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.
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.
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
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:siRNA knock-down of ZNF genes determined to impact gastrointestinal stromal tumor response to imatinib were used to determine functional significance of ZNFs and identify key targets related to imatinib resistance. exploratory array design to identify candidate effector genes for targeted study
Project description:siRNA knock-down of ZNF genes determined to impact gastrointestinal stromal tumor response to imatinib were used to determine functional significance of ZNFs and identify key targets related to imatinib resistance.
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.
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.