Integrated data analysis reveals distinct drivers and pathways disrupted by DNA methylation in papillary thyroid carcinomas
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE86961 | GEO | 2017/05/04
SECONDARY ACCESSION(S): PRJNA343092
REPOSITORIES: GEO
Similar Datasets
Project description:Mice with thyroid-specific expression of oncogenic BRAF (Tg-Braf) develop papillary thyroid cancers (PTC) that are locally invasive and have well-defined foci of poorly differentiated thyroid carcinoma (PDTC). To investigate the PTC-PDTC progression, we performed a microarray analysis using RNA from paired samples of PDTC and PTC collected from the same animals by laser capture microdissection. Analysis of 8 paired samples revealed a profound deregulation of genes involved in cell adhesion and intracellular junctions, with changes consistent with an epithelial-mesenchymal transition (EMT). This was confirmed by IHC, as vimentin expression was increased and E-cadherin lost in PDTC compared to adjacent PTC. Moreover, PDTC stained positively for phospho-Smad2, suggesting a role for transforming growth factor-beta (TGFbeta) in mediating this process. Accordingly, TGFbeta induced EMT in primary cultures of thyroid cells from Tg-Braf mice, whereas wild-type thyroid cells retained their epithelial features. TGFbeta-induced Smad2 phosphorylation, transcriptional activity and induction of EMT required MAPK pathway activation in Tg-Braf thyrocytes. Hence, tumor initiation by oncogenic BRAF renders thyroid cells susceptible to TGFbeta-induced EMT, through a MAPK-dependent process. Comparing the transcription profiles of 8 pairs of murine poorly differentiated thyroid cancer and papillary thyroid cancer collected from the same animals by laser capture microdissection. Co-hybridizations were done in triplicate with a single dye flip.
2011-03-22 | E-GEOD-27668 | biostudies-arrayexpress
Project description:BackgroundPapillary thyroid carcinoma (PTC) is a common endocrine neoplasm with a recent increase in incidence in many countries. Although PTC has been explored by gene expression and DNA methylation studies, the regulatory mechanisms of the methylation on the gene expression was poorly clarified. In this study, DNA methylation profile (Illumina HumanMethylation 450K) of 41 PTC paired with non-neoplastic adjacent tissues (NT) was carried out to identify and contribute to the elucidation of the role of novel genic and intergenic regions beyond those described in the promoter and CpG islands (CGI). An integrative and cross-validation analysis were performed aiming to identify molecular drivers and pathways that are PTC-related.ResultsThe comparisons between PTC and NT revealed 4995 methylated probes (88% hypomethylated in PTC) and 1446 differentially expressed transcripts cross-validated by the The Cancer Genome Atlas data. The majority of these probes was found in non-promoters regions, distant from CGI and enriched by enhancers. The integrative analysis between gene expression and DNA methylation revealed 185 and 38 genes (mainly in the promoter and body regions, respectively) with negative and positive correlation, respectively. Genes showing negative correlation underlined FGF and retinoic acid signaling as critical canonical pathways disrupted by DNA methylation in PTC. BRAF mutation was detected in 68% (28 of 41) of the tumors, which presented a higher level of demethylation (95% hypomethylated probes) compared with BRAF wild-type tumors. A similar integrative analysis uncovered 40 of 254 differentially expressed genes, which are potentially regulated by DNA methylation in BRAFV600E-positive tumors. The methylation and expression pattern of six selected genes (ERBB3, FGF1, FGFR2, GABRB2, HMGA2, and RDH5) were confirmed as altered by pyrosequencing and RT-qPCR.ConclusionsDNA methylation loss in non-promoter, poor CGI and enhancer-enriched regions was a significant event in PTC, especially in tumors harboring BRAFV600E. In addition to the promoter region, gene body and 3'UTR methylation have also the potential to influence the gene expression levels (both, repressing and inducing). The integrative analysis revealed genes potentially regulated by DNA methylation pointing out potential drivers and biomarkers related to PTC development.
| S-EPMC5414166 | biostudies-literature
Project description:RNA-Sequencing analysis of 18 papillary thyroid carcinoma biopsies and of 4 healthy donors' thyroids. In this analysis we assessed differential gene expression and investigated the mutational landscape in this tumor type. Analysis of gene fusion was also performed, leading to the identification of a novel chimeric transcript, potential driver in tumor initiation. Total RNA isolated from 18 papillary thyroid carcinoma biopsies and 4 healthy donors' thyroids.
2015-05-01 | E-GEOD-64912 | biostudies-arrayexpress
Project description:CONTEXT: BRAF V600E mutation (BRAF-mut.) confers aggressiveness in papillary thyroid carcinoma, but unidentified genomic abnormalities may be required for full phenotypic expression. OBJECTIVE: To perform deep sequencing to identify genes differentially expressed between BRAF-mut. and BRAF-wild-type (BRAF-WT) tumors, and to compare to patient clinical status. DESIGN: BRAF-mut. and BRAF-WT tumors were identified in patients with T1N0 and with T23N1 tumors. Expression levels of genes were determined from RNA sequencing (RNA-Seq) data and fusion transcripts were detected. NanoString was used to validate the RNA-Seq data for immune genes. SETTING: Patients were seen at two sites of a major referral medical center. PATIENTS: Twenty patients were studied. BRAF-mut. patients included 9 women, 3 men; 9 were TNM stage I and 3 were stage III; 3 (25%) had lymphocytic thyroiditis. BRAF-WT included 5 women; 3 men; all were stage I; 5 (62.5%) had lymphocytic thyroiditis. RESULTS: 560 of 13,085 genes were differentially expressed by RNA-Seq, and MetaCore analysis identified 55 immune function genes that were differentially expressed as a function of BRAF mutational status. Immune function genes were broadly underexpressed in BRAF-mut. tumors, with only 4 genes (HLA-G, CXCL14, TIMP1, IL1RAP) more highly expressed. NanoString validated the RNA Seq data for immune genes. Eleven high confidence fusion transcripts were detected, four being inter-chromosomal and seven intra-chromosomal. CONCLUSION: BRAF-mut. papillary thyroid cancers have less expression of immune and inflammatory response genes than BRAF-WT tumors. Thirteen of 20 (65%) tumors had between one and three fusion transcripts. Functional studies will be required to determine the potential role of the newly identified genomic abnormalities in contributing to the aggressiveness of BRAF-mut. and wild-type tumors. RNA-seq was performed on 20 thyroid carcinoma tumors
2015-07-01 | E-GEOD-48953 | biostudies-arrayexpress
Project description:We profiled the gene expression of 11 anaplastic thyroid carcinomas (ATC), 49 papillary thyroid carcinomas (PTC) and 45 normal thyroids (N)
2012-11-09 | GSE33630 | GEO
Project description:RNA-Sequencing analysis of 18 papillary thyroid carcinoma biopsies and of 4 healthy donors' thyroids. In this analysis we assessed differential gene expression and investigated the mutational landscape in this tumor type. Analysis of gene fusion was also performed, leading to the identification of a novel chimeric transcript, potential driver in tumor initiation.
2015-05-01 | GSE64912 | GEO
Project description:To investigate the effects of combined BRAF inhibition (dabrafenib) and ERK inhibition (ulixertinib) on papillary and anaplastic thyroid cancer transcriptional reprogramming
2023-06-15 | GSE221329 | GEO
Project description:We profiled the gene expression of 11 anaplastic thyroid carcinomas (ATC), 49 papillary thyroid carcinomas (PTC) and 45 normal thyroids (N) We hibridized a series of anaplastic thyroid carcinomas (ATC) and papillary thyroid carcinomas (PTC) onto Affymetrix U133 Plus 2.0 arrays. ATCs were obtained from different hospitals in France and Belgium. Paired RNA samples of PTCs and non-tumoral thyroid tissues were obtained from Ukraine via the Chernobyl Tissue Bank (www.chernobyltissuebank.com). Diagnoses were confirmed by the members of the International Pathology Panel of the Chernobyl Tissue Bank.
2012-11-09 | E-GEOD-33630 | biostudies-arrayexpress
Project description:CONTEXT: BRAF V600E mutation (BRAF-mut.) confers aggressiveness in papillary thyroid carcinoma, but unidentified genomic abnormalities may be required for full phenotypic expression. OBJECTIVE: To perform deep sequencing to identify genes differentially expressed between BRAF-mut. and BRAF-wild-type (BRAF-WT) tumors, and to compare to patient clinical status. DESIGN: BRAF-mut. and BRAF-WT tumors were identified in patients with T1N0 and with T23N1 tumors. Expression levels of genes were determined from RNA sequencing (RNA-Seq) data and fusion transcripts were detected. NanoString was used to validate the RNA-Seq data for immune genes. SETTING: Patients were seen at two sites of a major referral medical center. PATIENTS: Twenty patients were studied. BRAF-mut. patients included 9 women, 3 men; 9 were TNM stage I and 3 were stage III; 3 (25%) had lymphocytic thyroiditis. BRAF-WT included 5 women; 3 men; all were stage I; 5 (62.5%) had lymphocytic thyroiditis. RESULTS: 560 of 13,085 genes were differentially expressed by RNA-Seq, and MetaCore analysis identified 55 immune function genes that were differentially expressed as a function of BRAF mutational status. Immune function genes were broadly underexpressed in BRAF-mut. tumors, with only 4 genes (HLA-G, CXCL14, TIMP1, IL1RAP) more highly expressed. NanoString validated the RNA Seq data for immune genes. Eleven high confidence fusion transcripts were detected, four being inter-chromosomal and seven intra-chromosomal. CONCLUSION: BRAF-mut. papillary thyroid cancers have less expression of immune and inflammatory response genes than BRAF-WT tumors. Thirteen of 20 (65%) tumors had between one and three fusion transcripts. Functional studies will be required to determine the potential role of the newly identified genomic abnormalities in contributing to the aggressiveness of BRAF-mut. and wild-type tumors.
2015-07-01 | GSE48953 | GEO
Project description:Mice with thyroid-specific expression of oncogenic BRAF (Tg-Braf) develop papillary thyroid cancers (PTC) that are locally invasive and have well-defined foci of poorly differentiated thyroid carcinoma (PDTC). To investigate the PTC-PDTC progression, we performed a microarray analysis using RNA from paired samples of PDTC and PTC collected from the same animals by laser capture microdissection. Analysis of 8 paired samples revealed a profound deregulation of genes involved in cell adhesion and intracellular junctions, with changes consistent with an epithelial-mesenchymal transition (EMT). This was confirmed by IHC, as vimentin expression was increased and E-cadherin lost in PDTC compared to adjacent PTC. Moreover, PDTC stained positively for phospho-Smad2, suggesting a role for transforming growth factor-beta (TGFbeta) in mediating this process. Accordingly, TGFbeta induced EMT in primary cultures of thyroid cells from Tg-Braf mice, whereas wild-type thyroid cells retained their epithelial features. TGFbeta-induced Smad2 phosphorylation, transcriptional activity and induction of EMT required MAPK pathway activation in Tg-Braf thyrocytes. Hence, tumor initiation by oncogenic BRAF renders thyroid cells susceptible to TGFbeta-induced EMT, through a MAPK-dependent process.
2011-03-23 | GSE27668 | GEO