.A 31-year-old woman presenting a short stature and a palpable nodule in the front of her neck that had gradually increased in size during the last 2 years was referred to our department. She has experienced multiple fractures at lower limbs in the last 2 decades.The patient's clinical examination revealed short stature, underweight, a prominent forehead, stubby fingers, and a fixed nodule in the right thyroid lobe. Intraoral examination revealed multiple clinically malposed and missing teeth, as well as chronic periodontitis with a narrow and grooved palate. Radiographic examination revealed typical widely separated cranial sutures and an open anterior/posterior fontanel with an obtuse gonial angle, acroosteolysis, and osteosclerosis with narrowed medullary cavities. Ultrasonography of the thyroid gland showed a marked hypoechoic solid nodule in the right lobe in which tumor cell clusters were confirmed by ultrasound-guided fine needle aspiration biopsy and was suspected to be MTC. Laboratory tests revealed dramatically elevated serum calcitonin >2000?pg/L (reference range: 0-5?pg/L) and carcinoembryonic antigen (CEA) 134.37?ng/mL (reference range: 0-5?ng/mL). Genotypic screening revealed compound heterozygous mutations in the CTSK gene (c.158delA, P.Asn53Thr/c.C830T, P.Ala277Val) but no mutation associated with the familial forms of MTC.The patient underwent a total thyroidectomy with right-sided functional neck dissection.CEA and serum calcitonin decreased significantly postthyroidectomy, and no further fracture has been reported by the patient so far.The present study is the first to report a rare case of the coexistence of pycnodysostosis with a compound CTSK gene mutation and sporadic MTC. Radiological techniques and gene analysis play key roles in the definitive diagnosis.
| S-EPMC5815678 | biostudies-literature
Project description:In the "personalized medicine" era, one of the most difficult problems is identification of combined markers from different omics platforms. Many methods have been developed to identify candidate markers for each type of omics data, but few methods facilitate the identification of multiple markers on multi-omics platforms. microRNAs (miRNAs) is well known to affect only indirectly phenotypes by regulating mRNA expression and/or protein translation. To take into account this knowledge into practice, we suggest a miRNA-mRNA integration model for survival time analysis, called mimi-surv, which accounts for the biological relationship, to identify such integrated markers more efficiently. Through simulation studies, we found that the statistical power of mimi-surv be better than other models. Application to real datasets from Seoul National University Hospital and The Cancer Genome Atlas demonstrated that mimi-surv successfully identified miRNA-mRNA integrations sets associated with progression-free survival of pancreatic ductal adenocarcinoma (PDAC) patients. Only mimi-surv found miR-96, a previously unidentified PDAC-related miRNA in these two real datasets. Furthermore, mimi-surv was shown to identify more PDAC related miRNAs than other methods because it used the known structure for miRNA-mRNA regularization. An implementation of mimi-surv is available at http://statgen.snu.ac.kr/software/mimi-surv.
| S-EPMC8276759 | biostudies-literature
Project description:Medullary thyroid cancer (MTC) accounts for less than 5% of all thyroid cancers, and it is a rare neuroendocrine tumor which derives from calcitonin-secreting thyroid C cells.Given the underlying mechanism involved in MTC remain unclear, the development and the specific pathways of MTC require further investigation.here we employed the application of TMT6plex-based LC-MS/MS to identify and analyze the novel differentially-expressed proteins(DEPs) from MTC patients, To our best knowledge, it is the first study to comprehensively investigate the molecular mechanisms of MTC by proteomics technology from Chinese MTC patients’ tissues, and these DEPs identified in our study will provide a better understanding of the underlying pathophysiology of MTC, as well as may provide potential therapeutic targets for patients with MTC.
2020-05-26 | PXD005898 | Pride