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Transcriptional consequences of genomic structural aberrations in breast cancer

    • 1Cancer Biology and Pharmacology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
    • 2Genome Technology and Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
    • 3Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore;
    • 4Computational and Mathematical Biology, Genome Institute of Singapore, Genome, Singapore 138672, Singapore;
    • 5Institute of Medical Biology, Immunos, Singapore 138648, Singapore;
    • 6Department of Oncology–Pathology, Karolinska Institute, SE-17177 Stockholm, Sweden;
    • 7Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-17177 Stockholm, Sweden;
    • 8Department of Pathology, National University of Singapore, Singapore 119077, Singapore;
    • 9Research Computing, Genome Institute of Singapore, Genome, Singapore 138672, Singapore
    • 10 These authors contributed equally to this work.
    • 11 Corresponding author. E-mail [email protected]; fax 65-6808-8291.
Published April 5, 2011. https://doi.org/10.1101/gr.113225.110
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Abstract

Using a long-span, paired-end deep sequencing strategy, we have comprehensively identified cancer genome rearrangements in eight breast cancer genomes. Herein, we show that 40%–54% of these structural genomic rearrangements result in different forms of fusion transcripts and that 44% are potentially translated. We find that single segmental tandem duplication spanning several genes is a major source of the fusion gene transcripts in both cell lines and primary tumors involving adjacent genes placed in the reverse-order position by the duplication event. Certain other structural mutations, however, tend to attenuate gene expression. From these candidate gene fusions, we have found a fusion transcript (RPS6KB1–VMP1) recurrently expressed in ∼30% of breast cancers associated with potential clinical consequences. This gene fusion is caused by tandem duplication on 17q23 and appears to be an indicator of local genomic instability altering the expression of oncogenic components such as MIR21 and RPS6KB1.

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