Fusion genes and their discovery using high throughput sequencing

Annala, Matti; Parker, Brittany C.; Zhang, Wei; Nykter, Matti

doi:10.1016/j.canlet.2013.01.011

Cited by 75 publications

(65 citation statements)

References 66 publications

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“…26 However, the current study is the first to identify the FGFR3-TACC3 fusion gene, which promotes cell proliferation and transformation in NPC, in a cohort of NPC patients. Several fusion genes, such as UBR5-ZNF423, have been detected by RNA-seq in 6 EBV (C) NPC tumor lines.…”

Section: Discussionmentioning

confidence: 91%

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Li¹,

Liu²,

Lin

et al. 2014

Cancer Biology & Therapy

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These authors equally contributed to this work. Keywords: FGFR3-TACC3, fusion gene, NPC, proliferation, tumorigenesisAbbreviations: FGFR3, fibroblast growth factor receptor 3; TACC3, transforming acidic coiled-coil-containing protein 3; NPC, nasopharyngeal carcinoma; LTBR, lymphotoxin b receptor; CCND1, cyclin D1; RT-PCR, reverse transcription-PCR; FBS, fetal bovine serum; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide; SDS, sodium dodecyl sulfate; DTT, DL-dithiothreitol; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; PI, propidium iodide.Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies and exhibits regional differences in incidence. Because many fusion genes have been discovered in different types of tumors over the past few years, we aimed to investigate the existence of a fusion gene in primary NPC patients using RNA-seq. In this study, for the first time, we found that fibroblast growth factor receptor 3-transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3) fusion transcripts are recurrently detected in NPC. The presence of this fusion gene was also detected in head and neck cancer, esophageal squamous cell carcinoma (ESCC), and lung cancer. Furthermore, we found certain new isoforms of the FGFR3-TACC3 fusion transcripts, such as a gene fusion between exon 18 of FGFR3 and exon 6 or exon 14 of TACC3 and agene fusion between exon 19 of FGFR3 and exon 11 of TACC3. In addition, we showed that the FGFR3-TACC3 fusion gene promotes cell proliferation, colony formation, and transforming ability in vitro, whereas the FGFR3-TACC3 K508M mutant or treatment with the FGFR inhibitor PD173074 abrogates these effects, suggesting that FGFR3-TACC3 most likely exerts its effects through activation of FGFR kinase activity. This activation likely leads to the development of NPC. Additionally, FGFR3-TACC3 could trigger activation of the ERK and Akt signaling pathways, whereas FGFR3-TACC3 K508M mutant could not, suggesting that these 2 signaling pathways might be involved in the function of FGFR3-TACC3. Taken together, our data demonstrated the oncogenic role of FGFR3-TACC3 in vitro, indicating that FGFR3-TACC3 may be useful as a diagnostic marker and therapeutic target in cancers.

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Section: Discussionmentioning

confidence: 91%

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Li¹,

Liu²,

Lin

et al. 2014

Cancer Biology & Therapy

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“…As somatic recombination events are less likely to (1) occur in multiple biological samples or (2) be conserved across multiple species, PtNCL events can be distinguished from genetic rearrangements by this simple rule . More effective approaches utilize integration analysis of genome sequencing data and RNA‐seq data to detect potential rearrangement events . Nevertheless, most of these methods were specifically designed to identify NCL events that consist of sequence fragments from two or more different genes.…”

Section: Identification Of Exonic Circrnasmentioning

confidence: 99%

Biogenesis, identification, and function of exonic circular RNAs

2015

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Circular RNAs (circRNAs) arise during post‐transcriptional processes, in which a single‐stranded RNA molecule forms a circle through covalent binding. Previously, circRNA products were often regarded to be splicing intermediates, by‐products, or products of aberrant splicing. But recently, rapid advances in high‐throughput RNA sequencing (RNA‐seq) for global investigation of nonco‐linear (NCL) RNAs, which comprised sequence segments that are topologically inconsistent with the reference genome, leads to renewed interest in this type of NCL RNA (i.e., circRNA), especially exonic circRNAs (ecircRNAs). Although the biogenesis and function of ecircRNAs are mostly unknown, some ecircRNAs are abundant, highly expressed, or evolutionarily conserved. Some ecircRNAs have been shown to affect microRNA regulation, and probably play roles in regulating parental gene transcription, cell proliferation, and RNA‐binding proteins, indicating their functional potential for development as diagnostic tools. To date, thousands of ecircRNAs have been identified in multiple tissues/cell types from diverse species, through analyses of RNA‐seq data. However, the detection of ecircRNA candidates involves several major challenges, including discrimination between ecircRNAs and other types of NCL RNAs (e.g., trans‐spliced RNAs and genetic rearrangements); removal of sequencing errors, alignment errors, and in vitro artifacts; and the reconciliation of heterogeneous results arising from the use of different bioinformatics methods or sequencing data generated under different treatments. Such challenges may severely hamper the understanding of ecircRNAs. Herein, we review the biogenesis, identification, properties, and function of ecircRNAs, and discuss some unanswered questions regarding ecircRNAs. We also evaluate the accuracy (in terms of sensitivity and precision) of some well‐known circRNA‐detecting methods. WIREs RNA 2015, 6:563–579. doi: 10.1002/wrna.1294For further resources related to this article, please visit the WIREs website.

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“…Important biological effects of gene fusion can result from chromosomal rearrangements, DNA shuffling, abnormal transcription, and alternative splicing, leading to the formation of chimeric proteins that can have significance in human cancer (Mitelman et al, 2007;Annala et al, 2013). The altered chimeric protein can constitutively activate downstream target genes or destroy a critical cellular function (Annala et al, 2013), such as the chimeric BCR-ABL1 in leukemia (McWhirter et al, 1993), FGFR3-TACC3 fusions in glioblastoma (Singh et al, 2012), and the ALK fusions in anaplastic large cell lymphoma (Chiarle et al, 2008). The reports of gene fusion relevant to plant metabolism are limited, but at least two gene fusion events have been confirmed as relevant to benzylisoquinoline alkaloid metabolism (Li et al, 2016;Hagel and Facchini, 2017).…”

Section: Gene Fusions Can Play An Important Role In Developmental Biomentioning

confidence: 99%

The RIN-MC Fusion of MADS-Box Transcription Factors Has Transcriptional Activity and Modulates Expression of Many Ripening Genes

et al. 2017

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Fruit development and ripening is regulated by genetic and environmental factors and is of critical importance for seed dispersal, reproduction, and fruit quality. Tomato () () mutant fruit have a classic ripening-inhibited phenotype, which is attributed to a genomic DNA deletion resulting in the fusion of two truncated transcription factors, and In wild-type fruit, RIN, a MADS-box transcription factor, is a key regulator of the ripening gene expression network, with hundreds of gene targets controlling changes in color, flavor, texture, and taste during tomato fruit ripening; , on the other hand, has low expression in fruit, and the potential functions of the fusion gene in ripening remain unclear. Here, overexpression of in transgenic wild-type cv Ailsa Craig tomato fruits impaired several ripening processes, and down-regulating expression in the mutant was found to stimulate the normal yellow mutant fruit to produce a weak red color, suggesting a distinct negative role for in tomato fruit ripening. By comparative transcriptome analysis of and:: RNA interference fruits, a total of 1,168 and 1,234 genes were identified as potential targets of RIN-MC activation and inhibition. Furthermore, the fusion gene was shown to be translated into a chimeric transcription factor that was localized to the nucleus and was capable of protein interactions with other MADS-box factors. These results indicated that tomato RIN-MC fusion plays a negative role in ripening and encodes a chimeric transcription factor that modulates the expression of many ripening genes, thereby contributing to the mutant phenotype.

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Fusion genes and their discovery using high throughput sequencing

Cited by 75 publications

References 66 publications

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Biogenesis, identification, and function of exonic circular RNAs

The RIN-MC Fusion of MADS-Box Transcription Factors Has Transcriptional Activity and Modulates Expression of Many Ripening Genes

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