The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups (original) (raw)

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

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

References

  1. 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)
    Article ADS CAS Google Scholar
  2. Bignell, G. R. et al. Signatures of mutation and selection in the cancer genome. Nature 463, 893–898 (2010)
    Article ADS CAS Google Scholar
  3. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000)
    Article ADS CAS Google Scholar
  4. 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)
    Article ADS Google Scholar
  5. Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006)
    Article CAS Google Scholar
  6. 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)
    Article Google Scholar
  7. Parker, J. S. et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27, 1160–1167 (2009)
    Article Google Scholar
  8. Stranger, B. E. et al. Genome-wide associations of gene expression variation in humans. PLoS Genet. 1, e78 (2005)
    Article Google Scholar
  9. 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)
    Article CAS Google Scholar
  10. 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)
    Article CAS Google Scholar
  11. 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)
    Article CAS Google Scholar
  12. Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997)
    Article CAS Google Scholar
  13. 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)
    Article CAS Google Scholar
  14. Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010)
    Article ADS CAS Google Scholar
  15. McConechy, M. K. et al. Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas. J. Pathol. 223, 567–573 (2011)
    Article CAS Google Scholar
  16. 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)
    Article CAS Google Scholar
  17. 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)
    CAS PubMed Google Scholar
  18. Teng, D. H. et al. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Cancer Res. 57, 4177–4182 (1997)
    CAS PubMed Google Scholar
  19. 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)
    Article Google Scholar
  20. 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)
    Article CAS Google Scholar
  21. 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)
    Article ADS CAS Google Scholar
  22. Kapp, A. V. & Tibshirani, R. Are clusters found in one dataset present in another dataset? Biostatistics 8, 9–31 (2007)
    Article Google Scholar
  23. Hughes-Davies, L. et al. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115, 523–535 (2003)
    Article CAS Google Scholar
  24. Brown, L. A. et al. Amplification of 11q13 in ovarian carcinoma. Genes Chromosom. Cancer 47, 481–489 (2008)
    Article ADS CAS Google Scholar
  25. Russnes, H. G. et al. Genomic architecture characterizes tumor progression paths and fate in breast cancer patients. Sci. Transl. Med. 2, 38ra47 (2010)
    Article Google Scholar
  26. 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)
    Article Google Scholar
  27. Mahmoud, S. M. A. et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 29, 1949–1955 (2011)
    Article Google Scholar
  28. 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)
    Article ADS CAS Google Scholar
  29. Chen, Y. et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008)
    Article ADS CAS Google Scholar

Download references

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

Author notes

  1. Christina Curtis & Doug Speed
    Present address: 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.).,
  2. Christina Curtis, Sohrab P. Shah, Suet-Feung Chin and Gulisa Turashvili: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
    Christina Curtis, Suet-Feung Chin, Oscar M. Rueda, Andy G. Lynch, Shamith Samarajiwa, Yinyin Yuan, Stefan Gräf, Florian Markowetz, Simon Tavaré & Carlos Caldas
  2. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,
    Christina Curtis, Suet-Feung Chin, Oscar M. Rueda, Mark J. Dunning, Doug Speed, Andy G. Lynch, Shamith Samarajiwa, Yinyin Yuan, Stefan Gräf, Roslin Russell, Florian Markowetz, James D. Brenton, Simon Tavaré & Carlos Caldas
  3. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
    Sohrab P. Shah, Gulisa Turashvili, Gavin Ha, Gholamreza Haffari, Ali Bashashati, Steven McKinney, Peter Watson & Samuel Aparicio
  4. Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ,
    Sohrab P. Shah, Gulisa Turashvili, Steven McKinney, Peter Watson & Samuel Aparicio
  5. Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK,
    Doug Speed & Simon Tavaré
  6. Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway,
    Anita Langerød & Anne-Lise Børresen-Dale
  7. Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK,
    Andrew Green & Ian Ellis
  8. Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK ,
    Elena Provenzano, Gordon Wishart & Carlos Caldas
  9. King’s College London, Breakthrough Breast Cancer Research Unit, London WC2R 2LS, UK ,
    Sarah Pinder & Arnie Purushotham
  10. Manitoba Institute of Cell Biology, University of Manitoba, Manitoba R3E 0V9, Canada
    Peter Watson & Leigh Murphy
  11. NIHR Comprehensive Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London WC2R 2LS, UK ,
    Arnie Purushotham
  12. Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway ,
    Anne-Lise Børresen-Dale
  13. Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK ,
    James D. Brenton & Carlos Caldas
  14. Molecular and Computational Biology Program, University of Southern California, Los Angeles, 90089, California, USA
    Simon Tavaré
  15. Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK.,
    Christina Curtis†, James D. Brenton, Carlos Caldas (Principal Investigator), Suet-Feung Chin, Stefan Gräf, Bin Liu, Andy G. Lynch, Irene Papatheodorou, Carlos Caldas (Principal Investigator), Derek Chan, Ana-Teresa Maia, Carlos Caldas (Principal Investigator), Simon Tavaré (Principal Investigator), Stefan Gräf, Andy G. Lynch, Oscar M. Rueda, Shamith Samarajiwa, Florian Markowetz (Principal Investigator) & Yinyin Yuan
  16. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.,
    Christina Curtis†, James D. Brenton, Carlos Caldas (Principal Investigator), Suet-Feung Chin, Zhihao Ding, Stefan Gräf, Bin Liu, Andy G. Lynch, Irene Papatheodorou, Carlos Caldas (Principal Investigator), Claire Fielding, Ana-Teresa Maia, Sarah McGuire, Michelle Osborne, Sara M. Sayalero, Inmaculada Spiteri, James Hadfield, Carlos Caldas (Principal Investigator), Simon Tavaré (Principal Investigator), Mark J. Dunning, Stefan Gräf, Andy G. Lynch, Oscar M. Rueda, Roslin Russell, Shamith Samarajiwa, Doug Speed, Florian Markowetz (Principal Investigator) & Yinyin Yuan
  17. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.,
    Samuel Aparicio, Sohrab P. Shah, Samuel Aparicio, David Huntsman, Samuel Aparicio, Samuel Aparicio (Principal Investigator), David Huntsman, Steven McKinney, Gulisa Turashvili, Peter Watson, Samuel Aparicio (Principal Investigator), Gulisa Turashvili (Team Leader), David Huntsman, Samuel Aparicio (Principal Investigator), Sohrab P. Shah (Team Leader), Ali Bashashati, Gavin Ha, Gholamreza Haffari & Steven McKinney
  18. Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada.,
    Samuel Aparicio, Sohrab P. Shah, Samuel Aparicio, David Huntsman, Samuel Aparicio, Samuel Aparicio (Principal Investigator), Steven Chia, Karen Gelmon, David Huntsman, Steven McKinney, Caroline Speers, Gulisa Turashvili, Peter Watson, Samuel Aparicio (Principal Investigator), Gulisa Turashvili (Team Leader), Lynda Bell, Katie Chow, Nadia Gale, David Huntsman, Maria Kovalik, Ying Ng, Leah Prentice, Samuel Aparicio (Principal Investigator), Sohrab P. Shah (Team Leader) & Steven McKinney
  19. Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG5 1PB, UK.,
    Ian Ellis, Ian Ellis (Principal Investigator), Roger Blamey, Andrew Green, Douglas Macmillan & Emad Rakha
  20. King’s College London, Breakthrough Breast Cancer Research Unit, London, WC2R 2LS, UK.,
    Sarah Pinder, Arnie Purushotham, Arnie Purushotham (Principal Investigator), Cheryl Gillett, Anita Grigoriadis, Sarah Pinder, Emanuele de Rinaldis & Andy Tutt
  21. Manitoba Institute of Cell Biology, University of Manitoba, Manitoba R3E 0V9, Canada.,
    Leigh Murphy, Peter Watson, Leigh Murphy (Principal Investigator), Michelle Parisien & Sandra Troup
  22. Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK.,
    Linda Jones
  23. Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.,
    Stephen J. Sammut & Gordon Wishart
  24. Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Cambridge CB3 0WA, UK.,
    Simon Tavaré (Principal Investigator) & Doug Speed
  25. Molecular and Computational Biology Program, University of Southern California, Los Angeles, 90089, California, USA
    Simon Tavaré (Principal Investigator)

Authors

  1. Christina Curtis
    You can also search for this author inPubMed Google Scholar
  2. Sohrab P. Shah
    You can also search for this author inPubMed Google Scholar
  3. Suet-Feung Chin
    You can also search for this author inPubMed Google Scholar
  4. Gulisa Turashvili
    You can also search for this author inPubMed Google Scholar
  5. Oscar M. Rueda
    You can also search for this author inPubMed Google Scholar
  6. Mark J. Dunning
    You can also search for this author inPubMed Google Scholar
  7. Doug Speed
    You can also search for this author inPubMed Google Scholar
  8. Andy G. Lynch
    You can also search for this author inPubMed Google Scholar
  9. Shamith Samarajiwa
    You can also search for this author inPubMed Google Scholar
  10. Yinyin Yuan
    You can also search for this author inPubMed Google Scholar
  11. Stefan Gräf
    You can also search for this author inPubMed Google Scholar
  12. Gavin Ha
    You can also search for this author inPubMed Google Scholar
  13. Gholamreza Haffari
    You can also search for this author inPubMed Google Scholar
  14. Ali Bashashati
    You can also search for this author inPubMed Google Scholar
  15. Roslin Russell
    You can also search for this author inPubMed Google Scholar
  16. Steven McKinney
    You can also search for this author inPubMed Google Scholar
  17. Anita Langerød
    You can also search for this author inPubMed Google Scholar
  18. Andrew Green
    You can also search for this author inPubMed Google Scholar
  19. Elena Provenzano
    You can also search for this author inPubMed Google Scholar
  20. Gordon Wishart
    You can also search for this author inPubMed Google Scholar
  21. Sarah Pinder
    You can also search for this author inPubMed Google Scholar
  22. Peter Watson
    You can also search for this author inPubMed Google Scholar
  23. Florian Markowetz
    You can also search for this author inPubMed Google Scholar
  24. Leigh Murphy
    You can also search for this author inPubMed Google Scholar
  25. Ian Ellis
    You can also search for this author inPubMed Google Scholar
  26. Arnie Purushotham
    You can also search for this author inPubMed Google Scholar
  27. Anne-Lise Børresen-Dale
    You can also search for this author inPubMed Google Scholar
  28. James D. Brenton
    You can also search for this author inPubMed Google Scholar
  29. Simon Tavaré
    You can also search for this author inPubMed Google Scholar
  30. Carlos Caldas
    You can also search for this author inPubMed Google Scholar
  31. Samuel Aparicio
    You can also search for this author inPubMed Google Scholar

Consortia

METABRIC Group

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

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

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

PowerPoint slides

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

Download citation