Transcriptional consequences of genomic structural aberrations in breast cancer
- Koichiro Inaki1,10,
- Axel M. Hillmer2,10,
- Leena Ukil1,10,
- Fei Yao2,3,
- Xing Yi Woo4,
- Leah A. Vardy5,
- Kelson Folkvard Braaten Zawack4,
- Charlie Wah Heng Lee4,
- Pramila Nuwantha Ariyaratne4,
- Yang Sun Chan1,
- Kartiki Vasant Desai1,
- Jonas Bergh6,
- Per Hall7,
- Thomas Choudary Putti8,
- Wai Loon Ong9,
- Atif Shahab9,
- Valere Cacheux-Rataboul1,
- Radha Krishna Murthy Karuturi4,
- Wing-Kin Sung4,
- Xiaoan Ruan2,
- Guillaume Bourque4,
- Yijun Ruan2 and
- Edison T. Liu1,11
- 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
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↵10 These authors contributed equally to this work.
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.
Footnotes
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↵11 Corresponding author.
E-mail liue{at}gis.a-star.edu.sg; fax 65-6808-8291.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.113225.110.
- Received August 3, 2010.
- Accepted February 1, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press
Freely available online through the Genome Research Open Access option.
