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Accurate fusion transcript identification from long- and short-read isoform sequencing at bulk or single-cell
Qian Qin1, Victoria Popic1, Kirsty Wienand1
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Genome Research
|March 14, 2025
Summary
A new tool, CTAT-LR-Fusion, enhances the detection of gene fusions from long-read RNA sequencing data. This improves cancer diagnostics and therapeutic guidance by identifying fusion transcripts with greater accuracy in bulk and single cells.
Area of Science:
- Genomics
- Cancer Biology
- Bioinformatics
Background:
- Gene fusions are key drivers in various cancers, necessitating accurate detection for diagnostics and treatment.
- Current short-read RNA sequencing methods have limitations in comprehensively identifying fusion transcripts.
- Long-read sequencing offers higher resolution for detecting complex transcript structures, including gene fusions.
Purpose of the Study:
- To develop and validate a computational tool, CTAT-LR-Fusion, for detecting gene fusions from long-read RNA sequencing data.
- To assess the performance of CTAT-LR-Fusion compared to existing methods using simulated and real-world data.
- To apply CTAT-LR-Fusion to analyze bulk and single-cell transcriptomes for fusion detection in cancer samples.
Main Methods:
- Development of CTAT-LR-Fusion, a computational tool designed for long-read RNA sequencing data analysis.
- Benchmarking CTAT-LR-Fusion against alternative methods using simulated and genuine long-read RNA sequencing datasets.
- Application of CTAT-LR-Fusion to analyze bulk transcriptomes from nine tumor cell lines and single-cell transcriptomes from melanoma and ovarian cancer samples.
Main Results:
- CTAT-LR-Fusion demonstrated superior accuracy in detecting fusion transcripts compared to alternative methods.
- Long isoform reads showed higher sensitivity for fusion detection in both bulk and single-cell RNA sequencing.
- Combining short and long reads with CTAT-LR-Fusion maximized the detection of fusion splicing isoforms and fusion-expressing tumor cells.
Conclusions:
- CTAT-LR-Fusion is an effective tool for accurate gene fusion detection in long-read RNA sequencing.
- Long-read sequencing, especially when combined with short reads, significantly enhances the sensitivity of fusion transcript detection.
- This advancement aids in cancer diagnostics, prognostics, and the development of targeted therapies.
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