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         headline:The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups
         description: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. Integrative analysis of copy number and gene expression in 2,000 primary breast tumours with long-term clinical follow-up revealed putative cis-acting driver genes, novel subgroups and trans-acting aberration hotspots that modulate subgroup-specific gene networks.
         datePublished:2012-04-18T00:00:00Z
         dateModified:2012-06-20T00:00:00Z
         pageStart:346
         pageEnd:352
         sameAs:https://doi.org/10.1038/nature10983
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            Breast cancer
            Cancer genomics
            Epidemiology
            Transcriptomics
            Science
            Humanities and Social Sciences
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      headline:The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups
      description: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. Integrative analysis of copy number and gene expression in 2,000 primary breast tumours with long-term clinical follow-up revealed putative cis-acting driver genes, novel subgroups and trans-acting aberration hotspots that modulate subgroup-specific gene networks.
      datePublished:2012-04-18T00:00:00Z
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      keywords:
         Breast cancer
         Cancer genomics
         Epidemiology
         Transcriptomics
         Science
         Humanities and Social Sciences
         multidisciplinary
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      name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
      address:
         name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
         type:PostalAddress
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
      address:
         name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
         type:PostalAddress
      name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
      address:
         name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
         type:PostalAddress
      name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
      address:
         name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
         type:PostalAddress
      name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
      address:
         name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
         type:PostalAddress
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
      address:
         name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
         type:PostalAddress
      name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
      address:
         name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
         type:PostalAddress
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      address:
         name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
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      name:Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway
      address:
         name:Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway,
         type:PostalAddress
      name:School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK
      address:
         name:Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK,
         type:PostalAddress
      name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK
      address:
         name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK ,
         type:PostalAddress
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      address:
         name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK ,
         type:PostalAddress
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      address:
         name: King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK ,
         type:PostalAddress
      name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
      address:
         name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
         type:PostalAddress
      name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada
      address:
         name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
         type:PostalAddress
      name:Manitoba Institute of Cell Biology, University of Manitoba
      address:
         name:Manitoba Institute of Cell Biology, University of Manitoba, Manitoba R3E 0V9, Canada
         type:PostalAddress
      name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
      address:
         name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
         type:PostalAddress
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
      address:
         name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
         type:PostalAddress
      name:Manitoba Institute of Cell Biology, University of Manitoba
      address:
         name:Manitoba Institute of Cell Biology, University of Manitoba, Manitoba R3E 0V9, Canada
         type:PostalAddress
      name:School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK
      address:
         name:Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK,
         type:PostalAddress
      name: King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK
      address:
         name: King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK ,
         type:PostalAddress
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         name: NIHR Comprehensive Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London WC2R 2LS, UK ,
         type:PostalAddress
      name:Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway
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      address:
         name: Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway ,
         type:PostalAddress
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
      address:
         name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
         type:PostalAddress
      name: Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK
      address:
         name: Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK ,
         type:PostalAddress
      name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
      address:
         name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
         type:PostalAddress
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
      address:
         name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
         type:PostalAddress
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      address:
         name:Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK,
         type:PostalAddress
      name:Molecular and Computational Biology Program, University of Southern California
      address:
         name:Molecular and Computational Biology Program, University of Southern California, Los Angeles, USA
         type:PostalAddress
      name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
      address:
         name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
         type:PostalAddress
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
      address:
         name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
         type:PostalAddress
      name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK
      address:
         name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK ,
         type:PostalAddress
      name: Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK
      address:
         name: Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK ,
         type:PostalAddress
      name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
      address:
         name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
         type:PostalAddress
      name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada
      address:
         name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
         type:PostalAddress
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            name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
            address:
               name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
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            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
               type:PostalAddress
            type:Organization
            name: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.).
            address:
               name: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.).,
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      name:Sohrab P. Shah
      affiliation:
            name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
            address:
               name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
               type:PostalAddress
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            name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada
            address:
               name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
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      name:Suet-Feung Chin
      affiliation:
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            address:
               name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
               type:PostalAddress
            type:Organization
            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
               type:PostalAddress
            type:Organization
      name:Gulisa Turashvili
      affiliation:
            name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
            address:
               name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
               type:PostalAddress
            type:Organization
            name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada
            address:
               name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
               type:PostalAddress
            type:Organization
      name:Oscar M. Rueda
      affiliation:
            name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
            address:
               name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
               type:PostalAddress
            type:Organization
            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
               type:PostalAddress
            type:Organization
      name:Mark J. Dunning
      affiliation:
            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
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      name:Doug Speed
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            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
               type:PostalAddress
            type:Organization
            name:University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK
            address:
               name:Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK,
               type:PostalAddress
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            name: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.).
            address:
               name: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.).,
               type:PostalAddress
            type:Organization
      name:Andy G. Lynch
      affiliation:
            name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
            address:
               name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
               type:PostalAddress
            type:Organization
            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
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      name:Shamith Samarajiwa
      affiliation:
            name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
            address:
               name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
               type:PostalAddress
            type:Organization
            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
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      name:Yinyin Yuan
      affiliation:
            name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
            address:
               name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
               type:PostalAddress
            type:Organization
            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
               type:PostalAddress
            type:Organization
      name:Stefan Gräf
      affiliation:
            name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
            address:
               name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
               type:PostalAddress
            type:Organization
            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
               type:PostalAddress
            type:Organization
      name:Gavin Ha
      affiliation:
            name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
            address:
               name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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      name:Gholamreza Haffari
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            name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
            address:
               name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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      name:Ali Bashashati
      affiliation:
            name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
            address:
               name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
               type:PostalAddress
            type:Organization
      name:Roslin Russell
      affiliation:
            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
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      name:Steven McKinney
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            name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
            address:
               name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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            name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada
            address:
               name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
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            name:Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway
            address:
               name:Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway,
               type:PostalAddress
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      name:Andrew Green
      affiliation:
            name:School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK
            address:
               name:Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK,
               type:PostalAddress
            type:Organization
      name:Elena Provenzano
      affiliation:
            name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK
            address:
               name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK ,
               type:PostalAddress
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            name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK
            address:
               name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK ,
               type:PostalAddress
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      name:Sarah Pinder
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            name: King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK
            address:
               name: King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK ,
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      name:Peter Watson
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            name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
            address:
               name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
               type:PostalAddress
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            name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada
            address:
               name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
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            name:Manitoba Institute of Cell Biology, University of Manitoba
            address:
               name:Manitoba Institute of Cell Biology, University of Manitoba, Manitoba R3E 0V9, Canada
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            type:Organization
      name:Florian Markowetz
      affiliation:
            name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
            address:
               name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
               type:PostalAddress
            type:Organization
            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
               type:PostalAddress
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      name:Leigh Murphy
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            name:Manitoba Institute of Cell Biology, University of Manitoba
            address:
               name:Manitoba Institute of Cell Biology, University of Manitoba, Manitoba R3E 0V9, Canada
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      name:Ian Ellis
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            name:School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK
            address:
               name:Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK,
               type:PostalAddress
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      name:Arnie Purushotham
      affiliation:
            name: King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK
            address:
               name: King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK ,
               type:PostalAddress
            type:Organization
            name: NIHR Comprehensive Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London WC2R 2LS, UK
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               name: NIHR Comprehensive Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London WC2R 2LS, UK ,
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      name:Anne-Lise Børresen-Dale
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            name:Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway
            address:
               name:Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway,
               type:PostalAddress
            type:Organization
            name: Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway
            address:
               name: Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway ,
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            type:Organization
      name:James D. Brenton
      affiliation:
            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
               type:PostalAddress
            type:Organization
            name: Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK
            address:
               name: Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK ,
               type:PostalAddress
            type:Organization
      name:Simon Tavaré
      affiliation:
            name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
            address:
               name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
               type:PostalAddress
            type:Organization
            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
               type:PostalAddress
            type:Organization
            name:University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK
            address:
               name:Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK,
               type:PostalAddress
            type:Organization
            name:Molecular and Computational Biology Program, University of Southern California
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               name:Molecular and Computational Biology Program, University of Southern California, Los Angeles, USA
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            type:Organization
      name:Carlos Caldas
      affiliation:
            name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
            address:
               name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
               type:PostalAddress
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            name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
            address:
               name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
               type:PostalAddress
            type:Organization
            name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK
            address:
               name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK ,
               type:PostalAddress
            type:Organization
            name: Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK
            address:
               name: Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK ,
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Samuel Aparicio
      affiliation:
            name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
            address:
               name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
               type:PostalAddress
            type:Organization
            name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada
            address:
               name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name: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.).,
      name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
      name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
      name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
      name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
      name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name:Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK,
      name: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.).,
      name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
      name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
      name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
      name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
      name:Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway,
      name:Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK,
      name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK ,
      name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK ,
      name: King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK ,
      name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
      name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
      name:Manitoba Institute of Cell Biology, University of Manitoba, Manitoba R3E 0V9, Canada
      name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name:Manitoba Institute of Cell Biology, University of Manitoba, Manitoba R3E 0V9, Canada
      name:Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK,
      name: King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK ,
      name: NIHR Comprehensive Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London WC2R 2LS, UK ,
      name:Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway,
      name: Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway ,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name: Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK ,
      name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name:Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK,
      name:Molecular and Computational Biology Program, University of Southern California, Los Angeles, USA
      name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
      name: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
      name: Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK ,
      name: Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK ,
      name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
      name: Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
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