Gene expression data from GIST with KIT mutation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE20708 | GEO | 2010/08/27
SECONDARY ACCESSION(S): PRJNA129573
REPOSITORIES: GEO
Similar Datasets
Project description:In addition to KIT and PDGFRA mutations, sequential accumulation of other genetic events is involved in the development and progression of gastrointestinal stromal tumors (GISTs). Until recently, the significance of these other alterations has not been thoroughly investigated. The combination of gene expression profiling and high-resolution genomic copy number analysis offers a detailed molecular portrait of GISTs, providing an essential comprehensive knowledge necessary to guide the discovery of novel target genes involved in tumor development and progression. Fresh tissue specimens from 25 patients with GIST were collected and high-resolution genomic copy number analyses were performed using Affymetrix SNP array 6.0. GIST tumor samples from mutated (KIT or PDGFRA) or Wild Type patients were labeled for hybridization on Affymetrix microarrays. Copy number analysis of Affymetrix SNP6.0 arrays was performed for 25 GIST samples, then compared to gene expression data.
2010-08-27 | E-GEOD-20709 | biostudies-arrayexpress
Project description:In addition to KIT and PDGFRA mutations, sequential accumulation of other genetic events is involved in the development and progression of gastrointestinal stromal tumors (GISTs). Until recently, the significance of these other alterations has not been thoroughly investigated. The combination of gene expression profiling and high-resolution genomic copy number analysis offers a detailed molecular portrait of GISTs, providing an essential comprehensive knowledge necessary to guide the discovery of novel target genes involved in tumor development and progression. Fresh tissue specimens from 25 patients with GIST were collected and high-resolution genomic copy number analyses were performed using Affymetrix SNP array 6.0.
2010-08-27 | GSE20709 | GEO
Project description:In contrast to the paucity of clinic GIST (Gastrointestinal stromal tumor; 0.0014 % happening rate), there is a more than twenty thousand times higher rate for miniGISTs, about ~30% of human population could be identified to have miniGISTs. Exploring the molecular differences between miniGISTs and overt GISTs will help us to understand the transformation mechanisms along with GIST progression, but C-kit and PDGFRA mutations analysis failed to identify the differences between these two groups. Conclusion: miniGISTs have significant distinct gene expression profile with overt GISTs by both unsupervised and supervised analysis. Our finding indicated that c-kit and DOG1 expression are the very early events in the genesis of miniGIST and overt GIST, and miniGIST is a molecular distinct group with overt GIST. Within our study, we collected six miniGISTs with diameter less than 1cm from autopsies and seven overt GISTs from clinic, performed the first system-wide gene expression profiling of miniGISTs and overt GISTs by 3’end RNA Sequencing, and further compared the expression profiles between these two groups.
2014-12-25 | E-GEOD-52666 | biostudies-arrayexpress
Project description:In contrast to the paucity of clinic GIST (Gastrointestinal stromal tumor; 0.0014 % happening rate), there is a more than twenty thousand times higher rate for miniGISTs, about ~30% of human population could be identified to have miniGISTs. Exploring the molecular differences between miniGISTs and overt GISTs will help us to understand the transformation mechanisms along with GIST progression, but C-kit and PDGFRA mutations analysis failed to identify the differences between these two groups. Conclusion: miniGISTs have significant distinct gene expression profile with overt GISTs by both unsupervised and supervised analysis. Our finding indicated that c-kit and DOG1 expression are the very early events in the genesis of miniGIST and overt GIST, and miniGIST is a molecular distinct group with overt GIST.
2014-12-25 | GSE52666 | GEO
Project description:Activating mutation of KIT is well known as a key molecular event for the development of gastrointestinal stromal tumors(GISTs). Dysregulation of microRNAs(miRNA) might elucidate KIT mutation, KIT overexpression and the resulting tumorigenesis in GIST. Herein we identified miRNA expression profiles that associated with KIT mutation and KIT overexpression in GIST by miRNA microarrays and Real-time PCR in GISTs. The potentially target genes of selected miRNAs were analyzed by bioinformatic techniques with GO and KEGG pathway analysis. We showed that 6 miRNAs were differentially expressed in CD117IHC+/KITmutant GISTs compared to CD117IHC-/wild-type GISTs. Of these, 2 miRNAs including miR-483-3p and miR-589 were up-regulated, while the other 4 miRNAs including miR-140-5p, miR-148b-3p, miR-1587 and miR-4507 were down-regulated. GO and KEGG analysis demonstrated that miRNAs with significant change were involved in regulation of target genes related to the development of GIST. Among the candidate miRNAs studied, miR-148b-3p and miR-140-5p may be involved in GIST tumorigenesis via targeting mutant KIT or via intermediate molecules of PDGFRA, PI3K-AKT and MAPK pathway, such as AKT2, MAPK1, MAPK10, STAT5A, SMAD4, SMAD5 and PTEN. Furthermore, the reduced expression of miR-140-5p and miR-148b-3p were inversely correlated with high-risk grade, recurrence and metastasis of GIST. The current findings indicated that miR-148b-3p and miR-140-5p were not only involved in tumorigenesis of GIST, but might also participate in the progression of GIST and could be considered as novel biomarkers for potentially predicting the prognosis of GIST.
2018-04-25 | GSE73346 | GEO
Project description:Background & Aims: In gastrointestinal stromal tumors (GIST) KIT exon 11 deletions are associated with poor prognosis. The aim of this study was to determine the gene expression profile of GIST carrying KIT exon 11 deletions and to identify genes associated with poor prognosis. Methods: Expression profiling was performed on 9 tumors with KIT exon 11 deletions and 7 without KIT exon 11 mutations using oligonucleotide microarrays. In addition, gene expression profiles for 35 GISTs were analysed by meta-analysis. Differentially expressed genes were identified and confirmed by qPCR. Expression of CD133 (prominin-1) protein (AC133) was also examined by tissue microarray (TMA) analysis of 204 GISTs from a population-based study in Western Sweden. Survival analysis was performed using Cox regression model. Results: Gene expression profiling, meta-analysis and qPCR demonstrated up-regulation of the stem cell marker CD133 in GIST carrying KIT exon 11 deletions. Immunohistochemical analysis on TMA confirmed CD133 expression in 28% of all tumors. CD133 positivity was frequent in gastric GIST (48%) versus small intestinal GIST (4%). CD133 positivity was also frequent in GIST with KIT exon 11 mutations (41%) compared to tumors with mutations in KIT exon 9, PDGFRA, or wild-type tumors (0-17%). There was no significant correlation between CD133 staining and NIH risk score. Survival analysis demonstrated significant correlation between presence of CD133 and shorter overall survival. Conclusions: The stem cell marker CD133 is expressed in a subset of predominantly gastric GIST with KIT exon 11 mutations and associated with poor prognosis. Tumors with and without KIT exon 11 deletion were compared using a common reference design.
2010-06-30 | E-GEOD-14755 | biostudies-arrayexpress
Project description:Background & Aims: In gastrointestinal stromal tumors (GIST) KIT exon 11 deletions are associated with poor prognosis. The aim of this study was to determine the gene expression profile of GIST carrying KIT exon 11 deletions and to identify genes associated with poor prognosis. Methods: Expression profiling was performed on 9 tumors with KIT exon 11 deletions and 7 without KIT exon 11 mutations using oligonucleotide microarrays. In addition, gene expression profiles for 35 GISTs were analysed by meta-analysis. Differentially expressed genes were identified and confirmed by qPCR. Expression of CD133 (prominin-1) protein (AC133) was also examined by tissue microarray (TMA) analysis of 204 GISTs from a population-based study in Western Sweden. Survival analysis was performed using Cox regression model. Results: Gene expression profiling, meta-analysis and qPCR demonstrated up-regulation of the stem cell marker CD133 in GIST carrying KIT exon 11 deletions. Immunohistochemical analysis on TMA confirmed CD133 expression in 28% of all tumors. CD133 positivity was frequent in gastric GIST (48%) versus small intestinal GIST (4%). CD133 positivity was also frequent in GIST with KIT exon 11 mutations (41%) compared to tumors with mutations in KIT exon 9, PDGFRA, or wild-type tumors (0-17%). There was no significant correlation between CD133 staining and NIH risk score. Survival analysis demonstrated significant correlation between presence of CD133 and shorter overall survival. Conclusions: The stem cell marker CD133 is expressed in a subset of predominantly gastric GIST with KIT exon 11 mutations and associated with poor prognosis.
2010-06-30 | GSE14755 | GEO
Project description:Context: Gastrointestinal stromal tumors (GISTs) harboring mutations in the PDGFRA gene occur in only about 5–7% of patients. The most common PDGFRA mutation is exon 18 D842V, which is corre-lated with specific clinico-pathological features compared to the other PDGFRA mutated GISTs. Herein, we present a miRNA expression profile comparison of PDGFRA D842V mutant GISTs and PDGFRA with mutations other than D842V (non-D842V). miRNA expression profiling was carried out on 10 patients using a TLDA miRNA array. Then, miRNA expression was followed by bioinformatic analysis aimed at evaluating differential expression, pathway enrichment, and miRNA-mRNA networks. We highlighted 24 differentially expressed miRNAs between D842V and non-D842V GIST patients. Pathway enrichment analysis showed that deregulated miRNAs targeted genes that are mainly involved in the immune response pathways. The miRNA-mRNA networks highlighted a signature of miRNAs/mRNA that could explain the indolent behavior of the D842V mutated GIST. The results highlighted a different miRNA fingerprint in PDGFRA D842V GISTs compared to non-D842Vmutated patients, which could explain the different bio-logical behavior of this GIST subset.
2022-10-31 | GSE215402 | GEO
Project description:GISTs are the most common mesenchymal tumors and they display neuromuscular features. Gain-of-function mutations in KIT or PDGFRA are the initiating event in most of the cases and KIT oncogenic signaling is essential throughout all the disease. Interestingly, KIT oncogenic signaling is driven by PI3K/mTOR and RAS/MAPK pathways regardless of KIT primary or secondary mutations. Hence, dissection of KIT-downstream pathways may result in the identification of novel KIT critical effectors and a new opportunity to overcome disease heterogeneity of resistance mechanisms in GIST. Using human clinically representative GIST cell models, we undertook pharmacological and functional screenings such as Cell titer glo, kinase activation, apoptosis induction and proliferation to identify key signaling nodes within PI3K/mTOR and RAS/MAPK pathways. In vitro and in vivo validations were undertaken to model novel therapeutic strategies. Transcriptomic analysis (RNAseq) found essential genes co-regulated by both pathways. Functional studies, such as immunofluorescence, kinase activation, flow cytometry and proliferation were performed on a viral gene overexpression and knock-down models to elucidate their regulation and potential role in GIST biology. PI3K/mTOR and MEK1/2 are the most essential KIT-downstream mediators. Single node inhibition did not yield sustained antiproliferative and apoptotic effect, but simultaneous intermittent ablation was synergistic in vitro and in vivo, supporting the critical role of these two pathways.Transcriptomic analyses underscored FBXO32 (a SCF E3 ubiquitin-ligase and the main effector of muscular atrophy) as the most differentially expressed gene co-regulated by PI3K/mTOR and RAS/MAPK pathways. Functional studies demonstrated that FBXO32 is transcriptionally activated by FOXO3a which, in turn, is regulated by PI3K/mTOR and RAS/MAPK pathways. Notoriously, FBXO32 proved to have a pro-survival role in GIST cells. Microarray studies hinted a participation of FBXO32 in cell cycle arrest, which has been previously described as an adaptive pro-survival mechanism in GIST cells. This mechanism was further confirmed by functional studies. Remarkably, FBXO32 was expressed upon KIT inhibition in a panel of GIST cell lines, regardless the mutational status of KIT, and in a gene set database from GIST patients treated with first-line treatment, imatinib. PI3K/mTOR and MEK1/2 are the critical mediators of KIT oncogenic signaling in GIST, and their intermittent co-inhibition is an effective and well-tolerated therapeutic strategy to treat GIST tumors, independently of their KIT mutational status. FBXO32 emerges as a common mediator of KIT-downstream PI3K/mTOR and RAS/MAPK pathways with a critical pro-survival role in GIST participating in cell cycle arrest as pro-survival mechanism.
2021-10-08 | GSE156680 | GEO
Project description:Activating mutations in either KIT or PDGFRA are present in approximately 90% of gastrointestinal stromal tumors (GISTs). Although treatment with the KIT and PDGFR inhibitor imatinib can control advanced disease in about 80% of GIST patients, the beneficial effect is not durable. Here, we report that ligands from the FGF family reduced the effectiveness of imatinib in GIST cells, and FGF2 and FGFR1 are highly expressed in all primary GIST samples examined. The combination of KIT and FGFR inhibition showed increased growth inhibition in imatinib-sensitive GIST cell lines in the presence or absence of added FGF2 in vitro, and delayed tumor regrowth in vivo. In addition, inhibition of mitogen-activated protein kinase (MAPK) signaling by imatinib was not sustained in GIST cells. An extracellular signal-regulated kinase (ERK) rebound occurred through activation of FGF signaling, and was repressed by FGFR1 inhibition. Downregultation of Sprouty proteins played a role in the imatinib-induced feedback activation of FGF signaling in GIST cells. We used micorarrays to quantify the gene expression levels in GIST cell lines. Four GIST cell lines were split and cultured overnight. Cells were harvested for RNA extraction and hybridization on Affymetrix U133plus2 microarrays.
2015-01-08 | E-GEOD-64762 | biostudies-arrayexpress