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Chromosomal instability and deregulated cell cycle pathways are associated with increased metastatic capacity in treatment naïve, localized, high-risk gastrointestinal stromal tumours

ABSTRACT: The aim of the GIST Risk study was to identify genomic and transcriptomic profiles that could be associated with disease relapse and thus a more aggressive tumour phenotype. The cohort consisted of 21 patients with primary, untreated, resectable, high-risk GIST divided into two groups; patients who developed metastatic disease within three years and patients without disease relapse for more than five years follow-up after adjuvant imatinib treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225978 | GEO | 2023/11/08

REPOSITORIES: GEO

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Molecular comparison of imatinib-naïve and resistant gastrointestinal stromal tumors: differentially expressed microRNAs and mRNAs

Project description:Despite the success of imatinib in advanced gastrointestinal stromal tumor (GIST) patients, 50% of the patients experience resistance within two years of treatment underscoring the need to get better insight into the mechanisms conferring imatinib resistance. Here the microRNA and mRNA expression profiles in primary (imatinib-naïve) and imatinib-resistant GIST were examined. Fifty-three GIST samples harboring primary KIT mutations (exon 9; n=11/exon 11; n=41/exon 17; n=1) and comprising imatinib-naïve (IM-n) (n=33) and imatinib-resistant (IM-r) (n=20) tumors, were analyzed. The microRNA expression profiles were determined and from a subset (IM-n, n=14; IM-r, n=15) the mRNA expression profile was established. Ingenuity pathway analyses were used to unravel biochemical pathways and gene networks in IM-r GIST. Thirty-five differentially expressed miRNAs between IM-n and IM-r GIST samples were identified. Additionally, miRNAs distinguished IM-r samples with and without secondary KIT mutations. Furthermore 352 aberrantly expressed genes were found in IM-r samples. Pathway and network analyses revealed an association of differentially expressed genes with cell cycle progression and cellular proliferation thereby implicating genes and pathways involved in imatinib resistance in GIST. Differentially expressed miRNAs and mRNAs between IM-n and IM-r GIST were identified. Bioinformatic analyses provided insight into the genes and biochemical pathways involved in imatinib-resistance and highlighted key genes that may be putative treatment targets.

2019-06-12 | GSE132542 | GEO

Integrated Profiling and Immunohistochemistry Analyses Link circ-BRIP1, circ-EPHB4 and Their Host Genes with Imatinib Resistance in Gastrointestinal Stromal Tumors

Project description:Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract. The majority of GIST patients eventually develop resistance to imatinib therapy. To identify the responsible mechanisms, we investigated the differentially expressed mRNAs and circRNAs in imatinib-resistant GISTs using SBC ceRNA microarrays. We found that 107 mRNAs and 521 circRNAs were significantly differentially expressed between imatinib-naïve and imatinib-resistant GIST tissue samples. qRT-PCR analyses validated that circ-BRIP1, circ-EPHB4 and circ-RECQL4 and their host genes were upregulated in imatinib-resistant GISTs, and circ-BRIP1, circ-EPHB4, and RECQL4 were associated with imatinib resistance, tumor relapse and progression, and metastasis in GIST patients. The expression levels of circ-BRIP1, circ-EPHB4 and their host genes were also evaluated using TMAs with 150 human GISTs. The expression level of EPHB4 was significantly increased in high-grade GISTs in comparison to low-grade GISTs and correlated with imatinib resistance. Specifically, we first developed a method for high-throughput analysis of the expression of differentially expressed circRNAs by ISH-IHC in a set of FFPE-tissue microarrays in GIST. Our results also suggested a possible role for circ-BRIP1, circ-EPHB4, and their host genes in the progression of GISTs.

2024-11-01 | GSE188700 | GEO

Expression Data from Gastrointestinal Stromal Tumor (GIST) Cell Lines

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

Expression Data from Gastrointestinal Stromal Tumor (GIST) Cell Lines

2015-01-08 | E-GEOD-64762 | biostudies-arrayexpress

Anatomic and transcriptional determinants of gastrointestinal stromal tumor

Project description:Malignant transformation of the interstitial cells of Cajal (ICC) or their precursors gives rise to gastrointestinal stromal tumor (GIST). This mesenchymal neoplasm is characterized by activating mutations in the receptor tyrosine kinases KIT, or other less common mutational subtypes. GIST relies on a highly conserved core transcription factor (TF) network, with expression of accessory disease-state specific TFs. In this study, we define the divergent transcriptional programs supported by accessory TFs HAND1 and BARX1, with HAND1 modulating core TF and KIT gene expression to support GIST cell proliferation. HAND1 was expressed primarily in KIT mutant tumors, including the majority of metastatic tumors or those derived from small bowel, which intrinsically portend a more aggressive clinical course. Assessing archival GIST specimens, HAND1 and BARX1 expression patterns were superior predictors of relapse free survival compared to standard risk stratification. Metastatic tumors expressing HAND1 had a shorter progression free survival on first-line imatinib than those that were HAND1-negative. In contrast, BARX1 expression was enriched in more indolent forms of GIST. Signifying developmental origins of accessory TF expression, HAND1 was expressed solely in ICCs derived from the small intestine, while BARX1 expression was restricted to ICCs of the stomach. These results define the anatomic and transcriptional determinants of GIST clinical phenotypes, and may provide important biomarkers of disease risk stratification in GIST that will inform clinical decision making.

2022-05-23 | GSE151323 | GEO

Affymetrix human DMET Plus array in GIST patients treated with imatinib

Project description:To understand the contribution of germline DNA polymorphisms discriminating between imatinib clinical outcome and toxicity, 38 GIST patients (all with KIT exon 11 mutation) treated with imatinib were analyzed through Affymetrix human DMET Plus array.

2019-01-01 | GSE119558 | GEO

Identification of transcriptional difference between Imatinib-sensitive and resistant patients with gastrointerstinal stromal tumor (GIST)

Project description:Purpose: The goals of this study are to characterize the transcriptional dysregulation of GIST. More importantly, the transcriptome differences betweeen Imatinib-sensitive and resistant patients are compared to identify RNAs that may impact Imatinib resistance. Methods: High-throughput RNA sequencing (RNA-seq) was employed to capture the transcriptional changes in GIST compared to normal samples. RSEM was used to quantify gene expression and DESeq2 was utilized to compared expression changes between different sample groups.

2021-07-29 | GSE155800 | GEO

Genome wide analysis of mouse gastrointestinal stromal tumors (GIST) in a mouse model of spontaneous GIST.

Project description:Analysis of mouse GIST tumors at the gene expression level. The purpose of the study was to identify immunomodulatory genes in mouse GIST tumors after in vivo treatment with the specific tyrosine kinase inhibitor imatinib mesylate. Total RNA obtained from mouse GIST tumors after in vivo treatment with imatinib or vehicle control injected intraperitoneally.

2011-12-31 | E-GEOD-30416 | biostudies-arrayexpress

Identification of common features proffered by KIT and PDGFRA mutations in gastro-intestinal stromal tumors

Project description:Mutations in KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet derived growth factor receptor alpha (PDGFRA) are responsible for more than 85% of the gastrointestinal stromal tumors (GIST). The introduction of imatinib in the therapy scheme of GIST revolutionized the patient outcome. Unfortunately, the therapy allows a disease stabilization rather than curation. Resistance to the inhibitor arises in most cases within the two first years of therapy. The identification of new targets to treat GIST is now essential. We propose a thorough investigation of the activating mechanisms derived from the main PDGFRA and KIT mutants encountered in the GIST landscape. We identified striking differences among the different KIT mutants while PDGFRA mutants delivered a very uniform picture. KIT Exon 11 deletion mutant exhibited the highest intrinsic kinase activity and all KIT mutants were, in addition to their constitutive activation, responsive to stem cell factor (SCF) stimulation. This highlights the importance of evaluating the SCF expression profile in GIST patients. In contrast, PDGFRA mutants were not responsive to their ligand, PDGFAA, and displayed a very high intrinsic kinase activity. At the transcriptomic level, the mitogen-activated protein kinase (MAPK) pathway was established as the most prominent activated pathway, commonly up-regulated by all PDGFRA and KIT mutants. Inhibition of this pathway using the MEK inhibitor PD0325901 reduced the proliferation of GIST primary cells in the nanomolar range. This demonstrates the high value of MEK inhibitors for combination therapy in GIST treatment. This experiment contains expression data from HEK-293 cells expressing wild-type and mutant KIT. The mutants included in the study correspond to the main mutations found in GIST, mainly KIT Ex9 exhibits a duplication of AY502-503 and KIT Ex11 a deletion of residues 553 to 557.

2017-07-05 | E-MTAB-4548 | biostudies-arrayexpress

Gene expression analysis of imatinib-resistant GIST

Project description:To reveal mechanisms for acquired imatinib resistance in gastrointestinal stromal tumor (GIST), we have analyzed several cell lines with resistance to imatinib.

2016-12-27 | GSE69465 | GEO

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