DNA methylation biomarkers predict Wilms tumor disease progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE269241 | GEO | 2024/11/28
REPOSITORIES: GEO
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Project description:Wilms' tumor (WT) is the most common pediatric kidney cancer with more than a 90% overall survival rate in response to standard chemotherapy. However, less-differentiated blastemal type of WT often metastasize and relapse. To remodel the high-risk WT for therapeutic intervention, we partially reprogrammed WIT49, a mixed type of WT cell line, to iPSCs, which we termed as WiT49-PRCs (Partial reprogrammed iPSCs). WiT49-PRCs express stem cell markers. When implanted into the kidney capsule in mice, WiT49-PRCs formed kidney tumors and developed both liver and lung metastases, whereas WiT49 tumors do not metastasize. Histological characterization and gene expression signatures demonstrated that WiT49-PRC recapitulates blastema-dominant WTs. Moreover, screening FDA-approved drugs in isogeneic WiT49 and WiT49-PRC cells led to the identification of epithelial- or blastemal-dominant WT-sensitive drugs. A subset of drugs was discovered with selectivity towards blastemal WT patient derived xenografts (PDXs). HDAC inhibitors (e.g. panobinostat and romedipsin) were found universally effective across different WT and more potent than doxorubicin in PDXs. Taken together, WiT49-PRC serves as a blastemal-dominant WT model for therapeutic intervention to improve the treatment of high-risk WT patients.
2024-11-06 | GSE246479 | GEO
Project description:Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find novel therapeutic leads for this subgroup of patients, we analyzed 58 blastemal-type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large independent replication cohort. Recurrent mutations identified either somatically or in the germline included a hotspot mutation (Q177R) in the homeodomain of SIX1 and SIX2 in tumors with high proliferative potential, mutations in microprocessor genes like DROSHA, DGCR8, DICER1 and DIS3L2, and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations had a strong effect on miRNA expression patterns in tumors, which was functionally validated in cell lines transfected with mutant DROSHA. total samples analyzed are 16, each done as technical replicate
2015-02-18 | E-GEOD-60081 | biostudies-arrayexpress
Project description:Wilms tumor (WT), the commonest renal tumor of the childhood, is originated from pluripotent metanephric blastemal cells resulting in tumors with triphasic histology, composed by blastemal, epithelial, and stromal cells. Histological subtype and tumor stage have long been recognized as important prognostic factors and used for the current therapeutic approach with blastema considered as the component with the highest clinical impact. Current clinical and molecular research is directed toward identifying prognostic factors for both purposes, definition of the minimal or intense required therapy for successful treatment of children with low or high risk of relapse, respectively. In this study, to identify molecular prognostic markers predictive of tumor relapse, samples from 26 advanced (Stage III or IV) blastemal WT, whose patients presented (13 samples) or did not present (13 samples) relapse, were interrogated by 4,608 human genes immobilized in a customized cDNA platform. This analysis revealed a set of 69 differentially expressed genes, where the nine top genes were evaluated by qRT-PCR in the initial WT samples. TSPAN3, NCOA6, CDO1, MPP2 and MCM2 were technically confirmed showing down-regulation in relapse WT. TSPAN3 and NCOA6 were validated in an independent sample group. Gene trios containing these two genes combined with one of the remaining three reported a reasonable capability of discriminating relapse and no-relapse WT. Negative protein expression of MCM2 and NCOA6 was observed in around 62% and 72% of 34 independent stage III and IV WT patients, respectively without association with relapse. However, a significant association between MCM2 negative staining and chemotherapy as first treatment was observed suggesting that MCM2 protein expression is implicated anyhow with chemotherapy treatment in WT.
2011-06-01 | GSE22696 | GEO
Project description:Wilms tumor (WT) is the most common renal tumor in childhood. Among others, MYCN copy number gain and MYCN P44L and MAX R60Q mutations have been identified in WT. The proto-oncogene MYCN encodes a transcription factor that requires dimerization with MAX to activate transcription of numerous target genes. MYCN gain has been associated with adverse prognosis. The MYCN P44L and MAX R60Q mutations, located in either the transactivating or basic helix-loop-helix domain, respectively, are predicted to be damaging by different pathogenicity prediction tools. We screened a large cohort of unselected WTs and revealed frequencies of 3 % for MYCN P44L and 0.8 % for MAX R60Q, associated with a higher risk of relapse in the case of MYCN. Biochemical characterization identified a reduced transcriptional activation potential for MAX R60Q, while the MYCN P44L mutation did not change activation potential or protein stability. The protein interactome of N-MYC-P44L was likewise not altered as shown by mass spectrometric analyses of purified N-MYC complexes. Nevertheless, we could identify a number of novel N-MYC partner proteins, and several of these are known for their oncogenic potential. Correlated expression in WT samples suggests a role in WT oncogenesis and they expand the range of potential biomarkers for WT stratification and targeting, especially for high-risk WT.
2022-02-17 | PXD025996 | Pride
Project description:Wilms tumour (nephroblastoma) is the most common paediatric renal tumour, affecting 1 in 10,000 children. Despite the excellent survival of patients treated with a combination of surgery, chemotherapy and radiotherapy, approximately 15% will relapse and die of this disease. We have identified CACNA1E to be significantly overexpressed in relapsing tumours compared to non-relapsing. To investigate the involvement of CACNA1E in Wilms tumorigenesis, CACNA1E stably transfected HEK293 cell line and parental lines were obtained, grown and RNA extracted. To assess differential gene expression between the two cell lines, RNA was hybridised to Affymetrix Human Genome U133 Plus 2.0 GeneChip. Human embryonic kidney HEK293 parental and HEK2C6, (CACNA1E stably transfected cells) were kindly provided by Prof. Schneider, Cologne (Pereverzev et al., 1998).
2006-12-01 | E-MEXP-587 | biostudies-arrayexpress
Project description:Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find novel therapeutic leads for this subgroup of patients, we analyzed 58 blastemal-type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large independent replication cohort. Recurrent mutations identified either somatically or in the germline included a hotspot mutation (Q177R) in the homeodomain of SIX1 and SIX2 in tumors with high proliferative potential, mutations in microprocessor genes like DROSHA, DGCR8, DICER1 and DIS3L2, and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations had a strong effect on miRNA expression patterns in tumors, which was functionally validated in cell lines transfected with mutant DROSHA.
2015-02-18 | GSE60081 | GEO
Project description:To identify underlying mechanisms involved with metastasis formation in Wilms tumors (WTs), we performed comprehensive DNA methylation and gene expression analyses of matched normal kidney (NK), WT blastemal component, and metastatic tissues (MT) from patients treated under SIOP 2001 protocol. A linear Bayesian framework model identified 497 differentially methylated positions (DMPs) between groups that discriminated NK from WT, but MT samples were divided in two groups. Accordingly, methylation variance grouped NK and three MT samples tightly together and all WT with four MT samples that showed high variability. WT were hypomethylated compared to NK, and MT had a hypermethylated pattern compared to both groups. The methylation patterns were in agreement with methylases and demethylases expression. Methylation data pointed to the existence of two groups of metastases. While hierarchical clustering analysis based on the expression of all 2569 differentially expressed genes (DEGs) discriminated WT and MT from all NK samples, the hierarchical clustering based on the expression of 44 genes with a differentially methylated region (DMR) located in their promoter region revealed two groups: one containing all NKs and three MTs and one containing all WT and four MTs. Methylation changes might be controlling expression of genes associated with WT progression. The 44 genes are candidates to be further explored as a signature for metastasis formation in WT.
2020-12-17 | GSE163372 | GEO
Project description:Background: Nephroblastoma, also known as Wilms’ tumor (WT), is an embryonic malignant tumor and one of the most common malignant tumors in the abdominal region of children. Previous studies have demonstrated that aquaporin 1 (AQP1), a highly expressed channel protein in the kidneys, is closely associated with various diseases and also plays a significant role in tumorigenesis and progression. However, the exact role and underlying mechanisms of AQP1 in the occurrence and development of nephroblastoma remain unclear. Methods: After overexpression of AQP1, cell proliferation was assessed using the CCK-8 proliferation assay and EdU staining. Flow cytometry was employed to detect cell apoptosis, and Western blotting (WB) analysis was conducted to validate the expression of relevant protein markers. mRNA Sequencing (mRNA-Seq) was performed on WT cells with AQP1 overexpression to predict and characterize the associated mechanisms. Transmission electron microscopy was utilized to observe changes in the ultrastructure of WT cells undergoing apoptosis and pyroptosis following AQP1 overexpression. Functional in vivo validation was conducted through animal experiments. Results: We validated at both in vitro and in vivo levels that overexpression of AQP1 inhibited cell proliferation and promoted cell apoptosis and pyroptosis. mRNA-Seq analysis of WT cells with AQP1 overexpression suggested that these effects might be mediated through the inhibition of the JAK-STAT signaling pathway, which was further experimentally validated. Additionally, we discovered that overexpression of AQP1 activated the classical pyroptosis signaling pathway dependent on Caspase-1, thereby promoting pyroptosis in WT. Conclusion: These findings highlight the significant functional role of AQP1 in the pathobiology of nephroblastoma, providing novel insights into the development of this disease. Moreover, these results offer new perspectives on the potential therapeutic targeting of AQP1 as a treatment strategy for nephroblastoma.
2024-02-14 | GSE247460 | GEO
Project description:Precise regulation of transduction signaling pathways genes is crucial for correct differentiation of kidney cells and perturbation may lead to tumor onset. Wilms tumors (WT), or nephroblastoma, originates from the metanephric blastema cells, which were unable to complete the differentiation, resulting in a triphasic tumor composed by distinct cell types, blastemal, epithelial and stromal, where the former harbor molecular characteristics similar to cells of the earliest stages of kidney development. In this study, to identify key early events involved in the disruption of correct cell signaling during kidney differentiation that can drive WT, we developed a cDNA platform containing genes from signaling transduction pathways. By using bioinformatics tools, we defined high conserved regions between human and mouse orthologous genes and assessed the gene modulation in blastemal cells captured from WT and differentiated kidneys (DK) in human and from four temporal stages of kidney differentiation in mouse. We found 18 genes, whose transcriptional level of the earliest phases of blastemal cell differentiation was recapitulated in WT. PAX2, FZD10, SHPK, WNT5B, FZD2, CRABP2, FRZB, GRK7, TESK1, HDGF and IGF2 were up- and MAPK9, PIK3CA, FRAT2, ITPR3, CDH6, HIPK1 and TIMP3 were down-regulated in WT respectively. Hierarchical clustering based on the expression of this gene set grouped DK from both species, human and mouse, and discriminated them from fetal kidney and WT in human, and the earliest kidney stages in mouse, validating the model proposed by this study and reveling a transduction signaling signature of WT. High robustness of this data was detected since expression level was tested by quantitative RT-PCR in the initial and independent sample set, with 75 and 56% of agreement. Agreement of 62% was also observed in protein level assessing blastemal component of an independent group of 137 WT. Protein expression of CRABP2, IGF2, GRK7, TESK1, HDGF, WNT5B, FZD2 and TIMP3 was also characterized in human fetal kidneys revealing interesting aspects of kidney differentiation. This study identified key genes modulated during kidney differentiation which may play a determinant role for WT onset. As far as we know, FZD10, FRZB, HDGF, MAPK9, FRAT2, SHPK, WNT5B, GRK7, TESK1, HDGF, PIK3CA, ITPR3, HIPK1 and TIMP3 were not previously associated to WT.
2011-12-07 | GSE25965 | GEO
Project description:The IGF2-intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis. The expression levels of microRNAs were profiled in 20 human Wilms tumor samples (WT), 3 human normal adult kidney samples (AK) and 5 human fetal kidney samples (FK) using a Luminex bead platform.
2013-12-22 | E-GEOD-50505 | biostudies-arrayexpress