Beta-catenin in Desmoid Tumors: the role of T41A and S45F mutations on gene expression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE109023 | GEO | 2018/01/11
SECONDARY ACCESSION(S): PRJNA429452
REPOSITORIES: GEO
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Project description:Desmoid tumors (DT) are rare, benign, fibroblastic neoplasm with challenging histological diagnosis. DTs can occur sporadically or associated with the familial adenomatous polyposis coli (FAP). Most sporadic DTs are associated with β-catenin gene (CTNNB1) mutations, while mutated APC gene causes FAP disease. MicroRNAs (miRNAs) are involved in many human carcinogenesis. The miRNA profile was analyzed by microarray in formalin-fixed, paraffin-embedded (FFEP) specimens of 12 patients (8 sporadic, 4 FAP-associated) and 4 healthy controls. One hundred and one miRNAs were dysregulated, of which 98 miRNAs in sporadic DTs, 8 in FAP-associated DTs, 5 were shared by both tumors. Twenty-six miRNAs were then validated by RT-qPCR in 23 sporadic and 7 FAP-associated DT samples matched with healthy controls. The same qPCR method was used to evaluate the CTNNB1 mutational status in sporadic DTs. The correlation between sporadic DTs and miRNA expression showed that miR-21-3p increased in mutated versus wild-type DTs, while miR-197-3p was decreased. The mRNA expression of Tetraspanin3 and Serpin family A member 3, miR-21-3p targets, and L1 Cell Adhesion Molecule, miR-197-3p target, was also evaluated. CTNNB1 mutations associated to miRNA dysregulation could help histological diagnosis of sporadic DTs and could affect the genesis and the progression of this disease.
2017-05-01 | GSE89687 | GEO
Project description:Desmoid tumors (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumors arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most non-FAP (sporadic) desmoids carry somatic mutations in the beta-catenin gene. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumors. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumors, we analyzed 17 FAP-associated and 38 sporadic desmoids for copy number abnormalities (CNAs) by means of array comparative genomic hybridization and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Common gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumors. Frequent common losses were observed within a 700 kb region at 5q22.2, comprising the APC gene (11%), in a 2 Mb region at 6p21.2-p21.1 (15%), and in a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of CNAs (59%) than the sporadic tumors (37%). As predicted by the APC germline mutations among these patients, a relatively high percentage (29%) of the FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumors. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumor progression. Fifty-three fresh frozen tumor samples were collected at four institutes: Center for Human Genetics, University of Leuven, Belgium (21 samples); INSERM U674, Fondation Jean Dausset-CEPH, Paris, France (15 samples); Hospital for Sick Children, Toronto, Canada (13 samples); and the Italian Registry of Hereditary Colorectal Cancer (Dr. L. Bertario, 4 samples). In addition, DNA of two fresh frozen tumors, HDD-H of patient III:2 and HDD-I of patient III:6, of our hereditary desmoids disease (HDD) family10 was available (Table 1). In this family, multifocal desmoid tumors were inherited as an autosomal dominant trait, and HDD segregated with a 3' APC mutation at codon 1924. For the latter reason, they were classified as FAP tumors in this study. Three FAP tumors were derived from a family with 2 relatives in the study (D15-1 and D15-2 of a male patient and D16 of his sister). Colonic polyposis had been observed in 12 FAP patients, not in the 2 HDD-FAP patients and not in patient D15. The germline APC mutation was known in 14 of 17 FAP-associated tumors. In 28 of 38 non-FAP-associated desmoid tumors, the beta-catenin gene (CTNNB1) mutation in exon 3 was known and in 1 of 38 tumors an APC mutation was present (data not shown). The remaining tumors were characterized as FAP or non-FAP based on clinical data and positivity of tumor cells upon immunostaining for beta-catenin. DNA was extracted from the tumor samples according to standard methods.
2012-03-31 | E-GEOD-28458 | 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:Desmoid tumors (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumors arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most non-FAP (sporadic) desmoids carry somatic mutations in the beta-catenin gene. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumors. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumors, we analyzed 17 FAP-associated and 38 sporadic desmoids for copy number abnormalities (CNAs) by means of array comparative genomic hybridization and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Common gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumors. Frequent common losses were observed within a 700 kb region at 5q22.2, comprising the APC gene (11%), in a 2 Mb region at 6p21.2-p21.1 (15%), and in a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of CNAs (59%) than the sporadic tumors (37%). As predicted by the APC germline mutations among these patients, a relatively high percentage (29%) of the FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumors. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumor progression.
2012-04-01 | GSE28458 | 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:Gain-of-function mutations in exon 3 of beta-catenin (CTNNB1) are specific for Wilms' tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of beta-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms' tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms' tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct beta-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms' tumor, and indicate strong selection for stabilization of beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1. Experiment Overall Design: Identification of WNT/Beta-Catenin or WT1 target genes. 39 individual samples.
2008-06-14 | E-GEOD-6120 | biostudies-arrayexpress
Project description:Mutations of β-catenin gene (CTNNB1) are frequent in adrenocortical adenomas (AA) and carcinomas (ACC). However, the target genes of CTNNB1 have not yet been identified in adrenocortical tumors. Our objective was to identify genes de-regulated in adrenocortical tumors harbouring CTNNB1 genetic alterations. We compared gene expression profiles of AA with (n: 3) and without (n: 4) CTNNB1 mutations using Affymetrix arrays.
2011-04-09 | E-GEOD-28476 | biostudies-arrayexpress
Project description:Medulloblastoma is the most frequent malignant pediatric brain tumor. Considerable efforts are dedicated to identify markers that help to refine treatment strategies. The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favorable patient outcome. We report a series of 72 pediatric medulloblastomas evaluated for beta-catenin immunostaining, CTNNB1 mutations, and studied by comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-catenin showed extensive nuclear staining (>50% of the tumor cells) in 6 cases and focal nuclear staining (<10% of cells) in 3 cases. The other cases exhibited either a signal strictly limited to the cytoplasm (58 cases) or were negative (5 cases). CTNNB1 mutations were detected in all beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented a strong activation of the Wnt/beta-catenin pathway. Remarkably, 5 out of these 6 tumors showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumors with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5-121.2) from diagnosis. All three patients with a focal nuclear staining of beta-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumors represent a distinct molecular subgroup of medulloblastomas with favorable outcome, indicating that therapy de-escalation should be considered. Yet, international consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved. A series of 72 pediatric medulloblastoma tumors has been studied at the genomic level (array-CGH), screened for CTNNB1 mutations and beta-catenin expression (immunohistochemistry). A subset of 40 tumor samples has been analyzed at the RNA expression level (Affymetrix HG U133 Plus 2.0). Correlations between the genomic data, the expression data, the mutational screening, the pathological classification and clinical data is presented in the study. note: aCGH data not submitted to GEO
2009-02-02 | E-GEOD-12992 | biostudies-arrayexpress
Project description:Gain-of-function mutations in exon 3 of beta-catenin (CTNNB1) are specific for Wilms' tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of beta-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms' tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms' tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct beta-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms' tumor, and indicate strong selection for stabilization of beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1. Keywords: single channel
2006-10-28 | GSE6120 | GEO