Driver Gene and Potential Biomarker Investigation of Desmoid-type Fibromatosis Through RNA-seq Analysis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE266101 | GEO | 2025/09/09
REPOSITORIES: GEO
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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.
2023-10-31 | GSE237692 | GEO
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.
2023-11-01 | GSE239407 | GEO
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.
2023-11-01 | GSE239406 | GEO
Project description:Abstract: Many soft tissue tumors recapitulate features of normal connective tissue. We hypothesize that different types of fibroblastic tumors are representative of different populations of fibroblastic cells or different activation states of these cells. We examined two tumors with fibroblastic features, solitary fibrous tumor (SFT) and desmoid-type fibromatosis (DTF), by DNA microarray analysis and found that they have very different expression profiles, including significant differences in their patterns of expression of extracellular matrix genes and growth factors. Using immunohistochemistry and in situ hybridization on a tissue microarray, we found that genes specific for these two tumors have mutually specific expression in the stroma of nonneoplastic tissues. We defined a set of 786 gene spots whose pattern of expression distinguishes SFT from DTF. In an analysis of DNA microarray gene expression data from 295 previously published breast carcinomas, we found that expression of this gene set defined two groups of breast carcinomas with significant differences in overall survival. One of the groups had a favorable outcome and was defined by the expression of DTF genes. The other group of tumors had a poor prognosis and showed variable expression of genes enriched for SFT type. Our findings suggest that the host stromal response varies significantly among carcinomas and that gene expression patterns characteristic of soft tissue tumors can be used to discover new markers for normal connective tissue cells. Soft tissue tumor gene expression of 10 cases of DTF (blue), 13 cases of SFT (orange), and 35 other previously examined soft tissue tumors (black) based expression profiling on 42,000 -element cDNA microarrays. A clinical history design type is where the organisms clinical history of diagnosis, treatments, e.g. vaccinations, surgery etc. Computed
2006-03-14 | E-GEOD-4305 | biostudies-arrayexpress
Project description:Abstract: Many soft tissue tumors recapitulate features of normal connective tissue. We hypothesize that different types of fibroblastic tumors are representative of different populations of fibroblastic cells or different activation states of these cells. We examined two tumors with fibroblastic features, solitary fibrous tumor (SFT) and desmoid-type fibromatosis (DTF), by DNA microarray analysis and found that they have very different expression profiles, including significant differences in their patterns of expression of extracellular matrix genes and growth factors. Using immunohistochemistry and in situ hybridization on a tissue microarray, we found that genes specific for these two tumors have mutually specific expression in the stroma of nonneoplastic tissues. We defined a set of 786 gene spots whose pattern of expression distinguishes SFT from DTF. In an analysis of DNA microarray gene expression data from 295 previously published breast carcinomas, we found that expression of this gene set defined two groups of breast carcinomas with significant differences in overall survival. One of the groups had a favorable outcome and was defined by the expression of DTF genes. The other group of tumors had a poor prognosis and showed variable expression of genes enriched for SFT type. Our findings suggest that the host stromal response varies significantly among carcinomas and that gene expression patterns characteristic of soft tissue tumors can be used to discover new markers for normal connective tissue cells. Soft tissue tumor gene expression of 10 cases of DTF (blue), 13 cases of SFT (orange), and 35 other previously examined soft tissue tumors (black) based expression profiling on 42,000 -element cDNA microarrays. A clinical history design type is where the organisms clinical history of diagnosis, treatments, e.g. vaccinations, surgery etc. Keywords: clinical_history_design
2006-03-15 | GSE4305 | GEO
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
2010-03-25 | E-GEOD-18209 | biostudies-arrayexpress
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.
2023-11-01 | GSE244160 | GEO
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:Desmoid tumors are bland fibroblastic tumors with little histologic variation in different regions of the tumor. While desmoid tumors do not metastasize, they have a high rate of local recurrence after complete resection and no reliable predictors of clinical behavior exist. The presence of molecular intra- and inter-tumor heterogeneity has been well established in other, higher grade, sarcomas but little is known about molecular variability within histologically bland lesions. In this study, we sought to examine the extent of intra- and inter-tumoral clonal heterogeneity of desmoid tumors, which may contribute to their pathogenesis and possible relapse. We performed analysis of DNA methylation, DNA copy number alterations, point mutations and gene expression on 24 specimens from different areas from primary and recurrent desmoid tumors from 3 patients (7-9 specimens per patient). The studies showed a remarkable heterogeneity of DNA methylation, DNA copy number alterations, point mutations or gene expression in different regions in primary or recurrent tumors in each patient. We discovered the evidence for subclonal alterations in different areas of individual tumors. Among the four types of data, the transcriptomic profiles showed the highest degree of variability within tumors and between different tumors from the same patient. Gene expression signatures associated with favorable and unfavorable outcome were detected in different regions within the same tumor. This study shows an unexpected degree of intra- and inter-tumor heterogeneity in desmoid tumors. Our analysis indicates that even in this histologically monotonous lesion, molecular analysis of a single tumor biopsy may underestimate the magnitude of molecular alterations. We demonstrate that molecular intra- and inter-tumor heterogeneity is an important consideration in drug development and validation of prognostic and predictive biomarkers for these tumors.
2024-09-29 | GSE250403 | GEO
Project description:Desmoid tumors are bland fibroblastic tumors with little histologic variation in different regions of the tumor. While desmoid tumors do not metastasize, they have a high rate of local recurrence after complete resection and no reliable predictors of clinical behavior exist. The presence of molecular intra- and inter-tumor heterogeneity has been well established in other, higher grade, sarcomas but little is known about molecular variability within histologically bland lesions. In this study, we sought to examine the extent of intra- and inter-tumoral clonal heterogeneity of desmoid tumors, which may contribute to their pathogenesis and possible relapse. We performed analysis of DNA methylation, DNA copy number alterations, point mutations and gene expression on 24 specimens from different areas from primary and recurrent desmoid tumors from 3 patients (7-9 specimens per patient). The studies showed a remarkable heterogeneity of DNA methylation, DNA copy number alterations, point mutations or gene expression in different regions in primary or recurrent tumors in each patient. We discovered the evidence for subclonal alterations in different areas of individual tumors. Among the four types of data, the transcriptomic profiles showed the highest degree of variability within tumors and between different tumors from the same patient. Gene expression signatures associated with favorable and unfavorable outcome were detected in different regions within the same tumor. This study shows an unexpected degree of intra- and inter-tumor heterogeneity in desmoid tumors. Our analysis indicates that even in this histologically monotonous lesion, molecular analysis of a single tumor biopsy may underestimate the magnitude of molecular alterations. We demonstrate that molecular intra- and inter-tumor heterogeneity is an important consideration in drug development and validation of prognostic and predictive biomarkers for these tumors.
2024-09-29 | GSE250149 | GEO