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Characterizing MYCN targets in Wilms' tumour

ABSTRACT: Transcriptomic analysis of MYCN targets in anaplastic Wilms' tumour cells

PROVIDER: PRJEB41686 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR4907220_1.fastq.gz	Fastqsanger.gz
	ERR4907220_2.fastq.gz	Fastqsanger.gz
	ERR4907221_1.fastq.gz	Fastqsanger.gz
	ERR4907221_2.fastq.gz	Fastqsanger.gz
	ERR4907222_1.fastq.gz	Fastqsanger.gz

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Bromodomain 4 inhibition leads to MYCN downregulation in Wilms’ tumor cells

Project description:We have undertaken a functional genomics approach to uncover novel therapeutic strategies efficacious for those patients with anaplastic Wilms’ tumor. Genomic analysis, in vitro chemical screens and microfluidic experiments demonstrate that MYCN over-expression in Wilms’ tumor can be modulated via BRD4 inhibition resulting in a reduction in Wilms’ tumor cell growth.

2020-08-12 | GSE156065 | GEO

MYCN and MAX alterations in Wilms tumor and identification of novel interactors as biomarker candidates

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

Proteasome inhibition sensitizes anaplastic Wilms tumor to actinomycin D

Project description:Wilms tumor is the most common kidney cancer in children, and anaplastic Wilms tumor is the most chemoresistant histological subtype. Here we explore how anaplastic Wilms tumor cells evade the common chemotherapeutic drug actinomycin D, which inhibits ribosomal biogenesis. We found that, when ribosomal capacity is limited by actinomycin D treatment, anaplastic Wilms tumor cells preferentially translate proteasome components and upregulate proteasome activity. Accordingly, increased proteasome levels are associated with anaplastic histology and with worse prognosis in Wilms tumor. Lastly, we show that the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment both in vitro and in vivo.

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The Wilms' tumour 1 transcription factor regulates epigenetic states via DNA methyltransferase 3A

Project description:The Wilms' tumour 1 transcription factor regulates epigenetic states via DNA methyltransferase 3A.

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Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms' tumour

Project description:Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms' tumour

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MicroRNA profiling of Wilms Tumour 1 deleted and induced embryonic stem cells

Project description:We report the microRNA profiles of the mouse embryonic stem cell (E14IV), which have been deleted for tumour suppressor Wilms' Tumour 1 (WT1), and induced with retinoic acid. Additionally, cells that had an inducibe WT1 expression where also used to compare the microRNA profile during different time points of WT1 induction.

2024-03-26 | GSE169684 | GEO

Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms' tumour

Project description:Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms' tumour The data consists of five microarrays hybridized with methylated DNA immunoprecipitated from Wilms' tumours and from a normal foetal kidney control

2010-05-22 | E-GEOD-15027 | biostudies-arrayexpress

The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

Project description:Wilms tumour (WT), a childhood kidney cancer with embryonal origins, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of fetal kidney with two WT cell lines, using methyl-CpG immunoprecipitation. We filtered our results to remove common cancer-associated epigenetic changes, and to enrich for genes involved in early kidney development. This identified four candidate genes that were hypermethylated in WT cell lines compared to fetal kidney, of which ESRP2 (epithelial splicing regulatory protein 2), was the most promising gene for further study. ESRP2 was commonly repressed by DNA methylation early in WT development (in nephrogenic rests) and could be reactivated by DNA methyltransferase inhibition in WT cell lines. When ESRP2 was expressed in WT cell lines, it acted as an inhibitor of cellular proliferation in vitro and in vivo it suppressed tumour growth of orthotopic xenografts in nude mice. RNA-seq of the ESRP2-expressing WT cell lines identified several novel splicing targets, in addition to well-characterised targets of ESRP2. One of these targets, LEF1, is a component of the Wnt signalling pathway that is essential for kidney development and commonly disrupted in WT. We propose a model in which the Wnt pathway can be disrupted in early kidney development to generate WT, either by genetic abnormalities such as WT1 mutations, or by epigenetic defects, such as ESRP2 methylation. The microarray data in this deposition identified ESRP2 as a commonly hypermethylated gene in Wilms tumour.

2020-11-02 | GSE153047 | GEO

The developmental programme for genesis of the entire kidney is recapitulated in Wilms tumour

Project description:Expression profiling of Wilms tumour samples, which identified molecular signatures of the ureteric bud and collecting duct as well as those of the proximal and distal tubules in triphasic histology tumours. These observations indicate Wilms tumours can arise from a precursor cell capable of generating the entire kidney, such as the cells of the intermediate mesoderm from which both the metanephric mesenchym and ureteric bud are derived.

2017-12-31 | E-MTAB-3516 | biostudies-arrayexpress

Multiple mechanisms of MYCN dysregulation in Wilms tumour.

Project description:Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumours of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolve over time. We report a second bilateral case in which MYCN gain is a germline aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation.

| S-EPMC4466681 | biostudies-literature

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