Discovery of Non-ETS Gene Fusions in Human Prostate Cancer using Next Generation RNA Sequencing
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE21032phs000310.v1.p1
PROVIDER: PRJNA74905 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:<p>Half of prostate cancers harbor gene fusions between <i>TMPRSS2</i> and members of the <i>ETS</i> transcription factor family. To date little is known about the presence of non-ETS fusion events in prostate cancer. We employed next-generation transcriptome sequencing (RNA-Seq) in order to explore the whole transcriptome of 25 human prostate cancer samples for the presence of chimeric fusion transcripts. We generated more than 1 billion sequence reads and used a novel computational approach (FusionSeq) in order to identify novel gene fusion candidates with high confidence. In total, we discovered and characterized seven new cancer-specific gene fusions, two involving the ETS genes <i>ETV1</i> and <i>ERG</i>, and five involving non-ETS genes such as <i>CDKN1A</i> (p21), <i>CD9</i> and <i>IKBKB</i> (IKK-beta), genes known to exhibit key biological roles in cellular homeostasis or assumed to be critical in tumorigenesis of other tumor entities, as well as the oncogene PIGU and the tumor suppressor gene <i>RSRC2</i>. The novel gene fusions are found to be of low frequency but interestingly, the non-ETS fusions were all present in prostate cancer harboring the <i>TMPRSS2-ERG</i> gene fusion. Future work will focus on determining if the ETS rearrangements in prostate cancer are associated or directly predispose to a rearrangement prone phenotype.</p>
| phs000310.v1.p1 | EGA
Project description:Half of prostate cancers harbor gene fusions between TMPRSS2 and members of the ETS transcription factor family. To date, little is known about the presence of non-ETS fusion events in prostate cancer. We used next-generation transcriptome sequencing (RNA-seq) in order to explore the whole transcriptome of 25 human prostate cancer samples for the presence of chimeric fusion transcripts. We generated more than 1 billion sequence reads and used a novel computational approach (FusionSeq) in order to identify novel gene fusion candidates with high confidence. In total, we discovered and characterized seven new cancer-specific gene fusions, two involving the ETS genes ETV1 and ERG, and four involving non-ETS genes such as CDKN1A (p21), CD9, and IKBKB (IKK-beta), genes known to exhibit key biological roles in cellular homeostasis or assumed to be critical in tumorigenesis of other tumor entities, as well as the oncogene PIGU and the tumor suppressor gene RSRC2. The novel gene fusions are found to be of low frequency, but, interestingly, the non-ETS fusions were all present in prostate cancer harboring the TMPRSS2-ERG gene fusion. Future work will focus on determining if the ETS rearrangements in prostate cancer are associated or directly predispose to a rearrangement-prone phenotype.
| S-EPMC3012926 | biostudies-literature
Project description:<p>Half of prostate cancers harbor gene fusions between <i>TMPRSS2</i> and members of the <i>ETS</i> transcription factor family. To date little is known about the presence of non-ETS fusion events in prostate cancer. We employed next-generation transcriptome sequencing (RNA-Seq) in order to explore the whole transcriptome of 25 human prostate cancer samples for the presence of chimeric fusion transcripts. We generated more than 1 billion sequence reads and used a novel computational approach (FusionSeq) in order to identify novel gene fusion candidates with high confidence. In total, we discovered and characterized seven new cancer-specific gene fusions, two involving the ETS genes <i>ETV1</i> and <i>ERG</i>, and five involving non-ETS genes such as <i>CDKN1A</i> (p21), <i>CD9</i> and <i>IKBKB</i> (IKK-beta), genes known to exhibit key biological roles in cellular homeostasis or assumed to be critical in tumorigenesis of other tumor entities, as well as the oncogene PIGU and the tumor suppressor gene <i>RSRC2</i>. The novel gene fusions are found to be of low frequency but interestingly, the non-ETS fusions were all present in prostate cancer harboring the <i>TMPRSS2-ERG</i> gene fusion. Future work will focus on determining if the ETS rearrangements in prostate cancer are associated or directly predispose to a rearrangement prone phenotype.</p>
| phs000310 | dbGaP
Project description:Deregulated expression of ETS transcription factors with oncogenic and tumor suppressor function occurs frequently in prostate cancer leading to profound alterations of the cancer transcriptome. By integrating genomic and functional studies we identified key targets of the aberrantly expressed ETS factors, ERG and ESE3. Altered expression of ETS factors led to the induction of the polycomb group protein EZH2 and silencing of the tumor suppressor Nkx3.1. Nkx3.1 was controlled by ERG and ESE3 both directly via binding to ETS binding sites in the gene promoter and indirectly via EZH2-induced histone H3K27 methylation. This may represent a general mechanism linking aberrantly expressed ETS with deregulation of epigenetic pathways and global reprogramming of the prostate epithelial cell transcriptome in prostate tumorigenesis. Keywords: prostate cancer, gene expression profiling, ETS genes In this study we show that deregulated expression of ETS factors with opposite functions is highly frequent in prostate cancer. Our study uncovers a previously unrecognized link between aberrant expression of ETS factors, deregulation of epigenetic pathways and silencing of tumor suppressor genes in prostate cancer and shows that partially distinct transcriptional programs are associated with different ETS gene expression patterns. The presence of distinct prostate cancer subgroups with different biological features may have important clinical implications and suggests that assessment of ETS expression levels might be useful to distinguish tumors with different clinical outcome.
2010-06-09 | E-GEOD-14206 | biostudies-arrayexpress
Project description:BackgroundGene fusions represent promising targets for cancer therapy in lung cancer. Reliable detection of multiple gene fusions is therefore essential.MethodsFive commercially available parallel sequencing assays were evaluated for their ability to detect gene fusions in eight cell lines and 18 FFPE tissue samples carrying a variety of known gene fusions. Four RNA-based assays and one DNA-based assay were compared; two were hybrid capture-based, TruSight Tumor 170 Assay (Illumina) and SureSelect XT HS Custom Panel (Agilent), and three were amplicon-based, Archer FusionPlex Lung Panel (ArcherDX), QIAseq RNAscan Custom Panel (Qiagen) and Oncomine Focus Assay (Thermo Fisher Scientific).ResultsThe Illumina assay detected all tested fusions and showed the smallest number of false positive results. Both, the ArcherDX and Qiagen panels missed only one fusion event. Among the RNA-based assays, the Qiagen panel had the highest number of false positive events. The Oncomine Focus Assay (Thermo Fisher Scientific) was the least adequate assay for our purposes, seven fusions were not covered by the assay and two fusions were classified as uncertain. The DNA-based SureSelect XT HS Custom Panel (Agilent) missed three fusions and nine fusions were only called by one software version. Additionally, many false positive fusions were observed.ConclusionsIn summary, especially RNA-based parallel sequencing approaches are potent tools for reliable detection of targetable gene fusions in clinical diagnostics.
| S-EPMC7912891 | biostudies-literature
Project description:Deregulated expression of ETS transcription factors with oncogenic and tumor suppressor function occurs frequently in prostate cancer leading to profound alterations of the cancer transcriptome. By integrating genomic and functional studies we identified key targets of the aberrantly expressed ETS factors, ERG and ESE3. Altered expression of ETS factors led to the induction of the polycomb group protein EZH2 and silencing of the tumor suppressor Nkx3.1. Nkx3.1 was controlled by ERG and ESE3 both directly via binding to ETS binding sites in the gene promoter and indirectly via EZH2-induced histone H3K27 methylation. This may represent a general mechanism linking aberrantly expressed ETS with deregulation of epigenetic pathways and global reprogramming of the prostate epithelial cell transcriptome in prostate tumorigenesis. Keywords: prostate cancer, gene expression profiling, ETS genes
2010-05-25 | GSE14206 | GEO
Project description:Next Generation Gene Discovery in Familial Autism
| PRJNA325333 | ENA
Project description:ETS transcription factors have recently emerged as important elements in the pathogenesis of prostate cancer (PCa). ETS gene rearrangements leading to over-expression of ETS factors, like ERG, ETV1 and ETV4, are found in about 50% of prostate tumors. While the oncogenic potential of translocated ETS has been demonstrated in several contexts, the impact of endogenously expressed ETS factors on prostate tumorigenesis has been largely overlooked. Here we show that the epithelial-specific ETS factor ESE3, which is normally expressed in basal prostate epithelial (PrE) cells and frequently down-regulated in prostate tumors, serves as gatekeeper to maintain cell differentiation and its down-regulation leads to the acquisition of mesenchymal, stem cell (SC) and tumorigenic properties. ESE3 exerts this function by regulating critical genes involved in the epithelial to mesenchymal transition (EMT) and cell “stemness” and maintaining the equilibrium between cell differentiation and proliferation. Loss of ESE3 may be an important step in prostate tumorigenesis. Keywords: prostate epithelial cells, prostate cancer, gene expression profiling, ETS genes, EMT, cancer stem cells
2012-06-05 | GSE23197 | GEO
Project description:Approximately 50% of prostate cancers have chromosomal translocations resulting in the over-expression one of four ETS family transcription factors. However, it is not known why these four four family members are selected for oncogenic roles, while other ETS proteins are not. We found that the four oncogenic ETS family members have a specific role in prostate cell migration. Using chromatin immunoprecipitation coupled with next-generation sequencing, this specific biological function was matched to a specific set of genomic targets highlighted by the presence of an AP-1 binding site. ETS/AP-1 binding sites are prototypical Ras-responsive elements, but oncogenic ETS proteins could activate a Ras/MAPK transcriptional program in the absence of MAPK activation. These findings indicate that the specific function of ETS proteins over-expressed in prostate cancer is the activation of a Ras/MAPK gene expression program in the absence of signaling pathway mutations. ChIP sequencing two transcription factors in PC3 cells, four transcription factors plus a FLAG control in RWPE-1 cells and input DNA sequencing from each cell line.
2011-10-19 | E-GEOD-29808 | biostudies-arrayexpress
Project description:Approximately 50% of prostate cancers have chromosomal translocations resulting in the over-expression one of four ETS family transcription factors. However, it is not known why these four four family members are selected for oncogenic roles, while other ETS proteins are not. We found that the four oncogenic ETS family members have a specific role in prostate cell migration. Using chromatin immunoprecipitation coupled with next-generation sequencing, this specific biological function was matched to a specific set of genomic targets highlighted by the presence of an AP-1 binding site. ETS/AP-1 binding sites are prototypical Ras-responsive elements, but oncogenic ETS proteins could activate a Ras/MAPK transcriptional program in the absence of MAPK activation. These findings indicate that the specific function of ETS proteins over-expressed in prostate cancer is the activation of a Ras/MAPK gene expression program in the absence of signaling pathway mutations.
2011-10-20 | GSE29808 | GEO