Array CGH analysis of human gastrointestinal stromal tumors
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE22185 | GEO | 2010/06/20
SECONDARY ACCESSION(S): PRJNA128819
REPOSITORIES: GEO
Similar Datasets
Project description:Gastrointestinal stromal tumors (GISTs) are the most important mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs exhibit activating mutations of KIT or PDGFRA, but epigenetic alteration of GISTs is largely unknown. In this study, we aimed to clarify the involvement of DNA methylation in GIST malignancy. A total of 25 GIST specimens were studied using Human Genome CGH Microarray Kit 105A (G4412A, Agilent). Levels of LINE-1 methylation were analyzed using bisulfite-pyrosequencing. LINE-1 hypomethylation was correlated with risk grade, and high-risk GISTs exhibited lower levels of LINE-1 methylation than low- or intermediate-risk GISTs. Array CGH analysis revealed a significant correlation between LINE-1 hypomethylation and chromosomal aberrations. Our data suggest that LINE-1 hypomethylation correlates with the aggressiveness of GISTs. Hypomethylation may increase the malignant potential of GISTs by inducing accumulation of chromosomal aberrations. A total of 25 surgically obtained human gastrointestinal stromal tumors (GISTs) was analyzed using Agilent CGH microarray. Copy number aberration was compared with clinicopathological features and DNA methylation status.
2010-06-20 | E-GEOD-22185 | biostudies-arrayexpress
Project description:The anatomic site-dependent expression of hematopoietic progenitor cell antigen CD34 is a feature of gastrointestinal stromal tumours (GISTs). The basis for the differential CD34 expression is only incompletely understood. This study aimed at understanding the regulation of CD34 in GISTs and clarification of its site-dependent expression. Two sample sets of primary GISTs were interrogated including 52 fresh-frozen and 134 paraffin-embedded and formalin-fixed specimens. DNA methylation analysis was first performed by HumanMethylation450 BeadChip array in three cell lines, namely GIST-T1, GIST882 and GIST48b, that were derived from gastric and intestinal GISTs, and differentially methylated CpG sites were identified upstream of CD34. The methylation degree was further quantified by pyrosequencing and inversely correlated with CD34 mRNA and protein abundance. The gene's expression could be activated upon induction of DNA hypomethylation with 5-aza-2'-deoxycytidine in GIST-T1 and GIST882 cells. In patient samples, a strong inverse correlation of DNA methylation degree with immunohistochemically evaluated CD34 expression was documented. Both CD34 expression and DNA methylation levels were specific to the tumours' anatomic location and mutation status. A constant decrease in methylation levels was observed ranging from almost 100% hypermethylation in intestinal GISTs from duodenum to hypomethylation in rectum. CD34 was heavily methylated in gastric PDGFRA-mutant GISTs in comparison to hypomethylated KIT-mutant counterparts. Our results strongly suggest an epigenetic control of CD34 expression in GISTs by DNA methylation. Differential methylation and expression of CD34 in GISTs along the gastrointestinal tract axis and in tumours that harbour different gain-of-function mutations suggest the origin from different cell populations in the gastrointestinal tract.
2017-01-24 | GSE93963 | GEO
Project description:Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood. A subset of gastrointestinal stromal tumors (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH)-deficiency and global DNA hyper-methylation. Here we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant, and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary and strongly up-regulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetic state of the parental tumor, including hyper-methylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibitor, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers.
2019-10-16 | GSE107447 | 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:To clarify the microRNA (miRNA) expression signatures in gastrointestinal stromal tumors (GISTs), a series of 32 GIST specimens were analyzed using Agilent miRNA microarray V3. Unsupervised hierarchical clustering revealed that GISTs can be categorized into 2 groups according to the expression of a miRNA cluster encoded on chromosome 14q32.31. Total RNA was extracted from 32 fresh frozen GIST specimens obtained from surgical resections. Expression of 851 miRNAs was analyzed using Human miRNA Microarray V3 (Rel 12.0 G4470C; Agilent technologies, Santa Clara, CA, USA). Risk grade was assessed according to the risk definition system proposed by Fletcher et al. (Hum Pathol. 2002;33:459-65.)
2011-11-01 | E-GEOD-31741 | 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: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:To analyze the gene expression signatures in gastrointestinal stromal tumors (GISTs), a series of 14 GIST specimens were analyzed using Agilent Whole Human Genome Microarray (4x44K, G4112F). Total RNA was extracted from 32 fresh frozen GIST specimens obtained from surgical resections. Gene expression was analyzed using Agilent Whole Human Genome Microarray (4x44K, G4112F, Agilent technologies, Santa Clara, CA, USA). Risk grade was assessed according to the risk definition system proposed by Fletcher et al. (Hum Pathol. 2002;33:459-65.)
2011-11-01 | E-GEOD-31802 | 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. 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:KIT, PDGFRA, NF1, and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumors (GISTs), and additional genetic alterations are required for progression to malignancy. The most frequent secondary alteration, demonstrated in ~70% of GISTs, is chromosome 14q deletion. Here we report hemizygous or homozygous inactivating mutations of the chromosome 14q MAX gene in 16 of 76 GISTs (21%). We find MAX mutations in 17% and 50% of sporadic and NF1-syndromic GISTs, respectively, and we find loss of MAX protein expression in 48% and 90% of sporadic and NF1-syndromic GISTs, and in 3 of 8 micro GISTs, which are early GISTs. MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion, and MAX induction restores p16 expression and inhibits GIST proliferation. Hence, MAX inactivation is a common event in GIST progression, fostering cell cycle activity in early GISTs.
2017-02-03 | GSE93077 | GEO