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Abstract

The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in 40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.

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Change history

  • 20 June 2012

    The spelling of an author name (E.d.R.) was corrected.

Accessions

Data deposits

The associated genotype and expression data have been deposited at the European Genome-Phenome Archive (http://www.ebi.ac.uk/ega/), which is hosted by the European Bioinformatics Institute, under accession number EGAS00000000083.

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Acknowledgements

The METABRIC project was funded by Cancer Research UK, the British Columbia Cancer Foundation and Canadian Breast Cancer Foundation BC/Yukon. The authors also acknowledge the support of the University of Cambridge, Hutchinson Whampoa, the NIHR Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer Medicine Centre, the Centre for Translational Genomics (CTAG) Vancouver and the BCCA Breast Cancer Outcomes Unit. S.P.S. is a Michael Smith Foundation for Health Research fellow. S.A. is supported by a Canada Research Chair. This work was supported by the National Institutes of Health Centers of Excellence in Genomics Science grant P50 HG02790 (S.T.). The authors thank C. Perou and J. Parker for discussions on the use of the PAM50 centroids. They also acknowledge the patients who donated tissue and the associated pseudo-anonymized clinical data for this project.

Author information

Author notes

    • Christina Curtis
    •  & Doug Speed

    Present addresses: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA (Ch.C.); University College London, Genetics Institute, WC1E 6BT, UK (D.S.).

    • Christina Curtis
    • , Sohrab P. Shah
    • , Suet-Feung Chin
    •  & Gulisa Turashvili

    These authors contributed equally to this work.

Affiliations

  1. Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK

    • Christina Curtis
    • , Suet-Feung Chin
    • , Oscar M. Rueda
    • , Andy G. Lynch
    • , Shamith Samarajiwa
    • , Yinyin Yuan
    • , Stefan Gräf
    • , Florian Markowetz
    • , Simon Tavaré
    •  & Carlos Caldas
  2. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK

    • Christina Curtis
    • , Suet-Feung Chin
    • , Oscar M. Rueda
    • , Mark J. Dunning
    • , Doug Speed
    • , Andy G. Lynch
    • , Shamith Samarajiwa
    • , Yinyin Yuan
    • , Stefan Gräf
    • , Roslin Russell
    • , Florian Markowetz
    • , James D. Brenton
    • , Simon Tavaré
    •  & Carlos Caldas
  3. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada

    • Sohrab P. Shah
    • , Gulisa Turashvili
    • , Gavin Ha
    • , Gholamreza Haffari
    • , Ali Bashashati
    • , Steven McKinney
    • , Peter Watson
    •  & Samuel Aparicio
  4. Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada

    • Sohrab P. Shah
    • , Gulisa Turashvili
    • , Steven McKinney
    • , Peter Watson
    •  & Samuel Aparicio
  5. Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK

    • Doug Speed
    •  & Simon Tavaré
  6. Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway

    • Anita Langerød
    •  & Anne-Lise Børresen-Dale
  7. Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK

    • Andrew Green
    •  & Ian Ellis
  8. Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK

    • Elena Provenzano
    • , Gordon Wishart
    •  & Carlos Caldas
  9. King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK

    • Sarah Pinder
    •  & Arnie Purushotham
  10. Manitoba Institute of Cell Biology, University of Manitoba, Manitoba R3E 0V9, Canada

    • Peter Watson
    •  & Leigh Murphy
  11. NIHR Comprehensive Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London WC2R 2LS, UK

    • Arnie Purushotham
  12. Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway

    • Anne-Lise Børresen-Dale
  13. Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK

    • James D. Brenton
    •  & Carlos Caldas
  14. Molecular and Computational Biology Program, University of Southern California, Los Angeles, California 90089, USA

    • Simon Tavaré
  15. Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK.

    • Christina Curtis†
    • , James D. Brenton
    • , Carlos Caldas
    • , Suet-Feung Chin
    • , Stefan Gräf
    • , Bin Liu
    • , Andy G. Lynch
    • , Irene Papatheodorou
    • , Derek Chan
    • , Ana-Teresa Maia
    • , Simon Tavaré
    • , Oscar M. Rueda
    • , Shamith Samarajiwa
    • , Florian Markowetz
    •  & Yinyin Yuan
  16. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.

    • Christina Curtis†
    • , James D. Brenton
    • , Carlos Caldas
    • , Suet-Feung Chin
    • , Zhihao Ding
    • , Stefan Gräf
    • , Bin Liu
    • , Andy G. Lynch
    • , Irene Papatheodorou
    • , Claire Fielding
    • , Ana-Teresa Maia
    • , Sarah McGuire
    • , Michelle Osborne
    • , Sara M. Sayalero
    • , Inmaculada Spiteri
    • , James Hadfield
    • , Simon Tavaré
    • , Mark J. Dunning
    • , Oscar M. Rueda
    • , Roslin Russell
    • , Shamith Samarajiwa
    • , Doug Speed
    • , Florian Markowetz
    •  & Yinyin Yuan
  17. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.

    • Samuel Aparicio
    • , Sohrab P. Shah
    • , David Huntsman
    • , Steven McKinney
    • , Gulisa Turashvili
    • , Peter Watson
    • , Ali Bashashati
    • , Gavin Ha
    •  & Gholamreza Haffari
  18. Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada.

    • Samuel Aparicio
    • , Sohrab P. Shah
    • , David Huntsman
    • , Steven Chia
    • , Karen Gelmon
    • , Steven McKinney
    • , Caroline Speers
    • , Gulisa Turashvili
    • , Peter Watson
    • , Lynda Bell
    • , Katie Chow
    • , Nadia Gale
    • , Maria Kovalik
    • , Ying Ng
    •  & Leah Prentice
  19. Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK.

    • Ian Ellis
    • , Roger Blamey
    • , Andrew Green
    • , Douglas Macmillan
    •  & Emad Rakha
  20. King’s College London, Breakthrough Breast Cancer Research Unit, London, WC2R 2LS, UK.

    • Sarah Pinder
    • , Arnie Purushotham
    • , Cheryl Gillett
    • , Anita Grigoriadis
    • , Emanuele de Rinaldis
    •  & Andy Tutt
  21. Manitoba Institute of Cell Biology, University of Manitoba, Manitoba R3E 0V9, Canada.

    • Leigh Murphy
    • , Peter Watson
    • , Michelle Parisien
    •  & Sandra Troup
  22. Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK.

    • Linda Jones
  23. Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.

    • Stephen J. Sammut
    •  & Gordon Wishart
  24. Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK.

    • Simon Tavaré
    •  & Doug Speed
  25. Molecular and Computational Biology Program, University of Southern California, Los Angeles, California 90089, USA.

    • Simon Tavaré

Consortia

  1. METABRIC Group

    Co-chairs

    Writing committee

    Steering committee

    Tissue and clinical data source sites:

    University of Cambridge/Cancer Research UK Cambridge Research Institute

    British Columbia Cancer Agency

    University of Nottingham

    King’s College London

    Manitoba Institute of Cell Biology

    Cancer genome/transcriptome characterization centres:

    University of Cambridge/Cancer Research UK Cambridge Research Institute

    British Columbia Cancer Agency

    Data analysis subgroup:

    University of Cambridge/Cancer Research UK Cambridge Research Institute

    British Columbia Cancer Agency

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Contributions

Ch.C. led the analysis, designed experiments and wrote the manuscript. S.P.S. led the HMM-based analyses, expression outlier and TP53 analyses, and contributed to manuscript preparation. S.-F.C. generated data, designed and performed experiments. G.T. generated data, provided histopathology expertise and analysed TP53 sequence data. O.M.R., M.J.D., D.S., A.G.L., S.S., Y.Y., S.G., Ga.H., Gh.H., A.B., R.R., S.M. and F.M. performed analyses. G.T., A.G., E.P., S.P. and I.E. provided histopathology expertise. A.L. performed TP53 sequencing. A.-L.B.-D. oversaw TP53 sequencing. S.P., P.W., L.M., G.W., I.E., A.P., Ca.C. and S.A. contributed to sample selection. J.D.B. and S.T. contributed to study design. S.T. provided statistical expertise. The METABRIC Group contributed collectively to this study. Ca.C. and S.A. co-conceived and oversaw the study, and contributed to manuscript preparation and were responsible for final editing. Ca.C. and S.A. are joint senior authors and project co-leaders.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Samuel Aparicio or Samuel Aparicio or Samuel Aparicio or Samuel Aparicio or Samuel Aparicio or Samuel Aparicio or Carlos Caldas or Samuel Aparicio.

Supplementary information

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  1. 1.

    Supplementary Information

    This file contains Supplementary Methods (see Contents for more details), Supplementary References, Supplementary Figures 1-39 and legends for Supplementary Tables 1-47 (see separate zipped files for tables).

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  1. 1.

    Supplementary Tables 1

    This file contains Supplementary Tables 1-6.

  2. 2.

    Supplementary Tables 2

    This file contains Supplementary Tables 7-16.

  3. 3.

    Supplementary Tables 3

    This file contains Supplementary Tables 17-31.

  4. 4.

    Supplementary Tables 4

    This file contains Supplementary Tables 32-35.

  5. 5.

    Supplementary Tables 5

    This file contains Supplementary Tables 36-41.

  6. 6.

    Supplementary Tables 6

    This file contains Supplementary Tables 42-47.

About this article

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DOI

https://doi.org/10.1038/nature10983

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