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The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

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  • Christina Curtis

    (University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
    Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
    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.).)

  • Sohrab P. Shah

    (University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
    Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada)

  • Suet-Feung Chin

    (University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
    Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK)

  • Gulisa Turashvili

    (University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
    Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada)

  • Oscar M. Rueda

    (University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
    Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK)

  • Mark J. Dunning

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK)

  • Doug Speed

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
    University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK
    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.).)

  • Andy G. Lynch

    (University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
    Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK)

  • Shamith Samarajiwa

    (University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
    Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK)

  • Yinyin Yuan

    (University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
    Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK)

  • Stefan Gräf

    (University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
    Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK)

  • Gavin Ha

    (University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada)

  • Gholamreza Haffari

    (University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada)

  • Ali Bashashati

    (University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada)

  • Roslin Russell

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK)

  • Steven McKinney

    (University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
    Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada)

  • Anita Langerød

    (Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway)

  • Andrew Green

    (School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK)

  • Elena Provenzano

    (Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK)

  • Gordon Wishart

    (Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK)

  • Sarah Pinder

    (King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK)

  • Peter Watson

    (University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
    Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada
    Manitoba Institute of Cell Biology, University of Manitoba)

  • Florian Markowetz

    (University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
    Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK)

  • Leigh Murphy

    (Manitoba Institute of Cell Biology, University of Manitoba)

  • Ian Ellis

    (School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK)

  • Arnie Purushotham

    (King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK
    NIHR Comprehensive Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London WC2R 2LS, UK)

  • Anne-Lise Børresen-Dale

    (Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway
    Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway)

  • James D. Brenton

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
    Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK)

  • Simon Tavaré

    (University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
    Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
    University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK
    Molecular and Computational Biology Program, University of Southern California)

  • Carlos Caldas

    (University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
    Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
    Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK
    Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK)

  • Samuel Aparicio

    (University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
    Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada)

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.

Suggested Citation

  • Christina Curtis & Sohrab P. Shah & Suet-Feung Chin & Gulisa Turashvili & Oscar M. Rueda & Mark J. Dunning & Doug Speed & Andy G. Lynch & Shamith Samarajiwa & Yinyin Yuan & Stefan Gräf & Gavin Ha & Gh, 2012. "The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups," Nature, Nature, vol. 486(7403), pages 346-352, June.
    • Handle: RePEc:nat:nature:v:486:y:2012:i:7403:d:10.1038_nature10983
    DOI: 10.1038/nature10983
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