Transcriptomic Portraits and Molecular Pathway Activation Features of Adult Spinal Intramedullary Astrocytomas

Konovalov, Nikolay; Тimonin, S Yu; Asyutin, D S; Raevskiy, Mikhail; Sorokin, Maxim; Buzdin, Anton; Kaprovoy, Stanislav

doi:10.3389/fonc.2022.837570

Cited by 4 publications

(3 citation statements)

References 96 publications

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“… 65 For example, the chimeric EWSR1-FLI gene is characteristic for a number of sarcomas. 66 , 67 KIAA1549-BRAF fusion oncogene is characteristic for spinal intramedullary astrocytomas, 68 and fusions with JAZF1 and YWHAE genes frequently occur in leiomyosarcomas. 69 , 70 In many cases, fusion genes are just passenger mutations accompanying carcinogenesis that do not play any significant role in cancer progression.…”

Section: Novel Fusion Genes In Cancermentioning

confidence: 99%

Clinically relevant fusion oncogenes: detection and practical implications

et al. 2022

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Mechanistically, chimeric genes result from DNA rearrangements and include parts of preexisting normal genes combined at the genomic junction site. Some rearranged genes encode pathological proteins with altered molecular functions. Those which can aberrantly promote carcinogenesis are called fusion oncogenes. Their formation is not a rare event in human cancers, and many of them were documented in numerous study reports and in specific databases. They may have various molecular peculiarities like increased stability of an oncogenic part, self-activation of tyrosine kinase receptor moiety, and altered transcriptional regulation activities. Currently, tens of low molecular mass inhibitors are approved in cancers as the drugs targeting receptor tyrosine kinase (RTK) oncogenic fusion proteins, that is, including ALK, ABL, EGFR, FGFR1-3, NTRK1-3, MET, RET, ROS1 moieties. Therein, the presence of the respective RTK fusion in the cancer genome is the diagnostic biomarker for drug prescription. However, identification of such fusion oncogenes is challenging as the breakpoint may arise in multiple sites within the gene, and the exact fusion partner is generally unknown. There is no gold standard method for RTK fusion detection, and many alternative experimental techniques are employed nowadays to solve this issue. Among them, RNA-seq-based methods offer an advantage of unbiased high-throughput analysis of only transcribed RTK fusion genes, and of simultaneous finding both fusion partners in a single RNA-seq read. Here we focus on current knowledge of biology and clinical aspects of RTK fusion genes, related databases, and laboratory detection methods.

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Section: Novel Fusion Genes In Cancermentioning

confidence: 99%

Clinically relevant fusion oncogenes: detection and practical implications

et al. 2022

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“…Generally, fusion genes can be classified by their protein coding potentials. They can be capable of coding proteins, where the coding sequence of both fusion partners is in-frame, which gives rise to abnormal proteins with, for example, kinase or transcriptional factor activities ( 41 – 45 ). In addition, a frameshift fusion can occur when both fusion partners normally encode proteins, but the downstream partner open reading frame (ORF) is not in phase with that of the upstream gene ( 36 ).…”

Section: Introductionmentioning

confidence: 99%

Cancer fusion transcripts with human non-coding RNAs

Mohammad,

Zolotovskaia,

Suntsova

et al. 2024

Front. Oncol.

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Cancer chimeric, or fusion, transcripts are thought to most frequently appear due to chromosomal aberrations that combine moieties of unrelated normal genes. When being expressed, this results in chimeric RNAs having upstream and downstream parts relatively to the breakpoint position for the 5’- and 3’-fusion components, respectively. As many other types of cancer mutations, fusion genes can be of either driver or passenger type. The driver fusions may have pivotal roles in malignisation by regulating survival, growth, and proliferation of tumor cells, whereas the passenger fusions most likely have no specific function in cancer. The majority of research on fusion gene formation events is concentrated on identifying fusion proteins through chimeric transcripts. However, contemporary studies evidence that fusion events involving non-coding RNA (ncRNA) genes may also have strong oncogenic potential. In this review we highlight most frequent classes of ncRNAs fusions and summarize current understanding of their functional roles. In many cases, cancer ncRNA fusion can result in altered concentration of the non-coding RNA itself, or it can promote protein expression from the protein-coding fusion moiety. Differential splicing, in turn, can enrich the repertoire of cancer chimeric transcripts, e.g. as observed for the fusions of circular RNAs and long non-coding RNAs. These and other ncRNA fusions are being increasingly recognized as cancer biomarkers and even potential therapeutic targets. Finally, we discuss the use of ncRNA fusion genes in the context of cancer detection and therapy.

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“…In addition, integrity of an open reading frame can be easily assessed in the fusion gene product, as well as the presence of an intact kinase domain. Compared to the targeted RNAseq which interrogates RNAs captured by oligonucleotide hybridization or PCR primer panels specific for RTKs of interest, bulk RNAseq has the advantage of detection of both targeted and not specifically targeted types of fusion transcripts [ 23 , 24 , 25 , 26 ]. This advantage is especially important considering emerging pairs of complementary diagnostic fusion oncogenes and drugs on the way to acceptance and clinical use [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Experimentally Deduced Criteria for Detection of Clinically Relevant Fusion 3′ Oncogenes from FFPE Bulk RNA Sequencing Data

Rabushko

Suntsova

Seryakov³

et al. 2022

Biomedicines

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Drugs targeting receptor tyrosine kinase (RTK) oncogenic fusion proteins demonstrate impressive anti-cancer activities. The fusion presence in the cancer is the respective drug prescription biomarker, but their identification is challenging as both the breakpoint and the exact fusion partners are unknown. RNAseq offers the advantage of finding both fusion parts by screening sequencing reads. Paraffin (FFPE) tissue blocks are the most common way of storing cancer biomaterials in biobanks. However, finding RTK fusions in FFPE samples is challenging as RNA fragments are short and their artifact ligation may appear in sequencing libraries. Here, we annotated RNAseq reads of 764 experimental FFPE solid cancer samples, 96 leukemia samples, and 2 cell lines, and identified 36 putative clinically relevant RTK fusions with junctions corresponding to exon borders of the fusion partners. Where possible, putative fusions were validated by RT-PCR (confirmed for 10/25 fusions tested). For the confirmed 3′RTK fusions, we observed the following distinguishing features. Both moieties were in-frame, and the tyrosine kinase domain was preserved. RTK exon coverage by RNAseq reads upstream of the junction site were lower than downstream. Finally, most of the true fusions were present by more than one RNAseq read. This provides the basis for automatic annotation of 3′RTK fusions using FFPE RNAseq profiles.

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Transcriptomic Portraits and Molecular Pathway Activation Features of Adult Spinal Intramedullary Astrocytomas

Cited by 4 publications

References 96 publications

Clinically relevant fusion oncogenes: detection and practical implications

Clinically relevant fusion oncogenes: detection and practical implications

Cancer fusion transcripts with human non-coding RNAs

Experimentally Deduced Criteria for Detection of Clinically Relevant Fusion 3′ Oncogenes from FFPE Bulk RNA Sequencing Data

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