Chimeric transcript discovery by paired-end transcriptome sequencing

Christopher A. Maher, Nallasivam Palanisamy, John C. Brenner, Xuhong Cao, Shanker Kalyana-Sundaram, Shujun Luo, Irina Khrebtukova, Terrence R. Barrette, Catherine Grasso, Jindan Yu, Robert J. Lonigro, Gary Schroth, Chandan Kumar-Sinha, Arul M. Chinnaiyan

Research output: Contribution to journalArticlepeer-review

262 Scopus citations

Abstract

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 read-through 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.

Original languageEnglish (US)
Pages (from-to)12353-12358
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number30
DOIs
StatePublished - Jul 28 2009

Keywords

  • Bioinformatics
  • Breast cancer
  • Gene fusions
  • Prostate cancer
  • RNA-Seq

ASJC Scopus subject areas

  • General

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