Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of Targetable FGFR Gene Fusions in Diverse Cancers

ABSTRACT:

In this study, patients with advanced cancer across all histologies were enrolled in our IRB approved clinical sequencing program, called MI-ONCOSEQ, to go through an integrative sequencing which includes whole exome sequencing of the tumor and matched normal, and transcriptome sequencing. Four index cases were identified which harbor gene rearrangements of FGFR2 including two cholangiocarcinoma cases, a metastatic breast cancer case, and a metastatic prostate cancer case. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, including TCGA, we identified FGFR gene fusions with intact kinase domains of FGFR1, FGFR2, or FGFR3 in cholangiocarcinoma, breast cancer, prostate cancer, lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins in vitro induced cell proliferation, and bladder cancer cell lines that harbors FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Due to the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts which incorporate transcriptome analysis for gene fusions are poised to identify rare, targetable FGFR fusions across diverse cancer types.

PROVIDER: phs000602 | dbGaP |

SECONDARY ACCESSION(S): PRJNA191587PRJNA191588

REPOSITORIES: dbGaP

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	GapExchange_phs000602.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs000602.DiverseCancers_FGFR.v1.p1.MULTI.pdf	Pdf
	manifest_phs000602.DiverseCancers_FGFR.v1.p1.c1.DS-CA-NPU-MDS.pdf	Pdf
	datadict_v2.xsl	Other

Items per page:

1 - 5 of 31

Similar Datasets

Identification of Targetable FGFR Gene Fusions in Diverse Cancers

Project description:<p>In this study, patients with advanced cancer across all histologies were enrolled in our IRB approved clinical sequencing program, called MI-ONCOSEQ, to go through an integrative sequencing which includes whole exome sequencing of the tumor and matched normal, and transcriptome sequencing. Four index cases were identified which harbor gene rearrangements of FGFR2 including two cholangiocarcinoma cases, a metastatic breast cancer case, and a metastatic prostate cancer case. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, including TCGA, we identified FGFR gene fusions with intact kinase domains of FGFR1, FGFR2, or FGFR3 in cholangiocarcinoma, breast cancer, prostate cancer, lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins in vitro induced cell proliferation, and bladder cancer cell lines that harbors FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Due to the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts which incorporate transcriptome analysis for gene fusions are poised to identify rare, targetable FGFR fusions across diverse cancer types.</p>

| phs000602.v1.p1 | EGA

Genome-wide identification of oncogenic fusions in lung cancer by functional translocation sequencing

Project description:Fusions involving tyrosine kinases are oncogenic drivers in lung cancer and other solid tumors but also mediate resistance to targeted therapy. Despite gene rearrangements involving tyrosine kinases tending to show recurrent patterns in solid tumors, little is known about their mechanisms of formation and their selection process. To elucidate these mechanisms, we developed a functional high-throughput, genome-wide translocation sequencing (F-HTGTS) approach. We applied F-HTGTS to lung cancer cells under the selective pressure of EGFR inhibition to map genome-wide translocations when a DNA double-strand break occurs in the ALK, RET, ROS1 or NTRK1 tyrosine kinase. We found that translocations form spontaneously with several partners in the genome, generate functional fusion proteins and induce resistance to EGFR inhibitors. Several of these proteins reproduce precisely the fusions found in NSCLC patients either as original driver events or secondary to development of resistance to targeted therapy. Therefore, F-HTGTS is an approach that allows rapid and comprehensive mapping of tyrosine kinase fusions in the genome from common oncogenic kinases and provide insights on their mechanisms of formation.

2024-04-29 | GSE167155 | GEO

Spitz tumors and melanomas with MET fusion

Project description:Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumors with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumors lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K), and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist.

2015-12-01 | GSE67841 | GEO

Frequent miRNA-convergent fusion gene events in breast cancer

Project description:Studies of fusion genes have mainly focused on the formation of fusions that result in the production of hybrid proteins or, alternatively, on promoter-switching events that put a gene under the control of aberrant signals. However, gene fusions may also disrupt the transcriptional control of genes that are encoded in introns downstream of the breakpoint. By ignoring structural constraints of the transcribed fusions, we highlight the importance of a largely unexplored function of fusion genes. Using breast cancer as an example, we show that miRNA host genes are specifically enriched in fusion genes and that many different, low-frequency, 5' partners may deregulate the same miRNA irrespective of the coding potential of the fusion transcript. These results indicate that the concept of recurrence, defined by the rate of functionally important aberrations, needs to be revised to encompass convergent fusions that affect a miRNA independently of transcript structure and protein-coding potential.

2017-10-31 | GSE100769 | GEO

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

ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression

Project description:Anaplastic lymphoma kinase (ALK) fusion variants in non-small-cell-lung cancer (NSCLC) consist of numerous dimerising fusion partners, with the most common being EML4. Clinical data suggests that the degree of treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs among the variant present in the patient tumor. Therefore, a better understanding the oncogenic signaling networks driven by different ALK-fusion variants is important. Here, we developed highly controlled doxycycline-inducible cell models bearing four different ALK fusion proteins, namely EML4-ALK-V1, EML4-ALK-V3, KIF5B-ALK, and TFG-ALK, in the context of non-tumorigenic NL20 human bronchial epithelial cells. These were complimented by patient-derived NSCLC cell lines harboring either EML4-ALK-V1 or EML4-ALK-V3 fusions. RNAseq and phosphoproteomics analysis were employed to identify dysregulated genes and hyper/hypo-phosphorylated proteins associated with ALK fusion expression. Among ALK fusion induced responses, we noted a robust inflammatory signature that included up-regulation of the Serpin B4 serine protease inhibitor in both NL20-inducible cell models and ALK-positive NSCLC patient-derived cell lines. We show that STAT3 is a major transcriptional regulator of SERPINB4 downstream of ALK fusions, along with NF-B and AP1. The upregulation of SERPINB4 promotes survival of ALK fusion expressing cells and inhibits natural killer (NK) cell-mediated cytotoxicity. In conclusion, our study reveals a novel ALK downstream survival axis that regulates Serpin B4 expression and identifies a molecular target that has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.

2023-02-16 | PXD035100 | Pride

Genome-wide transcriptome analysis of PAK4 inhibition/knockdown in human bladder cancer cell line VMCUB1

Project description:Using multi-omic analyses, we identified PAK4 (P21 (RAC1) Activated Kinase 4) amplification and overexpression of Kinase PAK4 in a subset of bladder cancers. We confirmed the role of PAK4 in bladder cancer cell proliferation and invasion by in vitro experiments. Furthermore, our studies showed that PAK4 inhibitor is effective in curtailing bladder cancer cell growth. In order to understand the effect of PAK4 inhibition and knockdown on bladder cancer transcriptome, we performed RNA-sequencing of PAK4 siRNA transfected and PAK4 inhibitor (PF-3758309) treated bladder cancer cells (VM-CUB1). Analyses led to identification of direct targets of PAK4 in bladder cancer and associated pathways.

2020-04-20 | GSE130455 | GEO

CDK6 is an essential direct transcriptional target of NUP98-fusion-protein-driven acute myeloid leukemia

Project description:Fusion proteins involving Nucleoporin 98 (NUP98) are recurrently found in Acute Myeloid Leukemia (AML) with poor prognosis. Lack of mechanistic insight into NUP98-fusion-dependent oncogenic transformation has precluded the identification of efficient targeting strategies. We reasoned that shared transcriptional programs of direct NUP98-fusion-protein-mediated gene control converge on actionable targets. To study the transcriptional regulation mediated by NUP98 fusion proteins we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A and NUP98/DDX10. Integration of transcriptional changes after oncogene shutdown in vivo with ChIP-seq data identified a common core of direct NUP98-fusion target genes in AML. Among the direct targets of all NUP98-fusions, the CDK6 (cyclin-dependent kinase 6) gene was highly expressed in mouse and human AML samples. CDK6 loss severely attenuated NUP98-fusion-driven leukemogenesis, and NUP98-fusion AML was hypersensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing approved CDK4/CDK6 inhibitors as a rationale treatment option for AML patients with NUP98-fusions.

2020-05-08 | GSE134784 | GEO

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

Protein Interactions of 7 MLL-fusion Proteins

Project description:MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity of C-terminal fusion partners of MLL protein. While studies of selected MLL-fusions have revealed critical molecular pathways, unifying mechanisms across all MLL-fusions remain poorly understood. We present the first comprehensive survey of protein-protein interactions of seven distantly related MLL-fusion proteins: MLL-AF1p, MLL-AF4, MLL-AF9, MLL-CBP, MLL-EEN, MLL-ENL and MLL-GAS7.

2018-05-25 | PXD009338 | Pride