Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors
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ABSTRACT:
PROVIDER: PRJNA563592 | ENA |
REPOSITORIES: ENA
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Project description:Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GISTs), but insufficient for their malignant progression. Here, we explored to identify driver genes and signaling pathways relevant to GIST progression. We investigated gene expression along with genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, for 65 clinical specimens of surgically dissected GISTs, consisting of 6 metastasis and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations include oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OGs), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSGs). We assigned activated OGs and inactivated TSGs to 27 signaling pathways, whose activation was compared between malignant GISTs (metastasis and high-risk GISTs) and less malignant GISTs (low- and very low-risk GISTs). Integrative molecular profiling indicated that higher incidence of genetic alterations of driver genes were detected more in malignant GISTs (96%, 22 of 23) than in less malignant GISTs (73%, 24 of 33). The malignant GIST samples showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, whose expression was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GISTs. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GISTs.
2019-12-04 | GSE136755 | GEO
Project description:Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high-risk GIST) and less malignant GIST (low- and very low-risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST.
| S-EPMC6890443 | biostudies-literature
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:We have discovered a striking connection between mitochondrial dysfunction and epigenomic instability, manifested by global biallelic DNA cytosine 5-methylation and loss of 5-hydroxymethycytosine within succinate dehydrogenase (SDH)-null gastrointestinal stromal tumors (GIST) relative to those bearing KIT or PDGFRA tyrosine kinase driver mutations. The duality of Krebs versus kinase molecular and epigenomic profiles in GIST provides compelling evidence linking mitochondrial process to nuclear structure and function and underscores an essential role for succinate metabolism in the maintenance of epigenomic programming and tumor suppression. Bisulfite-converted DNA from 144 samples were analyzed with the Illumina GoldenGate Methylation Cancer Panel I array.
2013-05-22 | E-GEOD-34387 | biostudies-arrayexpress
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.
2010-06-20 | GSE22185 | GEO
Project description:To determine the circRNA expression profile in gastrointestinal stromal tumor and matched non-tumor tissues, we used circRNA microArray analysis from Arraystar to examine the expression of circRNAs in gastrointestinal stromal tumor and matched non-tumor tissues.
2020-06-22 | GSE147303 | GEO
Project description:We have discovered a striking connection between mitochondrial dysfunction and epigenomic instability, manifested by global biallelic DNA cytosine 5-methylation and loss of 5-hydroxymethycytosine within succinate dehydrogenase (SDH)-null gastrointestinal stromal tumors (GIST) relative to those bearing KIT or PDGFRA tyrosine kinase driver mutations. The duality of Krebs versus kinase molecular and epigenomic profiles in GIST provides compelling evidence linking mitochondrial process to nuclear structure and function and underscores an essential role for succinate metabolism in the maintenance of epigenomic programming and tumor suppression.
2013-05-22 | GSE34387 | GEO
Project description:Podoplanin is a marker but no driver for malignant progression in glioblastoma
| PRJNA473086 | ENA
Project description:Silencing of the adaptor SH3BP2 impairs Gastrointestinal stromal tumors growth through miRNAs We dissected SH3BP2 pathway in Gastrointestinal Stromal Tumor cells (GIST) performing a miRNA array in SH3BP2-silenced GIST cells
2022-09-23 | GSE213777 | GEO
Project description:The identification of driver genes is of great importance in modern medical research. It is also an essential factor in the development of individualization and has a positive effect on understanding the causes of cancer. Gene mutations are the primary cause of the outcomes of the process of tumorigenesis. Driver genes can be used as therapeutic targets for tumor-specific mutation-dependent overexpression. This study sought to identify mutation-based driver genes in gastric cancer (GC) by applying comprehensive gene expression and copy number analysis. Multiplatform analysis was used to identify four major genomic subtypes of GC. The most prominent cancer-related variations observed in this cohort were TTN mutations (found in 56% of tumors), followed by TP53 (51%), MUC16 (7%), and LRP1B (6%) mutations. In our analysis, mutation characteristics were mainly related to the DNA mismatch repair system. In addition, 34 candidate driver oncogenes were identified in GC. Further research identified six GC-related driver genes associated with the levels of immune infiltration of different immune cells and the majority of immune markers. Our mutation-based study of driver oncogenes identified potential drug targets in GC.
| S-EPMC9315095 | biostudies-literature