Identification of active promotor regions in Wilms tumor cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE98721 | GEO | 2020/05/09
REPOSITORIES: GEO
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Project description:Wilms tumor (nephroblastoma) is a pediatric kidney tumor that arises from renal progenitor cells. Since the blastemal type is associated with adverse prognosis, we characterized such Wilms tumors by exome and transcriptome analysis. We detected novel, recurrent somatic mutations affecting the SIX1/2 – SALL1 pathway implicated in kidney development, the DROSHA/DGCR8 microprocessor genes as well as alterations in MYCN and TP53, the latter being strongly associated with dismal outcome. The DROSHA mutations impair the RNase III domains, while DGCR8 exhibits stereotypic E518K mutations in the RNA binding domain - both may skew miRNA representation. SIX1 and SIX2 mutations affect a single hotspot (Q177R) in the homeodomain indicative of a dominant effect. In larger cohorts, these mutations cluster in blastemal and chemotherapy-induced regressive tumors that likely derive from blastemal cells and these are characterized by generally higher SIX1/2 expression. These findings broaden the spectrum of human cancer genes and may open new avenues for stratification and therapeutic leads for Wilms tumors. 53 Wilms tumor samples were selected for RNA extraction and hybridization on Affymetrix Affymetrix Human Genome U133 Plus 2.0 Arrays.
2015-02-18 | E-GEOD-53224 | biostudies-arrayexpress
Project description:Wilms tumor (nephroblastoma) is a pediatric kidney tumor that arises from renal progenitor cells. Since the blastemal type is associated with adverse prognosis, we characterized such Wilms tumors by exome and transcriptome analysis. We detected novel, recurrent somatic mutations affecting the SIX1/2 – SALL1 pathway implicated in kidney development, the DROSHA/DGCR8 microprocessor genes as well as alterations in MYCN and TP53, the latter being strongly associated with dismal outcome. The DROSHA mutations impair the RNase III domains, while DGCR8 exhibits stereotypic E518K mutations in the RNA binding domain - both may skew miRNA representation. SIX1 and SIX2 mutations affect a single hotspot (Q177R) in the homeodomain indicative of a dominant effect. In larger cohorts, these mutations cluster in blastemal and chemotherapy-induced regressive tumors that likely derive from blastemal cells and these are characterized by generally higher SIX1/2 expression. These findings broaden the spectrum of human cancer genes and may open new avenues for stratification and therapeutic leads for Wilms tumors.
2015-02-18 | GSE53224 | GEO
Project description:The aim of the study was to identify differentially expressed miRNAs in different Wilms tumor subtypes. Comparison of miRNA expression profiles in Wilms tumor of different subtypes (total n=62) compared to normal kidney tissue (n=4)
2015-02-11 | E-GEOD-57370 | biostudies-arrayexpress
Project description:The aim of the study was to identify key transcriptional regulators that might be responsible for the increased resistance to chemotherapy of blastemal Wilms tumors.
2020-04-28 | GSE98334 | GEO
Project description:The aim of the study was to identify differentially expressed miRNAs in different Wilms tumor subtypes.
2015-02-11 | GSE57370 | GEO
Project description:The aim of the study was to identify differentially expressed mRNAs in different Wilms tumor subtypes and correlate them to miRNA expression profiles of the same tumor samples.
2016-05-11 | GSE66405 | GEO
Project description:Here we have used H3K27ac ChIP-seq in primary Wilms tumors to identify active promoter and enhancer elements genome-wide.
2019-11-25 | GSE126774 | 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. Twenty-six blastemal-enriched advanced stage (III or IV) WT samples from sporadic and favorable histology WT were received from Children Oncology Group (COG) and used were used for microarray experiments, from which 13 samples were from patients without relapse in 5 years of follow up. Tumors were taken from primary nephrectomy at the time of initial diagnosis. Blastemal histological component was isolated following protocol described in Maschietto et al. (2008). Only samples with >80% of blastemal cells were used. Total RNA was isolated using TRIzol (Sigma) according to manufacturer´s instructions. RNA quantity and integrity was assessed by spectrophotometry (Nanodrop) and microfluidics-based electrophoresis (Agilent 2100 Bioanalyzer, Agilent), respectively, selecting only RNA samples with OD around 2.0 and RIN>5.0. A two-round RNA amplification procedure (Gomes et al. 2003) was carried out for all samples. Labeled cDNA was generated in a reverse transcriptase reaction using 4 ug of amplified RNA (aRNA), random hexamer primer (Invitrogen Life Technologies, Carlsbad, CA), Alexa-3 or 5-labeled dCTP (Amersham, Biosciences) and IMPROM (PROMEGA) using oligo-dT7(24), following manufacture recommendations. Five µg of test and reference cDNA reverse color Alexa-labeled aRNA targets were competitively hybridized against the cDNA probes in a customized cDNA platform with 4,608 ORESTES representing human genes. Dye-swap was performed for each sample as control for dye bias and used as replicate. Pre-hybridization and hybridization were performed as described (Maschietto et al. 2008). A pool of RNAs obtained from 15 distinct human cell lines as was used as reference. Signal intensities capture and analysis were performed as described in Maschietto et al (2008).
2011-06-01 | E-GEOD-22696 | 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