Page 60 - GTM-1-1

Global Translational Medicine Fusion events identified in tumor

pediatric low-grade glioma patients harboring KIAA1549- consists of three members, namely, NTRK1, NTRK2, and
BRAF fusion gene were administered with the inhibitor . NTRK3, which can activate the PI3K/AKT/mTOR and
[64]
RAF1 is another member of the RAF kinases that is the PLCγ/PLK pathways and have been identified in
[76]
associated with the activation of the RAS/MAPK pathway. several pediatric gliomas such as pilocytic astrocytoma,
Owing to the limited number of fusion events of RAF1, its high-grade glioma and glioblastoma [70,77,78] . In vitro and
prevalence and characterizations as well as effectiveness in vivo tests showed that ETV6-NTRK3 fusion protein
of inhibitory compounds are still unclear. The second- mainly activates RAS/MAPK and PI3K/AKT/mTOR
generation RAF inhibitors are effective for pediatric pathway. The activation of both pathways might induce
[79]
astrocytoma harboring BRAF fusions by inhibiting the tumorigenesis of pediatric CNS tumor . While
the activation of the RAS/MAPK pathway, but are not the percentage of NTRK fusion in other solid tumors is
effective for RAF1 fusions . It has been also reported that relatively low with a prevalence of around 5% in pediatric
[65]
the N-terminal partners in RAF1 fusions are key factors high-grade glioma and diffuse infiltrating pontine
for the tumorigenesis involving the fusion proteins. glioma, this fusion event still occurs in 40% of infants
[74]
Furthermore, several counterparts such as SGRAP and with non-brainstem high-grade glioma . NTRK could
QKI have already been implicated in other malignancies be a potential target for further targeted therapy in these
[66]
as well . This implies that the dimerization of these tumors.
fusion counterparts is necessary for the tumorigenesis of On the other hand, Quaking homolog genes (QKI),
the fusion protein. which are tumor suppressor genes, have been reported

ALK is a member of the insulin receptor superfamily of to fuse to MYB gene that suppresses expression of QKI,
RTKs, which is a membrane-bound receptor in nerve cells, leading to malignancy in low-grade middle-line pediatric
[14]
and can activates the PI3K/AKT/mTOR and JAK/STAT gliomas . A similar fusion event, which is associated with
pathways . ALK fusion proteins are common in all kinds FGFR3 gene, has been identified in adult glioma samples
[67]
of pediatric and adult cancers. HIP1-ALK, EML4-ALK, by RNA sequencing. All FGFR fusion proteins retain all
and PPP1CB-ALK fusions have been described in various C-terminal partners that consist of a coiled-coil domain
tumor types . The extent of oligomerization of ALK of FGFR and a kinase domain. In the fused mRNA, exon
[68]
[13]
protein differs per counterpart, leading to a diversity in 16 of FGFR3 fused to exon 8 of TACC3 . At the same
the tumorigenesis of different ALK fusion counterpart . time, the constitutive activation of FGFR3 also induces
[69]
[80]
Different ALK fusion proteins exhibit varying degree of the activation of RAS/MAPK pathway . Parker et al.
sensitivity to ALK inhibitors, which should be considered showed that FGFR3-TACC3 gene fusion escapes miR-99a
when treating patients with ALK inhibitors. Fusion proteins inhibition in GBM patients, inducing over-expression of
[81]
that induce the phosphorylation of ALK can activate the FGFR, leading to glioma malignancy . Then, Frattini
MAPK pathway . In vitro and in vivo tests with ALK et al. found the correlation between FGFR3-TACC3 fusion
[68]
inhibitors demonstrated pre-clinical characterizations for and metabolism of mitochondrion, indicating a novel
[82]
tumor shrinkage in a PPP1CB-ALK-positive tumor as a mechanism of fusion-induced pathway activation . Bao
response to lorlatinib, an ALK inhibitor . ROS1 is another et al. recently identified a novel recurrent fusion gene in
[70]
member of RTKs that have an extracellular domain, glioma, PTPRZ1-MET fusion (ZM) in approximately 15%
a transmembrane domain and an intracellular kinase of secondary GBM patients. The four fusion transcripts
domain, and is associated with the activation of RAS/ contain four different breakpoints within the PTPRZ1
MAPK as well as the JAK/STAT and PI3K/AKT/mTOR coding sequence, whereas the breakpoints in the MET
pathways . In pediatric CNS tumors, the most common gene are exactly the same. Survival analysis demonstrated
[71]
ROS1 fusion is GOPC-ROS1, which induces oncogenic that secondary GBM patients with ZM fusion had poorer
signaling by translocating to the Golgi apparatus rather overall survival than those without this fusion. The
researchers performed a screening on 19 GBM cell lines
than by dimerization . All the fusion counterparts consist using fusion-specific PCR primers to verify the recurrent
[72]
of a coiled-coil domain and occasionally a zipper domain, nature of ZM fusion, and they were able to detect the
leading to the dimerization and activation of the ROS1 fusion sequence in three cell lines and found significant
kinase. More in-depth research is required to understand MET, PI3K, and AKT overexpression in the ZM fusion-
whether other pathways and interactions also play a role in bearing GBM patients . Hu et al. subsequently identified
[15]
ROS1 kinase activation .
[73]
a novel glioma-associated MET alteration, that is, MET
In high-grade pediatric gliomas, neurotrophic RTK exon 14 skipping (METex14), which promotes MET
(NTRK) fusion gene has been identified as an oncogene overexpression and hyperactivation of MET signaling.
that activates MAPK-AKT pathway [74,75] . The NTRK family The co-expression of METex14 and ZM fusion activates

Volume 1 Issue 1 (2022) 5 https://doi.org/10.36922/gtm.v1i1.54