Fusion transcript

Fusion transcript refers to a hybrid RNA molecule originating from the transcription of a fusion gene. This phenomenon is a result of either chromosomal rearrangements, such as translocation, interstitial deletion, or inversion, or trans-splicing of pre-mRNAs. Fusion transcripts are significant in the context of cancer biology, as they often lead to the production of oncogenic proteins that contribute to the development and progression of cancer.

Formation

Fusion transcripts are formed through two primary mechanisms:

Chromosomal Rearrangements

In this scenario, parts of two separate genes on the same or different chromosomes are brought together through chromosomal rearrangements. The most common types of rearrangements include:

• Translocation: A segment of one chromosome is transferred to another chromosome.
• Interstitial deletion: A segment from the middle of a chromosome is deleted, bringing two previously separated genes together.
• Inversion: A chromosome segment is reversed end to end, potentially juxtaposing two genes that were not previously adjacent.

These rearrangements can lead to the creation of a new fusion gene, which is then transcribed into a fusion transcript.

Trans-splicing

Trans-splicing is a process by which exons from two different pre-mRNA molecules are joined together. This mechanism is less common than chromosomal rearrangements but can also result in the formation of fusion transcripts.

Clinical Significance

Fusion transcripts play a crucial role in the development of certain types of cancers. They can act as potent oncogenes, driving the malignant transformation of cells. For example, the BCR-ABL fusion transcript, resulting from the translocation between chromosomes 9 and 22 (the Philadelphia chromosome), is a hallmark of chronic myelogenous leukemia (CML). This fusion transcript encodes a constitutively active tyrosine kinase that promotes uncontrolled cell proliferation.

The identification of fusion transcripts has significant implications for cancer diagnosis, prognosis, and therapy. They can serve as biomarkers for specific types of cancer and as targets for personalized treatment. Drugs that specifically inhibit the activity of the proteins encoded by fusion transcripts, such as tyrosine kinase inhibitors (TKIs) for BCR-ABL in CML, have shown remarkable efficacy in treating certain cancers.

Detection

Techniques for detecting fusion transcripts include:

• Reverse transcription polymerase chain reaction (RT-PCR)
• Fluorescence in situ hybridization (FISH)
• Next-generation sequencing (NGS)

These methods have varying degrees of sensitivity and specificity and can be used to identify known and novel fusion transcripts.

Conclusion

Fusion transcripts are a critical aspect of molecular oncology, offering insights into the mechanisms of oncogenesis and providing avenues for targeted cancer therapy. Their detection and characterization are essential for the diagnosis and treatment of cancers driven by these aberrant RNA molecules.