Desmoid Tumor Comprehensive Molecular Profiling and Clinicopathological Properties
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ABSTRACT:
PROVIDER: PRJEB71995 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR12529104_1.fastq.gz | Fastqsanger.gz | |||
| ERR12529104_2.fastq.gz | Fastqsanger.gz | |||
| ERR12529105_1.fastq.gz | Fastqsanger.gz | |||
| ERR12529105_2.fastq.gz | Fastqsanger.gz | |||
| ERR12529106_1.fastq.gz | Fastqsanger.gz |
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Project description:(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. Then, we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort, n = 48) and The Cancer Genome Atlas (TCGA, n = 9235). Secondly, we established the novel patient-derived preclinical models (n = 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-β signaling pathway. Moreover, we selected the combination treatment comprising TGF-β inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-β inhibitor was more effective for tumor suppression than monotherapy. (4) Conclusion: We found preclinical indications that TGF-β inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.
| S-EPMC9737545 | biostudies-literature
Project description:Desmoid tumors (DTs) are rare mesenchymal monoclonal lesions that have a high risk of local recurrence but lack metastatic potential. Since the Notch pathway appears to be important in the carcinogenesis of several tumor types, in the past few years γ-secretase inhibitors (GSIs) have emerged as a potential therapeutic treatment by inhibiting cancer cell Notch signaling through NICD cleavage blockade. To investigate the antitumor effect of PF-03084014, a γ-secretase inhibitor, in DT models, cells treated with PF-03084014 were characterized by gene array analysis. Three cell strains of Desmoid tumors (Desm14, Desm27 and Desm39b) were subjected to either no treatment (control, called G-0) or treatment with 10μM of PF-03084014 (called G-10). The regimen for each treatment was ~8 days and ~30 days; multiple group comparison
2015-11-03 | E-GEOD-61097 | biostudies-arrayexpress
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
Project description:Desmoid tumors (DTs) are rare mesenchymal monoclonal lesions that have a high risk of local recurrence but lack metastatic potential. Since the Notch pathway appears to be important in the carcinogenesis of several tumor types, in the past few years γ-secretase inhibitors (GSIs) have emerged as a potential therapeutic treatment by inhibiting cancer cell Notch signaling through NICD cleavage blockade. To investigate the antitumor effect of PF-03084014, a γ-secretase inhibitor, in DT models, cells treated with PF-03084014 were characterized by gene array analysis.
2015-11-03 | GSE61097 | 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:Nodular fasciitis (NF) is a rapidly growing cellular mass composed of fibroblasts/myofibroblasts, usually localized in subcutaneous tissues, that typically undergoes fibrosis and almost never recurs. Desmoid tumors (DT) are rare forms of fibroblastic/myofibroblastic growth that arise in deep soft tissues, display propensity for local infiltration and recurrence but fail to metastasize. Given that both entities are primarily fibroblastic/myofibroblastic lesions with overlapping histological features, we compared their gene expression profile to identify differentially expressed genes that may provide not only potential diagnostic markers but also clues as to the pathogenesis of each disorder. Differentially expressed transcripts (89 clones displaying increased expression in DT and 246 clones displaying increased expression in NF), included genes encoding several receptor and non-receptor tyrosine kinases (EPHB3, PTPRF, GNAZ, SYK, LYN, EPHA4, BIRC3), transcription factors (TWIST1, PITX2, EYA2, OAS1, MITF, TCF20), and members of the Wnt signaling pathway (AXIN2, WISP1, SFRP). Remarkably, almost one fourth of the differentially expressed genes encode proteins associated with inflammation and tissue remodeling, including members of the interferon (IFN), tumor necrosis factor (TNF) and transforming growth factor beta (TGF-beta) signaling pathways as well as metalloproteinases (MMP1, 9, 13, 23), urokinase plasminogen activator (PLAU) and cathepsins. Our observations provide the first comparative molecular characterization of desmoid tumors and nodular fasciitis and suggest that selected tyrosine kinases, transcription factors and members of the Wnt, TGF-beta, IFN and TNF signaling pathways may be implicated in influencing and distinguishing their fate. Keywords: comparative genomic hybridization
2005-08-20 | GSE3127 | GEO
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: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