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

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, Gholamreza Haffari, Ali Bashashati, Roslin Russell, Steven McKinney, Anita Langerød, Andrew Green, Elena Provenzano, Gordon Wishart, Sarah Pinder, Peter Watson, Florian Markowetz, Leigh Murphy, Ian Ellis, Arnie Purushotham, Anne-Lise Børresen-Dale, James D. Brenton, Simon Tavaré, Carlos Caldas () and Samuel Aparicio ()
Additional contact information
Christina Curtis: University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
Sohrab P. Shah: University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
Suet-Feung Chin: University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
Gulisa Turashvili: University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
Oscar M. Rueda: University of Cambridge, Hills Road, Cambridge CB2 2XZ, 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
Andy G. Lynch: University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
Shamith Samarajiwa: University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
Yinyin Yuan: University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
Stefan Gräf: University of Cambridge, Hills Road, Cambridge CB2 2XZ, 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
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
Florian Markowetz: University of Cambridge, Hills Road, Cambridge CB2 2XZ, 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
Anne-Lise Børresen-Dale: Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway
James D. Brenton: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
Simon Tavaré: University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
Carlos Caldas: University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
Samuel Aparicio: University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada

Nature, 2012, vol. 486, issue 7403, 346-352

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature10983

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