Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 30, Pages 12353-12358Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0904720106
Keywords
bioinformatics; gene fusions; prostate cancer; breast cancer; RNA-Seq
Categories
Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [P50CA69568, R01 CA132874, P50 CA069568, K99 CA129565, 1K99CA129565-01A1, R01CA132874, U01 CA111275, K99 CA129565-01A1] Funding Source: Medline
- NIDA NIH HHS [U54 DA021519] Funding Source: Medline
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Recurrent gene fusions are a prevalent class of mutations arising from the juxtaposition of 2 distinct regions, which can generate novel functional transcripts that could serve as valuable therapeutic targets in cancer. Therefore, we aim to establish a sensitive, high-throughput methodology to comprehensively catalog functional gene fusions in cancer by evaluating a paired-end transcriptome sequencing strategy. Not only did a paired-end approach provide a greater dynamic range in comparison with single read based approaches, but it clearly distinguished the high-level driving'' gene fusions, such as BCR-ABL1 and TMPRSS2-ERG, from potential lower level passenger'' gene fusions. Also, the comprehensiveness of a paired-end approach enabled the discovery of 12 previously undescribed gene fusions in 4 commonly used cell lines that eluded previous approaches. Using the paired-end transcriptome sequencing approach, we observed readthrough mRNA chimeras, tissue-type restricted chimeras, converging transcripts, diverging transcripts, and overlapping mRNA transcripts. Last, we successfully used paired-end transcriptome sequencing to detect previously undescribed ETS gene fusions in prostate tumors. Together, this study establishes a highly specific and sensitive approach for accurately and comprehensively cataloguing chimeras within a sample using paired-end transcriptome sequencing.
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