Taste and smell disturbances in patients with gastrointestinal stromal tumors using tyrosine-kinase inhibitors.
Ontology highlight
ABSTRACT:
DISEASE(S): Gastro-intestinal Stromal Tumors
PROVIDER: 2442363 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Epigenetic alterations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). To obtain better insight into the GIST epigenome, we analyzed genome-wide histone modification and DNA methylation in GIST cells. Trimethylation of histone H3 lysine 3 (H3K4me3), DNA methylome, and transcriptome in GIST-T1 cells were analyzed by chromatin immunoprecipitation-sequencing (ChIP-seq), Infinium HumanMethylation450 BeacChip, and gene expression microarray. Enrichment of H3K4me3 at transcription start sites (TSSs) is positively correlated with gene expression, while DNA methylation is negatively associated with gene expression in GIST-T1 cells. We found that treatment with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor not only upregulated genes with DNA methylation, but also activated a number of interferon signaling-related genes. ChIP-seq analysis revealed that the drug treatment significantly upregulated H3K4me3 levels at TSS regions as well as retrotransposons including endogenous retroviruses (ERVs). Finally, by utilizing the omics data, we screened epigenetically silenced long non-coding RNA genes, and found that hypermethylation of MEG3 is a frequent event and an indicator of worse outcome in GIST patients. Our data suggest that epigenetic inhibitors may activate interferon signaling via viral mimicry in GIST cells. We also show that epigenome data obtained in this study could be a useful resource to identify novel GIST-related genes.
2021-06-21 | GSE171496 | GEO
Project description:Epigenetic alterations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). To obtain better insight into the GIST epigenome, we analyzed genome-wide histone modification and DNA methylation in GIST cells. Trimethylation of histone H3 lysine 3 (H3K4me3), DNA methylome, and transcriptome in GIST-T1 cells were analyzed by chromatin immunoprecipitation-sequencing (ChIP-seq), Infinium HumanMethylation450 BeacChip, and gene expression microarray. Enrichment of H3K4me3 at transcription start sites (TSSs) is positively correlated with gene expression, while DNA methylation is negatively associated with gene expression in GIST-T1 cells. We found that treatment with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor not only upregulated genes with DNA methylation, but also activated a number of interferon signaling-related genes. ChIP-seq analysis revealed that the drug treatment significantly upregulated H3K4me3 levels at TSS regions as well as retrotransposons including endogenous retroviruses (ERVs). Finally, by utilizing the omics data, we screened epigenetically silenced long non-coding RNA genes, and found that hypermethylation of MEG3 is a frequent event and an indicator of worse outcome in GIST patients. Our data suggest that epigenetic inhibitors may activate interferon signaling via viral mimicry in GIST cells. We also show that epigenome data obtained in this study could be a useful resource to identify novel GIST-related genes.
2021-06-21 | GSE171495 | GEO
Project description:Epigenetic alterations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). To obtain better insight into the GIST epigenome, we analyzed genome-wide histone modification and DNA methylation in GIST cells. Trimethylation of histone H3 lysine 3 (H3K4me3), DNA methylome, and transcriptome in GIST-T1 cells were analyzed by chromatin immunoprecipitation-sequencing (ChIP-seq), Infinium HumanMethylation450 BeacChip, and gene expression microarray. Enrichment of H3K4me3 at transcription start sites (TSSs) is positively correlated with gene expression, while DNA methylation is negatively associated with gene expression in GIST-T1 cells. We found that treatment with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor not only upregulated genes with DNA methylation, but also activated a number of interferon signaling-related genes. ChIP-seq analysis revealed that the drug treatment significantly upregulated H3K4me3 levels at TSS regions as well as retrotransposons including endogenous retroviruses (ERVs). Finally, by utilizing the omics data, we screened epigenetically silenced long non-coding RNA genes, and found that hypermethylation of MEG3 is a frequent event and an indicator of worse outcome in GIST patients. Our data suggest that epigenetic inhibitors may activate interferon signaling via viral mimicry in GIST cells. We also show that epigenome data obtained in this study could be a useful resource to identify novel GIST-related genes.
2021-06-21 | GSE171498 | GEO
Project description:Purpose: Management of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical obstacle. Development of effective treatment strategies for refractory GIST requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Experimental Design: Using Multiplexed Inhibitor Beads and Mass Spectrometry paired with a super-SILAC kinome standard, we explored the majority of the kinome in GIST specimens from three GIST subtypes (KIT-mutant, PDGFRA-mutant and succinate dehydrogenase-deficient GIST) to identify novel kinase targets. In vitro and in vivo studies were performed to evaluate the utility of targeting the identified kinases in GIST. Results: Kinome profiling revealed distinct signatures in three GIST subtypes. PDGFRA-mutant GIST had elevated tumor associated macrophage (TAM) kinases and immunohistochemical analysis confirmed increased TAMs present in these tumors. Kinome profiling with loss-of-function assays revealed a significant role for G2-M tyrosine kinase, Wee1, in GIST survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in both KIT and PDGFRA-mutant GIST cell lines, as well as notable efficacy of MK-1775 as a single agent in the PDGFRA-mutant line. Conclusions: These studies provide strong preclinical justification for the use of MK-1775 in GIST.
2021-09-09 | PXD020720 | Pride
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
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.
2015-01-08 | GSE64762 | GEO
Project description:Gastrointestinal stromal tumor (GIST) is a common sarcoma of gastrointestinal tract (GIT) with high metastatic and recurrence rates, but the proteomic features are still less understood. Here we performed systematic quantitative proteome profiling of GIST from 13 patients classified into very low/low, intermediate and high risk subgroups. An extended cohort of GIST (n = 131) was used for immunohistochemical validation of proteins of interest. In total, 10064 proteins were quantified, covering 61% of the GIT transcriptome from The Human Protein Altas. Out of the 10064 quantified proteins, 4938 proteins were observed in all 13 cases with 518 proteins upregulated and 190 proteins downregulated in tumorous tissues independent of risk rating. Pathway analysis showed that the downregulated proteins were mostly enriched in metabolic pathway, while the upregulated proteins mainly belonged to spliceosome pathway. In addition, 131 proteins showed differentially expressed patterns among GIST subgroups with statistical significance. The 13 GIST cases were classified into 3 subgroups perfectly based on the expression of these proteins. The molecular phenotypes of oncoproteins, tumor suppressors, phosphatase and kinases were summarized, and some important molecules were observed. Immunohistochemical analysis of two phosphatases PTPN1 (n = 117) and PPP2CB (n=113) revealed that the GIST patients with high PTPN1 had low chances of developing metastasis, and the expression of PPP2CB was likely to be associated with GIST risk. Collectively, this work provides valuable information for understanding the inherent biology and evolution of GIST.
2019-01-29 | PXD011299 | iProX
Project description:Activating mutations in the KIT or PDGFRA receptor tyrosine kinases are hallmarks of gastrointestinal stromal tumor (GIST). The biological underpinnings of recurrence following resection or disease progression beyond kinase mutation are poorly understood. Utilizing chromatin immunoprecipitation with sequencing (ChIP-seq) of tumor samples and cell lines, we describe the enhancer landscape of GIST, highlighting genes that reinforce and extend our understanding of these neoplasms. A group of core transcription factors can be distinguished from others unique to localized and metastatic disease. The transcription factor HAND1 emerges in metastatic disease, binds to established GIST-associated enhancers and is required for GIST cell proliferation and KIT gene expression. The pattern of transcription factor expression in primary tumors is predictive of metastasis-free survival in GIST patients. These results provide insight into the enhancer landscape and transcription factor network underlying GIST, and define a new strategy for predicting clinical behavior of this disease.
2018-05-21 | GSE95863 | GEO
Project description:Activating mutations in the KIT or PDGFRA receptor tyrosine kinases are hallmarks of gastrointestinal stromal tumor (GIST). The biological underpinnings of recurrence following resection or disease progression beyond kinase mutation are poorly understood. Utilizing chromatin immunoprecipitation with sequencing (ChIP-seq) of tumor samples and cell lines, we describe the enhancer landscape of GIST, highlighting genes that reinforce and extend our understanding of these neoplasms. A group of core transcription factors can be distinguished from others unique to localized and metastatic disease. The transcription factor HAND1 emerges in metastatic disease, binds to established GIST-associated enhancers and is required for GIST cell proliferation and KIT gene expression. The pattern of transcription factor expression in primary tumors is predictive of metastasis-free survival in GIST patients. These results provide insight into the enhancer landscape and transcription factor network underlying GIST, and define a new strategy for predicting clinical behavior of this disease.
2018-05-21 | GSE95862 | GEO
Project description:Activating mutations in the KIT or PDGFRA receptor tyrosine kinases are hallmarks of gastrointestinal stromal tumor (GIST). The biological underpinnings of recurrence following resection or disease progression beyond kinase mutation are poorly understood. Utilizing chromatin immunoprecipitation with sequencing (ChIP-seq) of tumor samples and cell lines, we describe the enhancer landscape of GIST, highlighting genes that reinforce and extend our understanding of these neoplasms. A group of core transcription factors can be distinguished from others unique to localized and metastatic disease. The transcription factor HAND1 emerges in metastatic disease, binds to established GIST-associated enhancers and is required for GIST cell proliferation and KIT gene expression. The pattern of transcription factor expression in primary tumors is predictive of metastasis-free survival in GIST patients. These results provide insight into the enhancer landscape and transcription factor network underlying GIST, and define a new strategy for predicting clinical behavior of this disease.
2018-05-21 | GSE95861 | GEO