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Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types (exon expression)

ABSTRACT: Custom Agilent 8 x 15K microarray interrogating exon level expression of a set of genes previously known to be involved in oncogenic rearrangements. The goal of this study was to discover novel gene fusions by screening for exonic expression transitions within individual genes. Sixteen cancer samples and cell lines, including eight positive controls with known gene fusions and eight sarcoma specimens, where gene fusions have yet to be discovered, were hybridized against a common reference mRNA control (pooled from 11 diverse cell lines)

ORGANISM(S): Homo sapiens

SUBMITTER: Craig Giacomini

PROVIDER: E-GEOD-39287 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types (exon expression)

Project description:Custom Agilent 8 x 15K microarray interrogating exon level expression of a set of genes previously known to be involved in oncogenic rearrangements. The goal of this study was to discover novel gene fusions by screening for exonic expression transitions within individual genes.

2013-05-31 | GSE39287 | GEO

Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types (RNA-seq)

Project description:We report the design and implementation of a "breakpoint analysis" pipeline to discover novel gene fusions by tell-tale transcript level or genomic DNA copy number transitions occurring within genes. We use this method to prioritize candidate rearrangements from high density array CGH datasets as well as exon-resolution expression microarrays. We mine both publicly available data as well as datasets generated in our laboratory. Several gene fusion candidates were chosen for further characterization, and corresponding samples were profiled using paired end RNA sequencing to discover the identity of the gene fusion. Using this approach, we report the discovery and characterization of novel gene fusions spanning multiple cancer subtypes including angiosarcoma, pancreatic cancer, anaplastic astrocytoma, melanoma, breast cancer, and T-cell acute lymphoblastic leukemia. Taken together, this study provides a robust approach for gene fusion discovery, and our results highlight a more widespread role of fusion genes in cancer pathogenesis. Breakpoint analysis for the discovery of novel gene fusions across human cancers

2013-05-31 | E-GEOD-45133 | biostudies-arrayexpress

Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types (RNA-seq)

2013-05-31 | GSE45133 | GEO

Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types.

Project description:Gene fusions, like BCR/ABL1 in chronic myelogenous leukemia, have long been recognized in hematologic and mesenchymal malignancies. The recent finding of gene fusions in prostate and lung cancers has motivated the search for pathogenic gene fusions in other malignancies. Here, we developed a "breakpoint analysis" pipeline to discover candidate gene fusions by tell-tale transcript level or genomic DNA copy number transitions occurring within genes. Mining data from 974 diverse cancer samples, we identified 198 candidate fusions involving annotated cancer genes. From these, we validated and further characterized novel gene fusions involving ROS1 tyrosine kinase in angiosarcoma (CEP85L/ROS1), SLC1A2 glutamate transporter in colon cancer (APIP/SLC1A2), RAF1 kinase in pancreatic cancer (ATG7/RAF1) and anaplastic astrocytoma (BCL6/RAF1), EWSR1 in melanoma (EWSR1/CREM), CDK6 kinase in T-cell acute lymphoblastic leukemia (FAM133B/CDK6), and CLTC in breast cancer (CLTC/VMP1). Notably, while these fusions involved known cancer genes, all occurred with novel fusion partners and in previously unreported cancer types. Moreover, several constituted druggable targets (including kinases), with therapeutic implications for their respective malignancies. Lastly, breakpoint analysis identified new cell line models for known rearrangements, including EGFRvIII and FIP1L1/PDGFRA. Taken together, we provide a robust approach for gene fusion discovery, and our results highlight a more widespread role of fusion genes in cancer pathogenesis.

| S-EPMC3636093 | biostudies-literature

Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types (RNA-seq)

| S-ECPF-GEOD-45133 | biostudies-other

Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types

Project description:This SuperSeries is composed of the SubSeries listed below.

2013-05-31 | GSE45137 | GEO

Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-05-31 | E-GEOD-45137 | biostudies-arrayexpress

Fusion partners influence cellular and molecular phenotypes of oncogenic BRAF fusions

Project description:Fusion genes can be oncogenic drivers in a variety of cancer types and represent potential targets for targeted therapy. The BRAF gene is frequently involved in oncogenic fusions, with fusion frequencies of 0.2-3% throughout different cancers. However, BRAF fusions rarely occur in the same gene configuration, potentially challenging personalized therapy design. In particular, the influence that is imposed by the wide variety of fusion partners on the oncogenic role of BRAF during tumor growth and drug response is unknown. Here, we used patient-derived colorectal cancer organoids to functionally characterize and cross-compare previously identified BRAF fusions containing various partner genes (AGAP3, DLG1 and TRIM24) with respect to cellular behaviour, downstream signaling activation and response to targeted therapies. We demonstrate that 5’ partner choice of BRAF fusions affects their subcellular localization and intracellular signaling capacity. In particular the DLG1-BRAF fusion protein showed distinct localization to the plasma membrane and exhibited increased activation of downstream MAPK signaling under unperturbed conditions. Moreover, phosphoproteomics and RNA sequencing identified distinct subsets of affected signaling pathways and altered gene expression of BRAF fusions. The different BRAF fusions exhibited varying sensitivities to simultaneous targeted inhibition of MEK and the EGF receptor family. However, all BRAF fusions conveyed resistance to targeted monotherapy against the EGF receptor family, suggesting that BRAF fusions should be screened alongside other MAPK pathway alterations to identify mCRC patients to exclude from cetuximab treatment

2020-01-16 | PXD013461 | Pride

ChIP-seq of TALE fusions

Project description:We present a strategy to investigate regulatory elements that leverages programmable reagents to selectively inactivate their endogenous chromatin state. The reagents, which comprise fusions between transcription activator- like effector (TALE) repeat domains and the LSD1 histone demethylase, efficiently remove enhancer-associated chromatin modifications from target loci, without affecting control regions. We find that inactivation of enhancer chromatin by these fusions frequently causes down- regulation of proximal genes. Our study demonstrates the potential of 'epigenome editing' tools to characterize a critical class of functional genomic elements. ChIP-seq analysis of TALE-Fusion Proteins

2013-07-26 | E-GEOD-48866 | biostudies-arrayexpress

Proteomic analysis of tyrosine phosphorylation induced by oncogenic kinase fusions identified in lung adenocarcinoma

Project description:Kinase fusions are considered oncogenic drivers in numerous types of cancer. In lung adenocarcinoma 5-10% of patients harbor kinase fusions. The most frequently detected kinase fusion involves the Anaplastic Lymphoma Kinase (ALK) and Echinoderm Microtubule-associated protein-Like 4 (EML4). In addition, oncogenic kinase fusions involving the tyrosine kinases RET and ROS1 are found in smaller subsets of patients. In this study, we employed quantitative mass spectrometry-based phosphoproteomics to define the cellular tyrosine phosphorylation patterns induced by different oncogenic kinase fusions identified in patients with lung adenocarcinoma. We show that the cellular expression of the kinase fusions leads to widespread tyrosine phosphorylation. Direct comparison of different kinase fusions demonstrates that the kinase part and not the fusion partner primarily defines the phosphorylation pattern. The tyrosine phosphorylation patterns differed between ALK, ROS1 and RET fusions, suggesting that oncogenic signaling induced by these kinases involves the modulation of different cellular processes.

2021-04-27 | PXD021904 | Pride

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