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

Oncogene 2015 Jan 3;34(5):568-77. Epub 2014 Feb 3.

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

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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http://dx.doi.org/10.1038/onc.2013.591DOI Listing
January 2015

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References

(Supplied by CrossRef)

R Siegel et al.
Cancer J Clin 2012

MM Shen et al.
Genes Dev 2010

SA Tomlins et al.
Science 2005

J-T Dong et al.
Cancer Metastasis Rev 2001

NJ Clegg et al.
PLoS One 2011

I Cheng et al.
Genes Chromosomes Cancer 2011

G Jin et al.
Carcinogenesis 2011

J Cuzick et al.
Lancet Oncol 2011

BS Taylor et al.
Cancer Cell 2010

P Vainio et al.
Prostate 2011

J Kim et al.
Biochim et Biophys Acta 2012

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