Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Combined Genome and Transcriptome Sequencing to Identify Allelic Selection in Epithelial Ovarian Cancer

ABSTRACT: Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those alleles could lead to new therapeutic strategies. Three cancer patients, three tumor samples per patient from different sites, two normal tissue samples from two different patients, four cell lines.

ORGANISM(S): Homo sapiens

SUBMITTER: Najeeb Halabi

PROVIDER: E-GEOD-75935 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

Combined Genome and Transcriptome Sequencing to Identify Allelic Selection in Epithelial Ovarian Cancer

Project description:Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those alleles could lead to new therapeutic strategies.

2015-12-12 | GSE75935 | GEO

RNA expression at chromosome 8q24 in human colon

Project description:An inherited variant on chromosome 8q24, rs6983267, is significantly associated with cancer pathogenesis. We present evidence that this region is a transcriptional enhancer, that the risk region physically interacts with the MYC proto-oncogene, and that the alleles of rs6983267 differentially bind transcription factor 7-like 2 (TCF7L2). These data provide strong support for a biological mechanism underlying this non-protein coding risk variant. Total RNA and genomic DNA were isolated from colon tissue in 5 individuals. cDNA and DNA were analyzed on separate tracks, with the genomic DNA used to identify sprurious cross-hybridization

2010-05-18 | E-GEOD-16228 | biostudies-arrayexpress

Natural WNT signaling variant potently synergizes with Cdkn2ab loss in skin carcinogenesis.

Project description:Cancer predisposing allelic variants have shown to be notoriously difficult to identify by conventional GWA studies. Searching for preferential co-occurrence with defined somatically acquired oncogenic lesions can significantly contribute to the identification of such alleles1. We here show that a natural Wnt-7b allelic variant in the mouse, which is not associated with increased tumour susceptibility, strongly synergizes with loss of the Cdkn2ab tumour suppressor locus in cancer development. Previously, we reported that Cdkn2ab-/- mice, generated from 129P2 ES cells develop skin carcinomas 2. The incidence of these carcinomas dropped gradually in the course of backcrossing to the FVB/N background suggesting that one or more 129P2 alleles cooperate with Cdkn2ab deficiency in skin carcinogenesis. Here we show that this skin cancer phenotype is linked to a 20Mb region of 129P2 chromosome 15 harboring the Wnt7b and Pdgfb genes. Both Wnt7b and Pdgfb are preferentially expressed from the 129P2 allele in skin carcinomas and derived cell lines. ChIPseq analysis showed enrichment of H3K27-Ac, a mark for active enhancers, in the 5’ region of the Wnt7b 129P2 gene. Moreover, the Wnt7b 129P2 allele appeared sufficient to cause in vitro transformation and anchorage-independent growth of Cdkn2ab deficient cell lines. Further we show that Wnt7b contributes to transformation through Cdk6 activation. Our observations imply that normally occurring variations in Wnt expression can elicit transformation of cells upon Cdkn2ab locus loss and point to a critical role of the Cdkn2ab locus in keeping the oncogenic potential of physiological levels of Wnt signaling in check. Consequently, it will be worthwhile to explore whether human tumours that show loss of CDKN2ab are associated with distinct allelic variants causing enhanced WNT signaling.

2019-02-12 | GSE125885 | GEO

4T1 RNA-Seq

Project description:Background: the transcription of tumor mutations from DNA into RNA has implications for biology, epigenetics and clinical practice. It is not clear if mutations are in general transcribed and, if so, at what proportion to the wild-type allele. Here, we examined the correlation between DNA mutation allele frequency and RNA mutation allele frequency. Methods: we sequenced the exome and transcriptome of tumor cell lines with large copy number variations, identified heterozygous single nucleotide mutations and absolute DNA copy number, and determined the corresponding DNA and RNA mutation allele fraction. Results: we found that 99% of the DNA mutations in expressed genes are expressed as RNA. Moreover, we found a high correlation between the DNA and RNA mutation allele frequency. Exceptions are mutations that cause premature termination codons and therefore activate nonsense-mediated decay. Beyond this, we did not find evidence of any wide-scale mechanism, such as allele-specific epigenetic silencing, preferentially promoting mutated or wild-type alleles. Conclusion: taken together, our data strongly suggest that genes are equally transcribed from all alleles, mutated and wild-type, and thus transcribed in proportion to their DNA allele frequency.

2014-03-05 | E-MTAB-2383 | biostudies-arrayexpress

CLUC CLUT DNA binding proteins

Project description:Alzheimers disease (AD) is the most common form of dementia in the elderly with no cure. Although huge efforts have been made to develop drugs for AD, most programs aimed for disease-modifying therapies have failed. Possible reasons for the high failure rate include insufficient understanding of mechanisms underlying AD pathogenesis. The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset AD. However, whether the CLU rs11136000 SNP is functional and what are molecular mechanisms underlying the risk effect of the CLU variant remain unknown. In this study, we identified the CLU rs11136000 SNP as a functional variant by CRIPSR/Cas9 knockout of the SNP. Moreover, by switching the risk C and the protective T alleles using CRISPR/Cas9 editing, we generated isogenic iPSCs with different alleles of the CLU rs11136000 SNP. Astrocytes derived from isogenic iPSCs carrying the C or T allele exhibited different CLU expression and differential inflammatory response. C/C astrocytes carrying two C alleles expressed higher level of CLU and exhibited elevated interferon (IFN) response and CXCL10 expression upon TNFalpha/IL1beta treatment. Furthermore, using human iPSC-derived astrocytes and OPCs co-cultured on nanofibers, we demonstrated that elevated CXCL10 expression in C/C astrocytes induced by TNFalpha/IL1beta led to inhibition of OPC proliferation and myelination. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk C allele carriers. This knowledge could help us to design more effective strategies to treat AD by targeting IFN response and CXCL10 that are upstream of myelination deficits, an early event in AD pathogenesis that proceeds before cognitive decline.

2022-01-07 | MSV000088660 | MassIVE

Transcription profiling by array of Apc-deficient mouse small intestinal epithelium upon Msx1 depletion.

Project description:The first step in the development of human colorectal cancer is the aberrant hyperactivation of the Wnt signaling pathway, predominantly caused by inactivating mutations in the adenomatous polyposis coli (Apc) gene encoding an essential tumor suppressor. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation in intestinal epithelium isolated in mice harboring the conditional allele of the Apc gene. To identify the gene signature in the small intestine upon Msx1 depletion, small intestinal epithelium from mice harboring conditional alleles of Apc and Msx1 was isolated and the gene expression profile was compared with control mice harboring the conditional allele of Apc only.

2019-11-01 | E-MTAB-6930 | biostudies-arrayexpress

PRM data for "Functional analysis of a common BAG3 allele associated with protection from heart failure"

Project description:Manuscript abstract: "Multiple genetic association studies have correlated a common allelic block linked to the BAG3 gene with a decreased incidence of heart failure, but the molecular mechanism for such protection remains elusive. One of the variants in this allele block is coding, changing cysteine to arginine at position 151 of BAG3 (rs2234962-BAG3C151R). Here, we use induced pluripotent stem cells (iPSC) to test if the BAG3C151R variant alters protein and cellular function in human cardiac myocytes. Quantitative protein interaction network analysis identified specific changes in BAG3C151R protein interaction partners in cardiomyocytes but not in iPSCs or an immortalized cell line. Knockdown of BAG3 interacting factors in cardiomyocytes followed by myofibrillar analysis revealed that BAG3C151R associates more strongly with proteins involved in the maintenance of myofibrillar integrity. Finally, we demonstrate that cardiomyocytes expressing the BAG3C151R variant have improved response to proteotoxic stress in an allele dose-dependent manner. This study suggests that the BAG3C151R variant increases cardiomyocyte protection from stress by enhancing the recruitment of factors critical to the maintenance of myofibril integrity, hinting that this variant could be responsible for the cardioprotective effect of the haplotype block. By revealing specific changes in preferential binding partners of the BAG3C151R protein variant, we also identify potential targets for the development of novel cardioprotective therapies."

2023-05-22 | PXD041228 | panorama

Contribution of CgPDR1-regulated genes in enhanced virulence of azole-resistant Candida glabrata (part 2)

Project description:In this study, we aimed to determine genome-wide changes in gene expression driven by seven individual CgPDR1 hyperactive alleles as compared to wild-type allele to identify i) the CgPdr1p target genes differentially expressed in presence of CgPDR1 hyperactive alleles and ii) potential virulence factor(s) regulated by CgPDR1 hyperactive alleles. Microarray experiments revealed a high number of genes (ranging from 80 to 400 genes) differentially regulated by individual CgPDR1 hyperactive alleles. Gene expression was measured in 2 C. glabrata clinical isolates (DSY717 and DSY2317). DSY2317 is azole-susceptible and contains a wild-type CgPDR1 allele. DSY717 is azole-resistant and contains a CgPDR1 allele with the gain-of-function mutation L1081F.

2010-12-31 | E-GEOD-23828 | biostudies-arrayexpress

Quantitative proteomic analysis of proteins bound to rs452384-T or rs452384-C

Project description:This project focuses on the functional characterization of a risk variant (SNP) implicated in the predisposition to uveal melanoma, rs452384. We sought to determine whether some nuclear factors could bind with allele-specificity a DNA sequence centered around rs452384 to regulate gene expression. We sought to identify by quantitative mass spectrometry the nuclear proteins bound to double-stranded DNA probes with identical DNA sequences except for rs452384-C or T alleles in the center of the probe. The goal was to quantify the binding of transcription factors to the DNA probes, and to select those enriched (or specific) to the C or T allele of rs452384. To identify proteins specifically bound to rs452384, we compared binding partners to those obtained with a negative control probe known not to recognize any transcription factor.

2022-11-15 | PXD028954 | Pride

Contribution of CgPDR1-regulated genes in enhanced virulence of azole-resistant Candida glabrata (part 2)

2010-12-31 | GSE23828 | GEO