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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
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.
Change history
20 June 2012
The spelling of an author name (E.d.R.) was corrected.
References
Leary, R. J. et al. Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers. Proc. Natl Acad. Sci. USA 105, 16224–16229 (2008)
Bignell, G. R. et al. Signatures of mutation and selection in the cancer genome. Nature 463, 893–898 (2010)
Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000)
Sørlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001)
Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006)
Chin, S. F. et al. High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer. Genome Biol. 8, R215 (2007)
Parker, J. S. et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27, 1160–1167 (2009)
Stranger, B. E. et al. Genome-wide associations of gene expression variation in humans. PLoS Genet. 1, e78 (2005)
Gilad, Y., Rifkin, S. A. & Pritchard, J. K. Revealing the architecture of gene regulation: the promise of eQTL studies. Trends Genet. 24, 408–415 (2008)
Teschendorff, A. E., Naderi, A., Barbosa-Morais, N. L. & Caldas, C. PACK: Profile analysis using clustering and kurtosis to find molecular classifiers in cancer. Bioinformatics 22, 2269–2275 (2006)
Holland, D. et al. ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium. EMBO Mol. Med. 3, 167–180 (2011)
Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997)
Santarius, T., Shiply, J., Brewer, D., Stratton, M. R. & Cooper, C. S. A census of amplified and overexpressed human cancer genes. Nature Rev. Cancer 10, 59–64 (2010)
Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010)
McConechy, M. K. et al. Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas. J. Pathol. 223, 567–573 (2011)
Tan, J. et al. B55β-associated PP2A complex controls PDK1-directed MYC signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell 18, 459–471 (2010)
Christopher, S. A., Diegelman, P., Porter, C. W. & Kruger, W. D. Methylthioadenosine phosphorylase, a gene frequently codeleted with p16 (CDKN2A/ARF), acts as a tumor suppressor in a breast cancer cell line. Cancer Res. 62, 6639–6644 (2002)
Teng, D. H. et al. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Cancer Res. 57, 4177–4182 (1997)
Hollestelle, A. et al. Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res. Treat. 121, 53–64 (2010)
Shen, R., Olshen, A. B. & Ladanyi, M. Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis. Bioinformatics 25, 2906–2912 (2009)
Tibshirani, R., Hastie, T., Narasimhan, B. & Chu, G. Diagnosis of multiple cancer types by shrunken centroids of gene expression. Proc. Natl Acad. Sci. USA 99, 6567–6572 (2002)
Kapp, A. V. & Tibshirani, R. Are clusters found in one dataset present in another dataset? Biostatistics 8, 9–31 (2007)
Hughes-Davies, L. et al. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115, 523–535 (2003)
Brown, L. A. et al. Amplification of 11q13 in ovarian carcinoma. Genes Chromosom. Cancer 47, 481–489 (2008)
Russnes, H. G. et al. Genomic architecture characterizes tumor progression paths and fate in breast cancer patients. Sci. Transl. Med. 2, 38ra47 (2010)
Blows, F. M. et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 7, e1000279 (2010)
Mahmoud, S. M. A. et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 29, 1949–1955 (2011)
Daniel, J., Coulter, J., Woo, J.-H., Wilsbach, K. & Gabrielson, E. High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells. Proc. Natl Acad. Sci. USA 108, 5384–5389 (2011)
Chen, Y. et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008)
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
Authors and Affiliations
Consortia
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.
Corresponding authors
Ethics declarations
Competing interests
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
This file contains Supplementary Tables 1-6. (ZIP 21188 kb)
Supplementary Tables 2
This file contains Supplementary Tables 7-16. (ZIP 18800 kb)
Supplementary Tables 3
This file contains Supplementary Tables 17-31. (ZIP 10046 kb)
Supplementary Tables 4
This file contains Supplementary Tables 32-35. (ZIP 27331 kb)
Supplementary Tables 5
This file contains Supplementary Tables 36-41. (ZIP 14795 kb)
Supplementary Tables 6
This file contains Supplementary Tables 42-47. (ZIP 29002 kb)
Rights and permissions
About this article
Cite this article
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). https://doi.org/10.1038/nature10983
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature10983
This article is cited by
-
Clustering of HR + /HER2− breast cancer in an Asian cohort is driven by immune phenotypes
Breast Cancer Research (2024)
-
Mutational landscape of HSP family on human breast cancer
Scientific Reports (2024)
-
E-cadherin interacts with EGFR resulting in hyper-activation of ERK in multiple models of breast cancer
Oncogene (2024)
-
Addiction biotypes: a paradigm shift for future treatment strategies?
Molecular Psychiatry (2024)
-
cGAS-STING pathway expression correlates with genomic instability and immune cell infiltration in breast cancer
npj Breast Cancer (2024)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.