• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • The same reservoir of genes is


    The same reservoir of Octreotide acetate is involved in fusions in all types of cancers, which predominantly encode kinases and transcriptional factors [102]. This makes fusion genes potential pan-cancer targets, and renders tumor categorization based on genetic profiling therapeutically reasonable. For instance, FGFR tyrosine kinase family fusions have been profiled across a dozen of solid tumors, and have emerged as promising therapeutic targets across a spectrum of cancers [103]. The roles played by fusion genes differ among cancer types [73], reflecting differential oncological mechanisms of various types of cancers and implicating distinct tumor-driving pathways and intervention strategies. Gene fusions in carcinomas are more likely associated with aberrant cell growth signaling than hematopoietic and mesenchymal cancers [73], due to possibly different differentiation histories [43]. Interestingly, in thyroid cancers which harbor the highest frequency of recurrent kinase fusions (13%), all kinase types of fusions involving ALK, BRAF, MET, NTRK1, NTRK2, RAF1, RET were mutually exclusive [68], suggesting the pivotal roles of the pathway they pathologically converge in driving tumorigenesis that needs particular focus regarding therapeutic intervention.
    Perspectives Given the prominent roles recognized for fusion genes in clinical studies, increasing efforts have been devoted to target oncogenic fusion genes and proteins. According to the latest statistics, 33 clinical trials targeting epithelial cancer fusions [65] are being conducted, with promiscuous fusions such as ALK, ETS and RET and drugs such as vandetanib, crizotinib dominating the scheme on the market [43,65]. This is suggestive of the upcoming clinical translation of these fusion genes, which are expected to enrich the current oncotherapeutic repertoire for patients carrying these fusions. Also, by taking advantage of the pan-cancer feature of many recurrent fusion genes, it is plausible to benefit patients sharing the same genetic aberration and/or oncogenic consequences from the same treatment modality, which represents a practical way for the development of fusion-gene based pharmacology. It is worth noting that splice-based fusions do not always represent rare events. Many genes have been identified transcriptionally fused to 5′-MLL sequences including, e.g., MLLT1/ENL, EPS15, AFF1/AF4, CT45A2, DCPS, ELL, MLLT3/AF9, MLLT4/AF6, MYO1F, SEPT5, ZFYVE19, resulting in spliced fusions [44]. Approximately 50% recombination events of MLL-MLLT1/ENL are spliced fusions, and 30% are MLL-EPS15 fusions [44]. The ‘trans-splicing mediation’ model has shed light on the template role of trans-splicing fusion transcripts in structural chromosomal alterations which, once held true, offers novel insights towards early oncogenic diagnosis. Spliced fusions may have prominent oncogenic functionalities undetermined beside the presumed templating role. Getting this information disclosed is of fundamental importance to translate these promising discoveries into medical use, which should urge more theoretical and clinical investigations and may lead the trend in the near future.
    Disclosure statement
    Funding details This work was supported by the National Natural Science Foundation of China [grant number 31471251]; Natural Science Foundation of Jiangsu Province [grant number BK20161130]; the Six Talent Peaks Project in Jiangsu Province [grant number SWYY-128]; the Fundamental Research Funds for the Central Universities [grant number JUSRP11507]; the Research Funds for the Medical School of Jiangnan University ESI special cultivation project (1286010241170320), and the Major Project of Science and Technology in Henan Province (161100311400).
    Transparency document
    Introduction Ewing sarcoma family tumors (ESFT), heretofore simply referred to as Ewing’s sarcoma (ES), are bone or soft tissue sarcomas that are found primarily in adolescents and young adults, with peak occurrence between ages 10 and 20 [1]. ES as a malignant entity is genetically characterized by chromosomal translocation involving the Ewing sarcoma breakpoint region 1 (EWSR1) gene. Translocation of EWSR1 on chromosome 22 to chromosome 11 occurs in 85% of ES cases, forming the fusion protein product EWS-FLI1 [2], [3]. In addition, fusion product EWS-ERG is identified in 10% of cases, whereas several other translocation types are rarely identified [4], [5], [6], [7], [8], [9] (Table 1). The EWSR1 breakpoint appears to be a hot spot for genetic translocations and can promiscuously bind other C-terminal genes in other sarcoma subtypes such as clear cell sarcoma, extraskeletal myxoid chondrosarcoma and others [10], [11], [12]. FLI1, ERG and other ETS genes contain the DNA-binding domain [13]. Consequently, EWS-FLI1 protein functions as an aberrant transcription factor regulating malignant transformation to ES.