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Gene & Protein in Disease Gene fusions and chimeric RNAs

progression and reduced overall survival. Inhibiting significant adverse effects. Izumi et al. (2021) discovered
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GOLMI–NAA35 expression significantly slowed tumor a novel fusion transcript, CLIP1–LTK, in NSCLC. CLIP1 is
growth in vivo, highlighting its role in ESCC progression. part of the microtubule plus-end tracking protein family
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A study conducted by Wang et al. in 2021 identified 7, whereas LTK belongs to the receptor tyrosine kinase 6
the chimeric RNA ASTN2–PAPPAas, which was likely subfamily. The CLIP1–LTK fusion transcript combines
generated through transcriptional read-through followed exon 16 from CLIP1 with exon 11 from LTK. Using in vitro
by splicing. This chimeric RNA originated from the and in vivo procedures, the authors found that CLIP1–
splicing of exons and antisense introns of two neighboring LTK functions as an oncogenic driver in NSCLC and
genes and is predominantly found in cancer cells within revealed that targeting the fusion protein with lorlatinib is
tumors but absent in normal esophageal tissues. Inhibition a promising therapeutic strategy. 63,64
of ASTN2–PAPPAas reduced cell migration and invasion
while promoting ESCC cell spread to lymph nodes and 3.4. Chimeric RNAs in thyroid cancer
enhancing stem cell characteristics via OCT4 regulation Thyroid cancer is a common endocrine cancer, accounting
both in vitro and in vivo. Luo et al. (2022) developed a for approximately 2.1% of all newly diagnosed cancer cases
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tamoxifen-inducible knock-in mouse model expressing globally. Over the last 30 years, thyroid cancer cases have
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ASTN2–PAPPAas by integrating the human sequence tripled, with an increase in annual mortality rate of 1.1%. It
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into the mouse genome. Mice with the ASTN2–PAPPAas was previously believed that gene fusions in thyroid cancer
knock-in gene exhibited no abnormalities in growth, were caused by exposure to radioactive rays. However,
fertility, and histological and biochemical characteristics. advancements in technology and research have led to the
The authors noted that this model could be used to study identification of numerous novel and known gene fusions
the role of chimeric RNAs in disease development and in thyroid cancer. In a recent study conducted by Jurkiewicz
potential targeted treatments. 59 et al. in 2021, a genetic fusion event involving an exon
of the striatin gene (STRN) and the common anaplastic
3.3. Chimeric RNAs in lung cancer lymphoma kinase (ALK) gene breakpoint at exon 20 was
In 2015, cancer accounted for 8.8 million deaths, with observed. The STRN–ALK fusion transcript includes the
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lung cancer responsible for approximately one-fifth (1.69 N-terminal caveolin-binding and coiled-coil domains of
million) of these deaths, making it the leading cause of STRN connected to the juxta-membrane region of ALK,
cancer-related deaths worldwide. Approximately 14% of which contains the tyrosine kinase domain. Both genes are
newly diagnosed cancers are attributed to lung cancer, located on chromosome 2, at positions 2p22.2 and 2p23.
confirming it as the primary contributor to cancer-related The STRN–ALK fusion activates ALK kinase through
deaths. Chimeric RNAs formed by gene fusions (RNA ligand-independent dimerization facilitated by the STRN
fusions) and splicing errors play a crucial role and represent coiled-coil domain, leading to the activation of the MAPK
viable treatment targets in NSCLC. In 2018, Gow et al. signaling pathway. Approximately 80% of thyroid cancer
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identified two cases of KIF5B–MET fusion. One was found cases are PTC, with most gene fusions involving rearranged
in a patient with adenocarcinoma and sarcomatoid tumor, during transfection (RET) fusions. Research by Staubitz
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whereas the other was found in a patient with pulmonary et al. (2019) revealed ANKRD26–RET gene fusion in PTC.
sarcomatoid carcinoma. In both cases, a fusion of exons Both genes are located on chromosome 10, with the fusion
1 – 24 from KIF5B with exons 15 – 21 from MET was composed of exon 29 of ANKRD and exon 12 of RET.
detected. The fusion protein includes the full kinesin The fusion of RET’s tyrosine kinase region with protein–
motor and coil-coiled regions from KIF5B along with protein interaction motifs in NKRD26–RET may lead to
the C-terminal tyrosine kinase domain from MET. The the continuous activation of tyrosine kinase. Similarly,
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authors confirmed that the KIF5B–MET fusion protein Krishnan et al. (2020) revealed a new gene fusion, TFG–
exhibits oncogenic properties and enhances tumor cell RET, in PTC. This fusion includes exons 1 – 4 from the 5'
proliferation in vitro and in vivo. Chen et al. (2020) used end of Trk fused gene (TFG) linked to the 3' end of RET
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next-generation sequencing on a patient with metastatic tyrosine kinase. The TFG–RET fusion transforms human
lung adenocarcinoma, identifying a novel oncogenic thyroid cells through a kinase-dependent mechanism.
fusion of SOS1–ALK. This fusion protein comprised amino Moreover, the TFG–RET fusion forms oligomers based
acids from the N-terminal of SOS1 and the C-terminal of on the PB1 domain, and this oligomerization process
ALK, resulting in the formation of the SOS1–ALK fusion is essential for the oncogenic transformation induced
with an allele frequency of 4.6%. The authors noted that by TFG–RET. Moreover, the authors reported that the
the patient, treated with crizotinib for 6 months, showed TFG–RET fusion expression enhanced cell viability
a notable and sustained positive response without any and proliferation, leading to tumor formation in vivo.
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Volume 4 Issue 1 (2025) 7 doi: 10.36922/gpd.3641