Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE45137 | GEO | 2013/05/31
SECONDARY ACCESSION(S): PRJNA192953
REPOSITORIES: GEO
Similar Datasets
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
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
| S-ECPF-GEOD-45133 | biostudies-other
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-05-31 | E-GEOD-45137 | biostudies-arrayexpress
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
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.
2013-05-31 | GSE45133 | GEO
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. 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)
2013-05-31 | E-GEOD-39287 | biostudies-arrayexpress
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
Project description:The tropomyosin receptor kinase (Trk) receptor family comprises 3 transmembrane proteins referred to as Trk A, B and C (TrkA, TrkB and TrkC) receptors that are encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively. These receptor tyrosine kinases are expressed in human neuronal tissue and play an essential role in the physiology of development and function of the nervous system through activation by neurotrophins. Gene fusions involving NTRK genes lead to transcription of chimeric Trk proteins with constitutively activated or overexpressed kinase function conferring oncogenic potential. These genetic abnormalities have recently emerged as targets for cancer therapy, because novel compounds have been developed that are selective inhibitors of the constitutively active rearranged proteins. Developments in this field are being aided by next generation sequencing methods as tools for unbiased gene fusions discovery. In this article, we review the role of NTRK gene fusions across several tumour histologies, and the promises and challenges of targeting such genetic alterations for cancer therapy.
| S-EPMC5070277 | biostudies-literature
Project description:Kinase fusions represent an important type of somatic alterations that promote oncogenesis and serve as diagnostic markers in lung cancer. We aimed to identify the landscape of clinically relevant kinase fusions in Chinese lung cancer and to explore rare kinase rearrangements; thus, providing valuable evidence for therapeutic decision making. We performed genomic profiling of 425 cancer-relevant genes from tumor/plasma biopsies from a total of 17,442 Chinese lung cancer patients using next generation sequencing (NGS). Patients' clinical characteristics and treatment histories were retrospectively studied. A total of 1162 patients (6.66%; 1162/17,442) were identified as having kinase fusions, including 906 adenocarcinomas (ADCs) and 35 squamous cell carcinomas (SCCs). In ADC, 170 unique gene fusion pairs were observed, including rare kinase fusions, SLC12A2-ROS1, NCOA4-RET, and ANK3-RET. As for SCC, 15 unique gene fusions were identified, among which the most frequent were EML4-ALK and FGFR3-TACC3. Analyses of oncogenic mutations revealed a dual role for the gene fusions, CCDC6-RET and FGFR3-TACC3, in driving oncogenesis or serving as acquired resistance mechanisms to kinase inhibitors. In addition, our real-world evidence showed that patients with recurrent kinase fusions with low frequency (two occurrences) could benefit from treatment with kinase inhibitors' off-label use. Notably, patients with stage IV ADC who had novel RORB-ALK or AFF2-RET fusions, but no other known oncogenic driver mutations, demonstrated favorable clinical outcomes on tyrosine kinase inhibitors. Our data provide a comprehensive overview of the landscape of oncogenic kinase fusions in lung cancer, which assist in recognizing potentially druggable fusions that can be translated into therapeutic applications.
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Project description:CGP results from >60,000 cases were screened to identify NTRK fusion events from cases of neuroendocrine tumors. 2417 NET patients from diverse anatomic sites were identified. From this dataset, six cases harbored NTRK fusions which included intra- and inter-chromosomal translocations. A NTRK fusion frequency of approximately 0.3% was found across all subtypes of NETs. Three cases involved translocations of NTRK1 with unique fusion partners (GPATCH4, PIP5K1A, CCDC19). Co-occurring alterations occurred in five cases. NTRK alterations were identified in nearly the full spectrum of NETs, including from the small intestine, pancreas, lung, and others. With the late stage clinical development of NTRK TKIs (including entrectinib and larotrectinib), these findings may further inform targeted approaches to therapy in NET.
| S-EPMC6254675 | biostudies-literature