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

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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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Figure 1: Germline and somatic variants influence tumour expression architecture.
Figure 2: Patterns of cis outlying expression refine putative breast cancer drivers.
Figure 3: Trans -acting aberration hotspots modulate concerted molecular pathways.
Figure 4: The integrative subgroups have distinct copy number profiles.
Figure 5: The integrative subgroups have distinct clinical outcomes.

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Data deposits

The associated genotype and expression data have been deposited at the European Genome-Phenome Archive (, which is hosted by the European Bioinformatics Institute, under accession number EGAS00000000083.

Change history

  • 20 June 2012

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


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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.

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Authors and Affiliations




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.

Corresponding authors

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

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The authors declare no competing financial interests.

Supplementary information

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). (PDF 24684 kb)

Supplementary Tables 1

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Supplementary Tables 2

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Supplementary Tables 3

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Supplementary Tables 4

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Supplementary Tables 6

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Curtis, C., Shah, S., Chin, SF. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).

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