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Complex landscapes of somatic rearrangement in human breast cancer genomes

Nature volume 462, pages 1005–1010 (2009)Cite this article

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.

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Figure 1: Somatic rearrangements observed in six of the twenty-four breast cancer samples screened.
Figure 2: Extent of overlapping microhomology at different architectural classes of rearrangement junctions.
Figure 3: ETV6–ITPR2 , an expressed, in-frame fusion gene generated by a 15-Mb inversion in the primary breast cancer PD3668a.

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Acknowledgements

We are grateful to M. Lambros, F. Geyer and R. Vatcheva for their assistance in the FISH experiments. We would like to acknowledge the support of the Kay Kendall Leukaemia Fund under Grant KKL282, Human Frontiers Award reference LT000561/2009-L, the Dana-Farber/Harvard SPORE in breast cancer under NCI grant reference CA089393, Breakthrough Breast Cancer, the Research Council of Norway Grants no. 155218 and 175240, and the Wellcome Trust under grant reference 077012/Z/05/Z.

Author Contributions M.R.S., P.A.F., P.J.C. and P.J.S. designed the experiment. S.E., D.J.M., P.J.S., M-L.L., I.V., L.J.M., J.B., M.A.Q., H.S., C.C., R.N., A.M.S., A.L., J.W.M.M. and C.Latimer carried out laboratory analyses. J.A.F., J.S.R.-F., L.v.V., A.L.R. D.P.S. and A.-L.B.-D. provided clinical samples. P.J.S., D.J.M., I.V., M.-L.L., E.D.P., J.T.S., L.A.S., C.Leroy, C.D.G., M.J., J.W.T., K.W.L., P.J.C., P.A.F., J.S.R.-F., J.W.M.M., A.M.S., J.A.F., M.R.S., H.E.G.R., A.L.R., A.-L.B.-D., L.v.V., A.L., P.J.C. and P.A.F. performed data analysis, informatics and statistics. M.R.S. wrote the manuscript with comments from P.J.S., P.A.F., P.J.C., A.-L.B.-D., J.S.R.-F., J.A.F., A.L.R., D.P.S. and L.v.V.

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Authors and Affiliations

  1. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK ,

    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, Peter J. Campbell, P. Andrew Futreal & Michael R. Stratton

  2. Molecular Pathology Laboratory, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK ,

    Rachael Natrajan & Jorge S. Reis-Filho

  3. Department of Medical Oncology, Josephine Nefkens Institute, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands,

    Anieta M. Sieuwerts, John W. M. Martens & John A. Foekens

  4. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Daniel P. Silver & Andrea L. Richardson

  5. Department of Genetics, Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310 Oslo, Norway,

    Anita Langerød, Hege E. G. Russnes & Anne-Lise Børresen-Dale

  6. The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands ,

    Laura van ’t Veer

  7. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Andrea L. Richardson

  8. Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway,

    Anne-Lise Børresen-Dale

  9. Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK. ,

    Michael R. Stratton

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Correspondence to P. Andrew Futreal or Michael R. Stratton.

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Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-7 with Legends. (PDF 5501 kb)

Supplementary Table 1

Summary of somatic rearrangements found in 24 breast cancers (XLS 845 kb)

Supplementary Table 2

Variation in the prevalence of rearrangement architectures in individual breast cancer genomes. (XLS 28 kb)

Supplementary Table 3

Base pair resolution of rearrangement breakpoints. (XLS 350 kb)

Supplementary Table 4

GC content analysis at rearrangement breakpoints. (XLS 22 kb)

Supplementary Table 5

Evaluation of motif enrichment at rearrangement breakpoints. (XLS 24 kb)

Supplementary Table 6

Gene Fusions. (PDF 135 kb)

Supplementary Table 7

Internally rearranged genes. (XLS 69 kb)

Supplementary Table 8

Known cancer genes that are rearranged. (XLS 36 kb)

Supplementary Table 9

Rearranged genes. (XLS 452 kb)

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Stephens, P., McBride, D., Lin, ML. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005–1010 (2009). https://doi.org/10.1038/nature08645

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