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Global Translational Medicine Fusion events identified in tumor

develop de novo in the elderly. By contrast, secondary of the breakpoint of DNA are led to close proximity; and
GBMs, which are IDH mutant and typically progress (3) DNA junctions frequently demonstrate small stretches
from low-grade diffuse gliomas within 5 – 10 years of of homology that is associated with VDJ abnormality
diagnosis , usually affect younger patients. and class switch recombination (CSR), and genomic or
[5]
[17]
The median survival period of Grade IV patients transcriptomic stress .
with either primary GBM or secondary GBM is only 14 It was thought that the DNA breakpoints are randomly
– 16 months , although standard treatment including selected and that many selections lead to various
[8]
maximal surgical resection and chemoradiotherapy is chromosomal rearrangements. However, it is now clear
applied. The chemotherapy standard in current clinical that various cell types, including tumor tissues, have
practice is based on the alkylating agent temozolomide, abnormal nuclear and morphological changes that may
but this agent may engender severe side effects and promote specific DNA breakpoint. The low frequency of
chemoresistance because of nonselective DNA damage . RET-CCDC6 breakpoints in breast cancer cells may lead
[9]
Molecular therapies targeting the genetic alterations that to the chromosomal rearrangement in breast cancers
drive glioma pathogenesis is expected to be more effective samples [18,19] .
than temozolomide and cause fewer side effects. Thus,
to improve therapies for glioma, it is crucial to identify 3. Major research findings on gene fusions
new genomic alterations driving glioma progression and in cancer
discover corresponding targeted drugs. Either National The discovery of Philadelphia chromosome in CML in
Comprehensive Cancer Network or Chinese Glioma 1960 has brought about a series of studies that successfully
[10]
[20]
Cooperative Group guideline has suggested standard identified fusion genes in a multitude of other neoplasia.
[11]
therapeutic strategies for GBM patients. However, a The detailed analysis of neoplastic cell genome only became
more standard treatment guideline for recurrent glioma possible in the early 1970s when the chromosome banding
is currently not available; at the present stage, only a few technique was introduced . These new techniques enabled
[21]
evidence-based therapy suggestions have been made. detection of previously undetectable small genomic or
Since the discovery of Philadelphia chromosome in transcriptomic rearrangements. The first analysis of
chronic myeloid leukemia (CML) back in 1960, many genomic or transcriptomic rearrangements revealed that
fusion genes and proteins have been identified using the Philadelphia chromosome in CML was one of the two
different approaches in other kinds of cancers over the past abnormal chromosomes between chromosomes 9 and
60 years . Deep sequencing provides a new means for 22 (t(9;22)(q34;q11)), and t(8;21)(q22;q22) . In the late
[22]
[12]
identifying fusion genes. The FGFR3–TACC3 and MYB- 1970s, the conception of how chromosome abnormality
[13]
QKI fusion transcripts were at first recognized as the contributes to tumor transformation by breakpoints of genes
[14]
recurrent fusion transcripts in GBMs and pediatric gliomas, or regulatory elements laid a foundation to the emergence of
respectively. In addition, recurrent fusion rearrangement fluorescence in situ hybridization (FISH) technique, which
involving PTPRZ1 and MET genes (ZM) was found in 15% can simultaneously locate and identify different structure
of secondary GBMs . The nature and incidence of ZM variants in different colors; this technique has dramatic impact
[15]
fusion in secondary GBMs and other grades of gliomas on the elucidation of molecular mechanisms governing
have been investigated to elucidate the mechanisms by the tumor-associated chromosome rearrangements [23,24] .
which ZM fusion contributes to glioma progression. High throughput technology for global genetic analyses,
including gene expression microarray and copy number
2. Gene fusion profiling, provided better means for the detection fusion
Chromosomal rearrangements, followed by translocation genes, and obviated the need for cell culturing. The first
and gene fusion, lead to the formation of hybrid genes fusion gene detected by the high-throughput methods
from two originally separate genes. Gene fusion can was the fusion of PAX3 and nuclear receptor co activator 1
[25]
occur as a result of translocation, interstitial deletion, or (NCOA1) in alveolar rhabdomyosarcoma . In addition,
chromosomal inversion. In cancers of epithelial origin, deep sequencing provided a means, which was of better
the overall rate of balanced rearrangements or gene quality and resolution, to identify fusions some 10 years ago
fusions has been evaluated as only 3%, while it is 29% in (Figure 1) [26,27] .
acute myelogenous leukemia and 19% in mesenchymal 4. Gene fusions in different types of cancer
tumors . The formation of a pathogenic fusion protein
[16]
involves several mechanisms, including cell-extrinsic and Either chromosomal translocation or RNA fusion may
intrinsic process: (1) Double-strand breaks (DSBs) are lead to aberrant activation of oncogenic kinase with
initiated by the cell-extrinsic mechanisms; (2) the ends a traditional paradigm in epithelial cancers. Nowell

Volume 1 Issue 1 (2022) 2 https://doi.org/10.36922/gtm.v1i1.54