Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing

  1. Mark A. Rubin1,13,14
  1. 1 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10021, USA;
  2. 2 Molecular Biophysics and Biochemistry Department, Yale University, New Haven, Connecticut 06510, USA;
  3. 3 Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut 06510, USA;
  4. 4 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA;
  5. 5 Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA;
  6. 6 Department of Urology, Weill Cornell Medical College, New York, New York 10021, USA;
  7. 7 Institute of Prostate Cancer, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York 10021, USA;
  8. 8 Prognosys Biosciences, Inc., La Jolla, California 92037, USA;
  9. 9 Howard Hughes Medical Institute, Department of Urology, and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA;
  10. 10 Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York 10021, USA;
  11. 11 Department of Computer Science, Yale University, New Haven, Connecticut 06510, USA

    1. ↵12 These authors contributed equally to this work.

    Abstract

    Half of prostate cancers harbor gene fusions between TMPRSS2 and members of the ETS transcription factor family. To date, little is known about the presence of non-ETS fusion events in prostate cancer. We used next-generation transcriptome sequencing (RNA-seq) in order to explore the whole transcriptome of 25 human prostate cancer samples for the presence of chimeric fusion transcripts. We generated more than 1 billion sequence reads and used a novel computational approach (FusionSeq) in order to identify novel gene fusion candidates with high confidence. In total, we discovered and characterized seven new cancer-specific gene fusions, two involving the ETS genes ETV1 and ERG, and four involving non-ETS genes such as CDKN1A (p21), CD9, and IKBKB (IKK-beta), genes known to exhibit key biological roles in cellular homeostasis or assumed to be critical in tumorigenesis of other tumor entities, as well as the oncogene PIGU and the tumor suppressor gene RSRC2. The novel gene fusions are found to be of low frequency, but, interestingly, the non-ETS fusions were all present in prostate cancer harboring the TMPRSS2–ERG gene fusion. Future work will focus on determining if the ETS rearrangements in prostate cancer are associated or directly predispose to a rearrangement-prone phenotype.

    Footnotes

    • Received May 21, 2010.
    • Accepted September 24, 2010.
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    1. Published in Advance October 29, 2010, doi: 10.1101/gr.110684.110 Genome Res. 21: 56-67 Copyright © 2011 by Cold Spring Harbor Laboratory Press

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