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Gene & Protein in Disease Gene fusions and chimeric RNAs

1. Introduction (i) Chromosomal translocation is a well-known
mechanism for generating gene fusions, with BCR–
Gene fusions and their products were initially believed ABL fusion, resulting from translocation between
to result solely from chromosomal rearrangements; thus, chromosomes 9 and 22, being a common example.
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they were recognized as cancer drivers and used for Chimeric RNAs are also linked to chromosomal
diagnosis. The fusion gene was first described in the inversions, such as EML4–ALK fusion, which is
1,2
1960s by Peter Nowell. The discovery of fusion genes associated with non-small cell lung cancer (NSCLC).
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9,10
opened new avenues for identifying fusions potentially Another mechanism for chimeric RNA production
related to or considered causative agents for cancer. BCR– involves interstitial deletion; TMPRSS2–ERG,
ABL, originating from chromosomal translocation, was frequently found in prostate cancer, is an example of this
the first fusion gene identified in human cancer in 1973 by mechanism. 11,12 Tandem duplications can also produce
Rowley. This fusion gene originated from a translocation fusion RNAs, such as C2orf44–ALK in colorectal cancer
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involving the q arms of chromosomes 9 and 22, and it and FGFR3–TACC3. 13,14 Chromothripsis can also
accounts for over 96% of chronic myelogenous leukemia result in fusions, where a chromosome or its segments
cases. Later, BCR–ABL was clinically used as a biomarker
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in chronic myeloid leukemia (CML). The advent of new shatter into fragments and are incorrectly reassembled.
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Examples include PVT1–NDRG1 and PVT1–MYC in
technologies and various bioinformatic tools revealed medulloblastoma and NDUFAF2–MAST4 in prostate
that interchromosomal translocation was not the sole cancer cell lines. 15,16
mechanism for fusion gene formation. Additional (ii) Exposure to various physical, chemical, and biological
mechanisms include intrachromosomal translocation,
transcriptional read-through, chromosome deletion, factors can cause genetic mutations and trigger gene
inversion, insertion, chromothripsis, and cis-SAGe. 7,8 fusion, as shown in Figure 3. After the Chernobyl
nuclear disaster, numerous studies reported a strong
The term “gene fusion” refers to fusion events at the link between radiation exposure and genetic mutations
DNA level, whereas “chimeric RNA” includes a wide range as well as gene fusions in thyroid cancer cases. In
of transcripts containing exons from different parental radiation-induced papillary thyroid carcinoma (PTC),
genes, including gene fusion transcripts. Notably, chimeric the occurrence rate of RET fusions is significantly
RNA generation is not solely dependent on gene fusion increased, ranging from 35% to 80%. A detailed
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transcription. Chimeric RNAs can also be formed through analysis of the prevalence of NCOA4–RET, involving
trans-splicing of two distinct precursor mRNAs and 2395 cases of radioactive and sporadic PTC, found
alternative splicing of a read-through transcript, known that radiation exposure increased the likelihood of
as cis-splicing of adjacent genes (cis-SAGe). Increasing RET/PTC, specifically in the western population for
9
evidence has indicated that chimeric RNAs may also arise the NCOA4–RET subtype. 18
through various splicing mechanisms. Splicing, a well- ETV6–NTRK3 fusion was identified in 14.5% of PTC
studied process, involves the exclusion of introns from cases caused by the Chernobyl disaster, with a strong link
pre-mRNA and aids in the formation of mature mRNA. to radiation exposure. In a study examining ionizing
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The splicing machinery utilizes spliceosomes, which are radiation and RET fusion in lung adenocarcinoma,
composed of small nuclear RNA molecules and a wide human 201T lung cells exposed to 1 Gy of gamma rays
array of proteins, forming an RNA–protein complex. Trans- showed RET fusions, and RET rearrangement was
esterification reactions catalyzed by spliceosomes remove detected in two out of 37 patients exposed to radiation.
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introns and connect exons. Increasing research has led to Other studies on genetic mutations in lung cancer
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the continuous identification of chimeric RNAs in both revealed a significantly higher incidence of gene fusions
tumor cells and non-cancerous tissues. These data are stored in patients exposed to tobacco and coal, with ALK fusion
in various databases, such as FusionGDB, ChimerDB, and and genetic rearrangement strongly associated with such
ChiTaRS. Different numbers of fusions in various cancer exposure. Another study investigating insecticides and
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types are deposited in the TCGA fusion gene database, as cancer-related mutations found ETV6–RUNX1 fusion in
illustrated in Figure 1. peripheral blood mononuclear cells significantly exposed
2. Mechanisms of chimeric RNA formation to permethrin. Permethrin exposure also led to ETV6–
RUNX1 and IGH–BCL2 fusions in K562 cells, whereas
Chromosome rearrangement, which alters chromosome malathion triggered KMT2A–AFF1 and ETV6–RUNX1
structure, was believed to be the sole mechanism underlying fusions. Similarly, EGFR–PPARGC1A fusion in squamous
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chimeric RNA formation. However, various mechanisms cell carcinoma of the head was linked to prolonged sunlight
lead to gene fusion formation, as shown in Figure 2. exposure. Research by Holly et al. in 2017 showed that
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Volume 4 Issue 1 (2025) 2 doi: 10.36922/gpd.3641