Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes

Celestino, Ricardo; Sigstad, Eva; Løvf, Marthe; Thomassen, Gard; Grøholt, Krystyna; Jørgensen, Lars; Berner, Aasmund; Castro, Patrícia; Bjøro, Trine; Sobrinho-Simões, Manuel; Soares, Paula; Skotheim, Rolf Inge

doi:10.1002/gcc.22003

Cited by 21 publications

(13 citation statements)

References 30 publications

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“…RET proto-oncogene fusions have been identified previously in both lung adenocarcinoma414 and thyroid cancer15. Consistent with these studies, we observed recurrent CCDC6 – RET fusions in thyroid cancer15 but also identified several RET fusions with novel partners, including AKAP13 , FKBP15 , SPECC1L and TBL1XR1 (Fig.…”

Section: Resultssupporting

confidence: 91%

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The landscape of kinase fusions in cancer

et al. 2014

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Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells. The genomic characterization of tumours has uncovered numerous genes recurrently mutated, deleted or amplified, but gene fusions have not been characterized as extensively. Here we develop heuristics for reliably detecting gene fusion events in RNA-seq data and apply them to nearly 7,000 samples from The Cancer Genome Atlas. We thereby are able to discover several novel and recurrent fusions involving kinases. These findings have immediate clinical implications and expand the therapeutic options for cancer patients, as approved or exploratory drugs exist for many of these kinases.

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Section: Resultssupporting

confidence: 91%

“…Consistent with these studies, we observed recurrent CCDC6 – RET fusions in thyroid cancer15 but also identified several RET fusions with novel partners, including AKAP13 , FKBP15 , SPECC1L and TBL1XR1 (Fig. 1, Supplementary Fig.…”

Section: Resultssupporting

confidence: 87%

The landscape of kinase fusions in cancer

et al. 2014

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“…RNA-seq has spurred important gene fusion discoveries for a number of different cancers, including lung [6, 7], prostate [3, 8, 9], breast [10–12], brain [13], thyroid [14] and bladder carcinomas [15]. One obvious benefit from gene fusion discovery is the potential to develop novel treatments that target these genetic abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Exploration of the gene fusion landscape of glioblastoma using transcriptome sequencing and copy number data

et al. 2013

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BackgroundRNA-seq has spurred important gene fusion discoveries in a number of different cancers, including lung, prostate, breast, brain, thyroid and bladder carcinomas. Gene fusion discovery can potentially lead to the development of novel treatments that target the underlying genetic abnormalities.ResultsIn this study, we provide comprehensive view of gene fusion landscape in 185 glioblastoma multiforme patients from two independent cohorts. Fusions occur in approximately 30-50% of GBM patient samples. In the Ivy Center cohort of 24 patients, 33% of samples harbored fusions that were validated by qPCR and Sanger sequencing. We were able to identify high-confidence gene fusions from RNA-seq data in 53% of the samples in a TCGA cohort of 161 patients. We identified 13 cases (8%) with fusions retaining a tyrosine kinase domain in the TCGA cohort and one case in the Ivy Center cohort. Ours is the first study to describe recurrent fusions involving non-coding genes. Genomic locations 7p11 and 12q14-15 harbor majority of the fusions. Fusions on 7p11 are formed in focally amplified EGFR locus whereas 12q14-15 fusions are formed by complex genomic rearrangements. All the fusions detected in this study can be further visualized and analyzed using our website: http://ivygap.swedish.org/fusions.ConclusionsOur study highlights the prevalence of gene fusions as one of the major genomic abnormalities in GBM. The majority of the fusions are private fusions, and a minority of these recur with low frequency. A small subset of patients with fusions of receptor tyrosine kinases can benefit from existing FDA approved drugs and drugs available in various clinical trials. Due to the low frequency and rarity of clinically relevant fusions, RNA-seq of GBM patient samples will be a vital tool for the identification of patient-specific fusions that can drive personalized therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-14-818) contains supplementary material, which is available to authorized users.

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“…Actually, modern RNA-sequencing technologies have provided us with thousands of RNA chimeras 14 . A tiny number of them are known to be transcribed from fusion genes that are formed due to genetic alterations, such as chromosomal translocation and genomic DNA deletion or amplification 9 . Unfortunately, the vast remaining majority, i.e., those not associated with a known genomic alteration, remain putative and are not very meaningful to us so far, because their existence has not been verified with a vigorous method and because their full-length sequence has not been cloned and, thus, their open reading frame is unclear 16 .…”

Section: Introductionmentioning

confidence: 99%

New methods as alternative or corrective measures for the pitfalls and artifacts of reverse transcription and polymerase chain reactions (RT-PCR) in cloning chimeric or antisense-accompanied RNA

2013

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We established new methods for cloning cDNA ends that start with reverse transcription (RT) and soon proceed with the synthesis of the second cDNA strand, avoiding manipulations of fragile RNA. Our 3′-end cloning method does not involve poly-dT primers and polymerase chain reactions (PCR), is low in efficiency but high in fidelity and can clone those RNAs without a poly-A tail. We also established a cDNA protection assay to supersede RNA protection assay. The protected cDNA can be amplified, cloned and sequenced, enhancing sensitivity and fidelity. We report that RT product using gene-specific primer (GSP) cannot be gene- or strand-specific because RNA sample contains endogenous random primers (ERP). The gene-specificity may be improved by adding a linker sequence at the 5′-end of the GSP to prime RT and using the linker as a primer in the ensuing PCR. The strand-specificity may be improved by using strand-specific DNA oligos in our protection assay. The CDK4 mRNA and TSPAN31 mRNA are transcribed from the opposite DNA strands and overlap at their 3′ ends. Using this relationship as a model, we found that the overlapped sequence might serve as a primer with its antisense as the template to create a wrong-template extension in RT or PCR. We infer that two unrelated RNAs or cDNAs overlapping at the 5′- or 3′-end might create a spurious chimera in this way, and many chimeras with a homologous sequence may be such artifacts. The ERP and overlapping antisense together set complex pitfalls, which one should be aware of.

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Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes

Cited by 21 publications

References 30 publications

The landscape of kinase fusions in cancer

The landscape of kinase fusions in cancer

Exploration of the gene fusion landscape of glioblastoma using transcriptome sequencing and copy number data

New methods as alternative or corrective measures for the pitfalls and artifacts of reverse transcription and polymerase chain reactions (RT-PCR) in cloning chimeric or antisense-accompanied RNA

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