Page 59 - GTM-1-1

Global Translational Medicine Fusion events identified in tumor

that the formation of ectopic fusion is necessary for the declining price after 2005. Focusing on genes with
oncogenesis, although the formation of the fusion is abnormal expression values, Tomlins et al. identified
distinct from that of RTK onco-fusion genes . Another prevalent genomic translocation of the transmembrane
[42]
interesting study also reported differences in component protease serine 2 gene (TMPRSS2), which fused to two
properties of condensates formed by different variants genes encoding v ets avian erythroblastosis virus E26
of EML4-ALK fusion protein. EML4-ALK variant 3 homologue (ERG; resulting in the TMPRSS2-ERG fusion
is more liquid-like compared to EML4-ALK variant gene) or ets variant 1 (ETV1; leading to the TMPRSS2-
1 . Compared to variant 3, the EML4-ALK variant 1 ETV1 fusion gene); these were the first fusion genes
[41]
harbors an additional tandem atypical propeller in EMLs’ that have been found to define a major subgroup of
[50]
domain, leading to increased valence and more binding a epithelial tumor . Intriguingly, the chromosomal
sites that reduce the mobility of the EML4-ALK protein. rearrangement underlying a gene fusion, which
G protein-coupled receptors (GPCRs) proteins activate retains two loci at the same chromosome band, could
ligand-dependent signaling pathways such as the protein not have been investigated with the use of chromosome
kinase A (PKA) pathway. Pathway activation by GPCRs banding technology. Peptidomimemic inhibitors against
is coupled with the conversion of ATP to cAMP, a second the product of ERG fusion have been proven to inhibit
[51]
messenger protein that relates PKA subunit to active prostate cell growth in prostate cancer , in a rate that
downstream signaling proteins. The regulatory subunit of is half of the cell inhibition rate caused by the inhibitors
PKA in the presence of cAMP induces phase separation against TMPRSS2-ERG fusion protein. In the recent
of the cell cycle . However, the DnaJB1-PKAcat fusion 5 – 10 years, the most frequently reported fusion event
[43]
protein formed by fused N terminus of DnaJB1 and the has been ALK fusion in lung cancer [52,53] . Furthermore,
C terminus of PKAcat disrupts the formation of DNA Shinji et al. identified a novel CD74-NRG2a fusion from
condensate through a specific mechanism , leading to Japanese patients with lung adenocarcinoma who were
[44]
[54]
increased release of cAMP and its dispersion to other either nonsmokers or light smokers . Jerby-Arnon et al.
cellular effectors. The decreased activation of downstream reported SS18-SSX fusion-induced suppressive immune
signaling contributes to the activation of reprogramming microenvironment that shapes oncogenic programs in
[55]
and oncogenesis of undesirable pathways. Promyelocytic synovial sarcoma , revealing the association between
leukemia protein (PML) protein, which is often found in the fusion event and tumor microenvironment.
the nucleus, is involved in multiple functions, including 5. Gene fusions in brain tumor
DNA damage response, transcriptional regulation, and
immune suppression. In addition, the PML protein Although an increasing amount of gene fusions have been
serves as a scaffold that is paramount for condensate identified in some major neoplasia subtypes, there are few
[12]
formation . The PML - retinoic acid receptor (RARα) recurrent fusion events in CNS , especially in the pediatric
[45]
fusion protein embodies the domain of RARα and CNS tumors. RAF kinases, such as BRAF and RAF1, exist
PML, which could lead to acute promyelocytic leukemia as fusion proteins with various and different counterparts.
(APL). Depicted as the dominant-negative regulator that BRAF is associated with an array of hematological as well
inhibits the transcript variant of PML , PML-RARα as solid malignancies. Most of the BRAF aberrations are
[46]
fusion protein could dysregulate the DNA strand repair mutations, occurring within the kinase domain at amino
function . ABL is another famous tyrosine kinase that acid V600. However, BRAF inhibitors, such as dabrafenib
[47]
has DNA-binding activity and is involved in apoptosis and vemurafenib, which are effective in other tumors,
and DNA damage repair; CML could be resulted due do not seem to be able to inhibit tumor proliferation
[56]
to the juxtaposition of ABL to BCR protein . The in pediatric astrocytomas bearing BRAF fusions . In
[48]
fusion proteins are characterized as having liquid-like pediatric CNS neoplasia, 14 different BRAF fusions have
properties, while the ABL kinase activity is necessary been reported. The C-terminal part of BRAF is fused to the
for promoting oncogenesis . The fusion proteins N-terminal part of other partners, including KIAA1549,
[49]
activate pathways involved in cell proliferation, adhesion, CLCN6, GNAI1, GTF2I, GIT2, and FAM131B [57-62] . The
th
differentiation, and cell survival , and promote the breakpoints often take place at the 9 exon of BRAF,
[48]
enrichment of stress granules . It is believed that the which is the inhibitory regulatory domain. So far, there
[49]
fusion protein alters the properties and composition has not been found that the N-terminal counterparts is of
of stress granules. Nonetheless, low resolution of great importance other than the removal of the inhibitory
[63]
sequencing for the detection of fusion gene continually domain .
limited the search for chromosomal rearrangements Selumetinib, one of the MEK inhibitors, has been
until the emergence of next-generation sequencing and demonstrated to be effective in a phase I/II trial where

Volume 1 Issue 1 (2022) 4 https://doi.org/10.36922/gtm.v1i1.54