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Gene & Protein in Disease Gene fusions and chimeric RNAs

research, technology, and bioinformatics tools have led • RNA stability: Chimeric RNAs have the potential
to the discovery of chimeric RNAs in various healthy to alter transcript stability. Depending on the
tissues and cells. The fusion transcript DUS4L–BCAP29 combination of exons, these chimeric RNAs may
was initially linked to gastric cancer, but a study by Tang et either be more stable or more prone to degradation
al. (2019) revealed that DUS4L–BCAP29 is also present in than their non-chimeric counterparts
normal tissues, with the junction sequence identical to that • Protein translation: Some chimeric RNAs may be
reported in gastric cancer. Overexpression of this fusion translated to produce novel fusion proteins. These
transcript promoted cell growth and motility in non- fusion proteins might have combined or altered
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cancerous cell lines. Babiceanu et al. (2016) also reported functions compared with the original proteins,
the presence of chimeric RNAs in normal tissues and cells, potentially affecting cellular activities and pathways 99
identifying CTNNBIP1–CLSTN1 and CTBS–GNG5 fusion • Epigenetic regulation: Chimeric RNAs could also
transcripts in both normal tissues and cell lines. Knocking impact epigenetic modifications by influencing
down the CTBS–GNG5 chimeric RNA suppressed the recruitment of chromatin-modifying enzymes
cell growth and reduced cell motility, and inhibiting to specific genomic regions, thereby altering the
CTNNBIP1–CLSTN1 also led to reduced growth and expression of neighboring genes. 100
motility. Li et al. (2008) reported the presence of the JAZF1–
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JJAZ1 fusion transcript in normal endometrial stromal 5. Chimeric RNAs as a biomarker and
cells, which was formed as a result of RNA trans-splicing molecular target
rather than chromosomal rearrangement. The PAX3–
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FOXO1 chimeric RNA, linked to rhabdomyosarcoma and Since the discovery of the BCR–ABL fusion transcript,
used as a biomarker, was also detected in normal muscle numerous fusion transcripts have been identified across
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cell lines and muscle biopsies. Moreover, Chen et al. various cancer types, emerging as promising biomarkers
(2021) revealed the presence of chimeric RNAs in various for cancer diagnosis and treatment. A simple example
non-malignant cell lines, including HEK-293T, HUVEC, is shown in Figure 5. The EML4–ALK fusion serves as a
and LO2 cells. 76 biomarker in NSCLC, guiding the use of ALK inhibitors
to improve patient outcomes. Similarly, the TMPRSS2–
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When examining chimeric RNAs in healthy tissues, ERG gene fusion is detectable in the early stages of prostate
there is potential to uncover novel aspects of typical cellular cancer and is valuable for prognostic assessments. In a
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function or regulation. These discoveries may provide a study by Lin et al. (2019), the chimeric RNA seGOLM1–
deeper understanding of how regular cellular mechanisms NAA35 was proposed as a potential biomarker and early
are co-opted in oncological contexts. Analysis of RNA- indicator for human ESCC, potentially predicting early
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seq data from 16 distinct healthy human tissues revealed recurrence or disease progression more effectively than
that numerous sense–antisense chimeric transcripts were standard radiological methods. Wu et al. (2018) also
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expressed across multiple tissues. This suggests a potential reported the frequent presence of LHX6–NDUFA8 in
link between sense–antisense chimeras and normal cervical cancer and pap smear specimens, suggesting
physiological processes. Furthermore, an evolutionary it could be used as a biomarker for cervical cancer
analysis of sense–antisense fusions across different species detection. Furthermore, Izumi et al. (2019) identified
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identified several shared genes capable of producing these CLIP1–LTK fusion in patients with NSCLC. This fusion
chimeric transcripts in humans, mice, fruit flies, and has been recognized as an oncogenic driver in NSCLC,
pigs. This finding implies that the emergence of sense– with individuals harboring this fusion showing a strong,
antisense chimeric transcripts from specific genes may favorable response to lorlatinib, a tyrosine kinase inhibitor
offer evolutionary advantages, as these genes have been that targets receptor tyrosine kinases linked to cancer
evolutionarily selected to enhance functional diversity in
response to various cellular conditions. 97 development. The fusion protein can be targeted using
lorlatinib. A list of gene fusions with diagnostic and
4.1. Potential effects of chimeric RNAs on therapeutic potential is provided in Table 2. 102-117
subsequent gene expression Similarly, intergenically spliced chimeric RNAs offer a

• Gene regulation: Chimeric RNAs can influence gene unique set of biomarkers and potential therapeutic targets.
expression by acting as competitive endogenous RNAs In NEPC, several chimeric RNAs, including TMPRSS2–
(ceRNAs). These molecules bind to microRNAs, ERG (e2e4), EEF2–SLC25A42, SNX13–ATP2C1, and
preventing them from degrading target mRNAs FXYD2–DSCAML1, have been identified and validated,
leading to increased expression of genes that would all exhibiting specific expression patterns in NEPC
otherwise be suppressed by microRNAs 98 cells. Notably, TMPRSS2–ERG (e2e4) showed elevated

Volume 4 Issue 1 (2025) 9 doi: 10.36922/gpd.3641