Project description:Unsupervised clustering of desmoid tumors and normal mesenchymal tissues was performed using henes associated with HIF1 activity. This accurately distiguished neoplastic tissues from normal controls The study sought to identify genes differentially expressed in desmoid-type fibromatosis as opposed to normal mesenchymal tissues. We noted that beta-catenin, the central driver in desmoid-type fibromatosis, appeared to regulate HIF1 signaling in in vitro studies. Genes associated with HIF1 and angiogenesis pathways were then used to perform unsupervised clustering on desmoid tumors and normal mesenchymal tissues. The genes accurately differentiated neoplastic and normal samples.
Project description:The mechanisms underlying oncogenesis in desmoid-type fibromatosis are poorly understood. This project sought to understand how β-catenin may function to promote desmoid formation and how external signaling by PDGFRβ modulates this activity. To examine this question, RNA-seq was performed on CTNNB1 knock-downs. Gene set enrichment analysis suggested that the oncogene controlled HIF1 and angiogenesis pathways; expression of related genes accurately differentiated desmoids analyzed by U133A array from normal mesenchymal tissues. We identified c-ABL as a direct transcriptional target of β-catenin that promoted HIF1α expression in desmoid cells. We also noted that c-ABL activity was enhanced by PDGFRβ. PDGFRβ enhanced desmoid cell proliferation and c-ABL was necessary for desmoid proliferation. To identify potential markers of PDGFRβ/c-ABL activity in vivo, we assessed RNA-seq of desmoid cells treated with PDGF-BB. ERG1 transcription was highly upregulate and IHC of ERG1 was subsequently used to assess outcomes in desmoid patients with biopsies available for testing.
Project description:The mechanisms underlying oncogenesis in desmoid-type fibromatosis are poorly understood. This project sought to understand how β-catenin may function to promote desmoid formation and how external signaling by PDGFRβ modulates this activity. To examine this question, RNA-seq was performed on CTNNB1 knock-downs. Gene set enrichment analysis suggested that the oncogene controlled HIF1 and angiogenesis pathways; expression of related genes accurately differentiated desmoids analyzed by U133A array from normal mesenchymal tissues. We identified c-ABL as a direct transcriptional target of β-catenin that promoted HIF1α expression in desmoid cells. We also noted that c-ABL activity was enhanced by PDGFRβ. PDGFRβ enhanced desmoid cell proliferation and c-ABL was necessary for desmoid proliferation. To identify potential markers of PDGFRβ/c-ABL activity in vivo, we assessed RNA-seq of desmoid cells treated with PDGF-BB. ERG1 transcription was highly upregulate and IHC of ERG1 was subsequently used to assess outcomes in desmoid patients with biopsies available for testing.
Project description:Gene expression microarrays are the most widely used technique for genome-wide expression profiling. However, microarrays do not perform well on formalin fixed paraffin embedded tissue (FFPET). Consequently, microarrays cannot be effectively utilized to perform gene expression profiling on the vast majority of archival tumor samples. To address this limitation of gene expression microarrays, we designed a novel procedure (3'-end sequencing for expression quantification (3SEQ)) for gene expression profiling from FFPET using next-generation sequencing. We performed gene expression profiling by 3SEQ and microarray on both frozen tissue and FFPET from two soft tissue tumors (desmoid type fibromatosis (DTF) and solitary fibrous tumor (SFT)) (total n = 23). Analysis of 3SEQ data revealed many genes differentially expressed between the tumor types (FDR < 0.01) on both the frozen tissue (~9.6K genes) and FFPET (~8.1K genes). Analysis of microarray data from frozen tissue revealed fewer differentially expressed genes (~4.64K), and analysis of microarray data on FFPET revealed very few (69) differentially expressed genes. Functional gene set analysis of 3SEQ data from both frozen tissue and FFPET identified biological pathways known to be important in DTF and SFT pathogenesis and suggested several additional candidate oncogenic pathways in these tumors. These findings demonstrate that 3SEQ is an effective technique for gene expression profiling from archival tumor samples and may facilitate significant advances in translational cancer research. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Preservation: either frozen (FROZEN) or formalin fixed paraffin embedded tissue (FFPET) Disease State: Tumor type: desmoid type fibromatosis (DTF) or solitary fibrous tumor (SFT) Keywords: Logical Set Computed
Project description:Micro RNAs are deregulated in a variety of human cancers.In this study we analayzed baseline expression levels of circulating human micro RNAs from patients of the Ph 3 RESORCE trial for predictive value of overall survival and time to progression.
Project description:Gene expression microarrays are the most widely used technique for genome-wide expression profiling. However, microarrays do not perform well on formalin fixed paraffin embedded tissue (FFPET). Consequently, microarrays cannot be effectively utilized to perform gene expression profiling on the vast majority of archival tumor samples. To address this limitation of gene expression microarrays, we designed a novel procedure (3'-end sequencing for expression quantification (3SEQ)) for gene expression profiling from FFPET using next-generation sequencing. We performed gene expression profiling by 3SEQ and microarray on both frozen tissue and FFPET from two soft tissue tumors (desmoid type fibromatosis (DTF) and solitary fibrous tumor (SFT)) (total n = 23). Analysis of 3SEQ data revealed many genes differentially expressed between the tumor types (FDR < 0.01) on both the frozen tissue (~9.6K genes) and FFPET (~8.1K genes). Analysis of microarray data from frozen tissue revealed fewer differentially expressed genes (~4.64K), and analysis of microarray data on FFPET revealed very few (69) differentially expressed genes. Functional gene set analysis of 3SEQ data from both frozen tissue and FFPET identified biological pathways known to be important in DTF and SFT pathogenesis and suggested several additional candidate oncogenic pathways in these tumors. These findings demonstrate that 3SEQ is an effective technique for gene expression profiling from archival tumor samples and may facilitate significant advances in translational cancer research. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Preservation: either frozen (FROZEN) or formalin fixed paraffin embedded tissue (FFPET) Disease State: Tumor type: desmoid type fibromatosis (DTF) or solitary fibrous tumor (SFT) Keywords: Logical Set
2010-03-26 | GSE18209 | GEO
Project description:DNA methylation in desmoid-type fibromatosis tumors
Project description:Analysis of gene expression in 17 low-grade fibromyxoid sarcoma (LGFMS) samples compared to that of histologically similar tumors. LGFMS is characterized by the specific translocations t(7;16)(q33;p11) or t(11;16)(p11;p11) and corresponding fusion genes FUS-CREB3L2 or FUS-CREB3L1. The results identifies a LGFMS-specific gene expression profile and provide insight into FUS-CREB3L2 regulated gene expression. RNA was extracted from 17 LGFMS tumor biopsies and hybridized to Affymetrix arrays. RNA from 6 myxofibrosarcoma (MFS), 6 desmoid fibromatosis (DFM), 5 solitary fibrous tumor (SFT) and 6 extraskeletal myxoid chondrosarcoma (EMCS) tumor biopsies was used as comparison. Two pools of skeletal muscle RNA was also included in the comparison.
Project description:Purpose: This study sought to identify signaling pathways that modulate β-catenin function in desmoid cells, affecting natural history and sorafenib response. Experimental Design: In vitro experiments utilized primary desmoid cell lines to examine interaction of β-catenin signaling with other pathways. Relevance of in vitro results was assessed in surgical specimens and Alliance trial A091105 correlative biopsies. Results: CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α. Expression of hypoxia-associated genes clustered desmoids separately from normal mesenchymal tissue. ChIP-seq identified ABL1 as a β-catenin transcriptional target that modulated HIF1α protein expression and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1 inhibited the ability of desmoid cells to induce VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRβ signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by activation of PDGF signaling. Reduction in PDGFRβ and c-Abl phosphorylation was commonly observed in samples from patients after treatment with sorafenib; baseline samples in patients with greater drug response tended to have higher baseline PDGFRβ/c-Abl pathway activation. Conclusions: The β-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α protein expression in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.
Project description:Global gene expression analysis of desmoplastic fibroblastoma (DF) and histologically similar tumors. FOSL1 is identified as a candidate target gene for the 11q12 rearrangments in DF. RNA was extracted from 3 frozen desmoplastic fibroblastoma (DF) biopsies and hybridized onto Affymetrix Human Gene 1.0 ST arrays. RNA from 6 myxofibrosarcoma (MFS), 6 desmoid fibromatosis (DFM), 5 solitary fibrous tumor (SFT) and 17 low-grade fibromyxoid sarcomas (LGFMS) were used as controls. The control dataset has been previously published and is available in the GEO database under Series accession GSE24369. The complete dataset representing: (1) the 3 desmoplastic fibroblastoma Samples and (2) the 34 control Samples from Series GSE24369 (re-processed using RMA), is linked below as a supplementary file.