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Improved detection ...
Improved detection of clinically relevant fusion transcripts in cancer by machine learning classification
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- Hafstað, Völundur (author)
- Lund University,Lunds universitet,Experimentell onkologi,Forskargrupper vid Lunds universitet,Funktionell bröstcancergenomik,Experimental oncology,Lund University Research Groups,Functional Breast Cancer Genomics
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- Häkkinen, Jari (author)
- Lund University,Lunds universitet,Experimentell onkologi,Forskargrupper vid Lunds universitet,Experimental oncology,Lund University Research Groups
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- Larsson, Malin (author)
- Linköping University,Linköpings universitet,Bioinformatik,Tekniska fakulteten,Science for Life Laboratory
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- Staaf, Johan (author)
- Lund University,Lunds universitet,Forskningsgrupp Lungcancer,Forskargrupper vid Lunds universitet,Bröst/lungcancer,Research Group Lung Cancer,Lund University Research Groups,Breast/lung cancer
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- Vallon-Christersson, Johan (author)
- Lund University,Lunds universitet,Experimentell onkologi,Forskargrupper vid Lunds universitet,Experimental oncology,Lund University Research Groups
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- Persson, Helena (author)
- Lund University,Lunds universitet,Bröst- och ovarialcancer,Forskargrupper vid Lunds universitet,Experimentell onkologi,Funktionell bröstcancergenomik,Breast and Ovarian Cancer Genomics,Lund University Research Groups,Experimental oncology,Functional Breast Cancer Genomics
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(creator_code:org_t)
- BMC, 2023
- 2023
- English.
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In: BMC Genomics. - : BMC. - 1471-2164. ; 24:1
- Related links:
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http://dx.doi.org/10... (free)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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Abstract
Subject headings
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- BackgroundGenomic rearrangements in cancer cells can create fusion genes that encode chimeric proteins or alter the expression of coding and non-coding RNAs. In some cancer types, fusions involving specific kinases are used as targets for therapy. Fusion genes can be detected by whole genome sequencing (WGS) and targeted fusion panels, but RNA sequencing (RNA-Seq) has the advantageous capability of broadly detecting expressed fusion transcripts.ResultsWe developed a pipeline for validation of fusion transcripts identified in RNA-Seq data using matched WGS data from The Cancer Genome Atlas (TCGA) and applied it to 910 tumors from 11 different cancer types. This resulted in 4237 validated gene fusions, 3049 of them with at least one identified genomic breakpoint. Utilizing validated fusions as true positive events, we trained a machine learning classifier to predict true and false positive fusion transcripts from RNA-Seq data. The final precision and recall metrics of the classifier were 0.74 and 0.71, respectively, in an independent dataset of 249 breast tumors. Application of this classifier to all samples with RNA-Seq data from these cancer types vastly extended the number of likely true positive fusion transcripts and identified many potentially targetable kinase fusions. Further analysis of the validated gene fusions suggested that many are created by intrachromosomal amplification events with microhomology-mediated non-homologous end-joining.ConclusionsA classifier trained on validated fusion events increased the accuracy of fusion transcript identification in samples without WGS data. This allowed the analysis to be extended to all samples with RNA-Seq data, facilitating studies of tumor biology and increasing the number of detected kinase fusions. Machine learning could thus be used in identification of clinically relevant fusion events for targeted therapy. The large dataset of validated gene fusions generated here presents a useful resource for development and evaluation of fusion transcript detection algorithms.
Subject headings
- NATURVETENSKAP -- Biologi -- Bioinformatik och systembiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Bioinformatics and Systems Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Fusion transcript; Gene fusion; Cancer genomics; Tumor biology; Precision medicine; Machine learning; Microhomology; Kinase
Publication and Content Type
- ref (subject category)
- art (subject category)
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