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Next-generation sequencing reveals novel rare fusion events with functional implication in prostate cancer

Oncogene volume 34, pages 568–577 (2015)Cite this article

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Abstract

Gene fusions, mainly between TMPRSS2 and ERG, are frequent early genomic rearrangements in prostate cancer (PCa). In order to discover novel genomic fusion events, we applied whole-genome paired-end sequencing to identify structural alterations present in a primary PCa patient (G089) and in a PCa cell line (PC346C). Overall, we identified over 3800 genomic rearrangements in each of the two samples as compared with the reference genome. Correcting these structural variations for polymorphisms using whole-genome sequences of 46 normal samples, the numbers of cancer-related rearrangements were 674 and 387 for G089 and PC346C, respectively. From these, 192 in G089 and 106 in PC346C affected gene structures. Exclusion of small intronic deletions left 33 intergenic breaks in G089 and 14 in PC346C. Out of these, 12 and 9 reassembled genes with the same orientation, capable of generating a feasible fusion transcript. Using PCR we validated all the reliable predicted gene fusions. Two gene fusions were in-frame: MPP5–FAM71D in PC346C and ARHGEF3–C8ORF38 in G089. Downregulation of FAM71D and MPP5–FAM71D transcripts in PC346C cells decreased proliferation; however, no effect was observed in the RWPE-1-immortalized normal prostate epithelial cells. Together, our data showed that gene rearrangements frequently occur in PCa genomes but result in a limited number of fusion transcripts. Most of these fusion transcripts do not encode in-frame fusion proteins. The unique in-frame MPP5–FAM71D fusion product is important for proliferation of PC346C cells.

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Acknowledgements

We would like to thank André Uitterlinden from the Department of Internal Medicine, Erasmus MC for microarray assistance, Arno van Leenders from the Department of Pathology, Erasmus MC for patient sample selection, Wytske van Weerden from the Department of Urology, Erasmus MC for the expertise in PC346C cell line model systems, Complete Genomics Inc. for assistance with the NGS data and the patients whose material was used for this study. This research was made possible by financial contributions from CTMM, project PCMM (project number 03O-203), the FP7 Marie Curie Initial Training Network PRO-NEST (grant number 238278) and the Foundation for Scientific Urological Research (SUWO).

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Authors and Affiliations

  1. Department of Urology and Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

    I Teles Alves

  2. Department of Urology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

    T Hartjes, S Hiltemann, R Böttcher, N Dits & G Jenster

  3. Department of Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands

    E McClellan, P van der Spek & A Stubbs

  4. Department of Mathematical and Computer Sciences, Metropolitan State University of Denver, Colorado, USA

    E McClellan

  5. CMNS-Institute for Advanced Computer Studies, University of Maryland, College Park, MD, USA

    M R Temanni

  6. ServiceXS B.V., Leiden, The Netherlands

    B Janssen & W van Workum

  7. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

    A de Klein & B Eussen

  8. Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

    J Trapman

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Teles Alves, I., Hartjes, T., McClellan, E. et al. Next-generation sequencing reveals novel rare fusion events with functional implication in prostate cancer. Oncogene 34, 568–577 (2015). https://doi.org/10.1038/onc.2013.591

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