Complex landscapes of somatic rearrangement in human breast cancer genomes

Philip J. Stephens, David J. McBride, Meng-Lay Lin, Ignacio Varela, Erin D. Pleasance, Jared T. Simpson, Lucy A. Stebbings, Catherine Leroy, Sarah Edkins, Laura J. Mudie, Chris D. Greenman, Mingming Jia, Calli Latimer, Jon W. Teague, King Wai Lau, John Burton, Michael A. Quail, Harold Swerdlow, Carol Churcher, Rachael Natrajan, Anieta M. Sieuwerts, John W. M. Martens, Daniel P. Silver, Anita Langerød, Hege E. G. Russnes, John A. Foekens, Jorge S. Reis-Filho, Laura van ’t Veer, Andrea L. Richardson, Anne-Lise Børresen-Dale, Peter J. Campbell, P. Andrew Futreal () and Michael R. Stratton ()
Additional contact information
Philip J. Stephens: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
David J. McBride: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Meng-Lay Lin: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Ignacio Varela: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Erin D. Pleasance: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Jared T. Simpson: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Lucy A. Stebbings: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Catherine Leroy: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Sarah Edkins: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Laura J. Mudie: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Chris D. Greenman: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Mingming Jia: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Calli Latimer: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Jon W. Teague: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
King Wai Lau: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
John Burton: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Michael A. Quail: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Harold Swerdlow: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Carol Churcher: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Rachael Natrajan: Molecular Pathology Laboratory, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
Anieta M. Sieuwerts: Josephine Nefkens Institute, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
John W. M. Martens: Josephine Nefkens Institute, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
Daniel P. Silver: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
Anita Langerød: Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310 Oslo, Norway
Hege E. G. Russnes: Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310 Oslo, Norway
John A. Foekens: Josephine Nefkens Institute, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
Jorge S. Reis-Filho: Molecular Pathology Laboratory, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
Laura van ’t Veer: The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands
Andrea L. Richardson: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
Anne-Lise Børresen-Dale: Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310 Oslo, Norway
Peter J. Campbell: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
P. Andrew Futreal: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Michael R. Stratton: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK

Nature, 2009, vol. 462, issue 7276, 1005-1010

Abstract: Abstract Multiple somatic rearrangements are often found in cancer genomes; however, the underlying processes of rearrangement and their contribution to cancer development are poorly characterized. Here we use a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by non-homologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. The study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development.

Date: 2009
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DOI: 10.1038/nature08645

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