Expression Profiling Identifies Key Genes in GIST Patients with Liver Metastasis
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ABSTRACT: GIST (gastrointestinal stromal tumor) is the most prominent mesenchymal neoplasms of the gastrointestinal tract, and liver is the most common metastasis site for GIST. The molecular mechanism leading to liver metastasis of GIST is currently unclear. With the goal of revealing the underlying mechanism, we performed whole-genome gene expression profiling in 18 pairs of RNA samples comprised of liver metastasis tissues and corresponding non-tumor tissues. To reveal the underlying mechanism leading to liver metastasis of GIST
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.
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.
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.
Project description:To reveal mechanisms for acquired imatinib resistance in gastrointestinal stromal tumor (GIST), we have analyzed several cell lines with resistance to imatinib.
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.
Project description:Although the main cause of gastrointestinal stromal tumor (GIST) is due to gain-of-function mutation of the c-kit gene in the interstitial cells of Cajal, concomitant genetic or epigenetic changes other than c-kit are thought to occur in the development of metastasis. We used microarrays to identify genes that were up-regulated and down-regulated in the metastatic liver GIST. Three primary gastric GISTs without synchronous or metachronous metastasis and five metastatic liver tumors originated from gastric GIST were utilized for RNA extraction and hybridization on Affymetrix microarrays. No patients had received imatinib therapy before surgery.
Project description:This SuperSeries is composed of the following subset Series: GSE19396: ETV1 knockdown in GIST cell lines GSE22433: Imatinib Treatment of GIST882 GSE22441: Mapping of ETV1 genomic binding sites in gastrointestinal stromal tumor (GIST). Refer to individual Series
Project description:Prognosis in Gastrointestinal Stromal Tumors (GIST) depends on clinical and pathological parameters that may be little objective, thus it is necessary to have other molecular biomarkers in the management of the disease.
Project description:Although the main cause of gastrointestinal stromal tumor (GIST) is due to gain-of-function mutation of the c-kit gene in the interstitial cells of Cajal, concomitant genetic or epigenetic changes other than c-kit are thought to occur in the development of metastasis. We used microarrays to identify genes that were up-regulated and down-regulated in the metastatic liver GIST.