Comprehensive molecular portraits of human breast tumours

Journal name:
Nature
Volume:
490,
Pages:
61–70
Date published:
DOI:
doi:10.1038/nature11412
Received
Accepted
Published online
Corrected online

Abstract

We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.

At a glance

Figures

  1. Significantly mutated genes and correlations with genomic and clinical features.
    Figure 1: Significantly mutated genes and correlations with genomic and clinical features.

    Tumour samples are grouped by mRNA subtype: luminal A (n = 225), luminal B (n = 126), HER2E (n = 57) and basal-like (n = 93). The left panel shows non-silent somatic mutation patterns and frequencies for significantly mutated genes. The middle panel shows clinical features: dark grey, positive or T2–4; white, negative or T1; light grey, N/A or equivocal. N, node status; T, tumour size. The right panel shows significantly mutated genes with frequent copy number amplifications (red) or deletions (blue). The far-right panel shows non-silent mutation rate per tumour (mutations per megabase, adjusted for coverage). The average mutation rate for each expression subtype is indicated. Hypermutated: mutation rates >3 s.d. above the mean (>4.688, indicated by grey line).

  2. Coordinated analysis of breast cancer subtypes defined from five different genomic/proteomic platforms.
    Figure 2: Coordinated analysis of breast cancer subtypes defined from five different genomic/proteomic platforms.

    a, Consensus clustering analysis of the subtypes identifies four major groups (samples, n = 348). The blue and white heat map displays sample consensus. b, Heat-map display of the subtypes defined independently by miRNAs, DNA methylation, copy number (CN), PAM50 mRNA expression, and RPPA expression. The red bar indicates membership of a cluster type. c, Associations with molecular and clinical features. P values were calculated using a chi-squared test.

  3. Integrated analysis of the PI(3)K, TP53 and RB1 pathways.
    Figure 3: Integrated analysis of the PI(3)K, TP53 and RB1 pathways.

    Breast cancer subtypes differ by genetic and genomic targeting events, with corresponding effects on pathway activity. ac, For PI(3)K (a), TP53 (b) and RB1 (c) pathways, key genes were selected using prior biological knowledge. Multiple mRNA expression signatures for a given pathway were defined (details in Supplementary Methods; PI(3)K:Saal, PTEN loss in human breast tumours; CMap, PI(3)K/mTOR inhibitor treatment in vitro; Majumder, Akt overexpression in mouse model; TP53: IARC, expert-curated p53 targets; GSK, TP53 mutant versus wild-type cell lines; KANNAN, TP53 overexpression in vitro; TROESTER, TP53 knockdown in vitro; RB: CHICAS, RB1 mouse knockout versus wild type; LARA, RB1 knockdown in vitro; HERSCHKOWITZ, RB1 loss of heterozygosity (LOH) in human breast tumours) and applied to the gene expression data, in order to score each tumour for relative signature activity (yellow, more active). The PI(3)K panel includes a protein-based (RPPA) proteomic signature. Tumours were ordered first by mRNA subtype, although specific ordering differs between the panels. P values were calculated by a Pearson’s correlation or a Chi-squared test.

  4. Mutual exclusivity modules in cancer (MEMo) analysis.
    Figure 4: Mutual exclusivity modules in cancer (MEMo) analysis.

    Mutual exclusivity modules are represented by their gene components and connected to reflect their activity in distinct pathways. For each gene, the frequency of alteration in basal-like (right box) and non-basal (left box) is reported. Next to each module is a fingerprint indicating what specific alteration is observed for each gene (row) in each sample (column). a, MEMo identified several overlapping modules that recapitulate the RTK–PI(3)K and p38–JNK1 signalling pathways and whose core was the top-scoring module. b, MEMo identified alterations to TP53 signalling as occurring within a statistically significant mutually exclusive trend. c, A basal-like only MEMo analysis identified one module that included ATM mutations, defects at BRCA1 and BRCA2, and deregulation of the RB1 pathway. A gene expression heat map is below the fingerprint to show expression levels.

  5. Comparison of breast and serous ovarian carcinomas.
    Figure 5: Comparison of breast and serous ovarian carcinomas.

    a, Significantly enriched genomic alterations identified by comparing basal-like or serous ovarian tumours to luminal cancers. b, Inter-sample correlations (yellow, positive) between gene transcription profiles of breast tumours (columns; TCGA data, arranged by subtype) and profiles of cancers from various tissues of origin (rows; external ‘TGEN expO’ data set, GSE2109) including ovarian cancers.

Change history

Corrected online 03 October 2012
The spelling of an author name (J.B.) was corrected.

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Author information

Affiliations

  1. The Genome Institute, Washington University, St Louis, Missouri 63108, USA.

    • Daniel C. Koboldt,
    • Robert S. Fulton,
    • Michael D. McLellan,
    • Heather Schmidt,
    • Joelle Kalicki-Veizer,
    • Joshua F. McMichael,
    • Lucinda L. Fulton,
    • David J. Dooling,
    • Li Ding,
    • Elaine R. Mardis &
    • Richard K. Wilson
  2. Department of Genetics, Washington University, St Louis, Missouri 63110, USA.

    • Li Ding,
    • Elaine R. Mardis &
    • Richard K. Wilson
  3. Siteman Cancer Center, Washington University, St Louis, Missouri 63110, USA.

    • Elaine R. Mardis,
    • Richard K. Wilson,
    • Matthew J. Ellis &
    • Ron Bose
  4. Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada.

    • Adrian Ally,
    • Miruna Balasundaram,
    • Yaron S. N. Butterfield,
    • Rebecca Carlsen,
    • Candace Carter,
    • Andy Chu,
    • Eric Chuah,
    • Hye-Jung E. Chun,
    • Robin J. N. Coope,
    • Noreen Dhalla,
    • Ranabir Guin,
    • Carrie Hirst,
    • Martin Hirst,
    • Robert A. Holt,
    • Darlene Lee,
    • Haiyan I. Li,
    • Michael Mayo,
    • Richard A. Moore,
    • Andrew J. Mungall,
    • Erin Pleasance,
    • A. Gordon Robertson,
    • Jacqueline E. Schein,
    • Arash Shafiei,
    • Payal Sipahimalani,
    • Jared R. Slobodan,
    • Dominik Stoll,
    • Angela Tam,
    • Nina Thiessen,
    • Richard J. Varhol,
    • Natasja Wye,
    • Thomas Zeng,
    • Yongjun Zhao,
    • Inanc Birol,
    • Steven J. M. Jones &
    • Marco A. Marra
  5. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Andrew D. Cherniack,
    • Gordon Saksena,
    • Robert C. Onofrio,
    • Nam H. Pho,
    • Scott L. Carter,
    • Steven E. Schumacher,
    • Barbara Tabak,
    • Bryan Hernandez,
    • Jeff Gentry,
    • Huy Nguyen,
    • Andrew Crenshaw,
    • Kristin Ardlie,
    • Rameen Beroukhim,
    • Wendy Winckler,
    • Gad Getz,
    • Stacey B. Gabriel &
    • Matthew Meyerson
  6. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

    • Steven E. Schumacher &
    • Barbara Tabak
  7. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.

    • Rameen Beroukhim
  8. Departments of Cancer Biology and Medical Oncology, and the Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

    • Rameen Beroukhim
  9. Department of Medical Oncology and the Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

    • Matthew Meyerson &
    • Lynda Chin
  10. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02215, USA.

    • Matthew Meyerson &
    • Andrew H. Beck
  11. Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

    • Lynda Chin
  12. The Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Peter J. Park &
    • Nils Gehlenborg
  13. Department of Genetics, Harvard Medical School and Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA.

    • Raju Kucherlapati
  14. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    • Katherine A. Hoadley,
    • Xiaping He,
    • Hann-Hsiang Chao,
    • Aleix Prat,
    • Grace O. Silva,
    • Michael D. Iglesia,
    • Wei Zhao,
    • Jonathan S. Berg,
    • Michael Adams &
    • Charles M. Perou
  15. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    • Katherine A. Hoadley,
    • Cheng Fan,
    • Yidi J. Turman,
    • Yan Shi,
    • Ling Li,
    • Michael D. Topal,
    • Xiaping He,
    • Hann-Hsiang Chao,
    • Aleix Prat,
    • Grace O. Silva,
    • Michael D. Iglesia,
    • Wei Zhao,
    • Jerry Usary,
    • Jonathan S. Berg,
    • Junyuan Wu,
    • Anisha Gulabani,
    • Tom Bodenheimer,
    • Alan P. Hoyle,
    • Janae V. Simons,
    • Matthew G. Soloway,
    • Lisle E. Mose,
    • Stuart R. Jefferys,
    • Saianand Balu,
    • Joel S. Parker,
    • D. Neil Hayes,
    • Charles M. Perou,
    • W. Kimryn Rathmell,
    • Leigh Thorne,
    • Mei Huang,
    • Lori Boice &
    • Ashley Hill
  16. Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    • J. Todd Auman
  17. Institute for Pharmacogenetics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    • J. Todd Auman
  18. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    • Michael D. Topal,
    • Jessica Booker &
    • Charles M. Perou
  19. Department of Internal Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    • D. Neil Hayes
  20. USC Epigenome Center, University of Southern California, Los Angeles, California 90033, USA.

    • Simeen Malik,
    • Swapna Mahurkar,
    • Hui Shen,
    • Daniel J. Weisenberger,
    • Timothy Triche Jr,
    • Phillip H. Lai,
    • Moiz S. Bootwalla,
    • Dennis T. Maglinte,
    • Benjamin P. Berman,
    • David J. Van Den Berg &
    • Peter W. Laird
  21. Cancer Biology Division, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland 21231, USA.

    • Stephen B. Baylin
  22. Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.

    • Chad J. Creighton &
    • Lawrence A. Donehower
  23. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.

    • Chad J. Creighton &
    • Lawrence A. Donehower
  24. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

    • Lawrence A. Donehower
  25. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA.

    • Lawrence A. Donehower
  26. The Eli and Edythe L. Broad Institute of Massachusetts Institute Of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.

    • Gad Getz,
    • Michael Noble,
    • Doug Voet,
    • Gordon Saksena,
    • Nils Gehlenborg,
    • Daniel DiCara,
    • Hailei Zhang,
    • Spring Yingchun Liu,
    • Michael S. Lawrence,
    • Lihua Zou,
    • Andrey Sivachenko,
    • Pei Lin,
    • Petar Stojanov,
    • Rui Jing,
    • Juok Cho,
    • Raktim Sinha,
    • Richard W. Park,
    • Marc-Danie Nazaire,
    • Jim Robinson,
    • Helga Thorvaldsdottir,
    • Jill Mesirov &
    • Lynda Chin
  27. Institute for Applied Cancer Science, Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.

    • Juinhua Zhang &
    • Lynda Chin
  28. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.

    • Chang-Jiun Wu
  29. Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA.

    • Peter J. Park
  30. Informatics Program, Children’s Hospital, Boston, Massachusetts 02115, USA.

    • Peter J. Park
  31. Institute for Systems Biology, Seattle, Washington 98109, USA.

    • Sheila Reynolds,
    • Richard B. Kreisberg,
    • Brady Bernard,
    • Ryan Bressler,
    • Jake Lin,
    • Vesteinn Thorsson &
    • Ilya Shmulevich
  32. Tampere University of Technology, Tampere, Finland.

    • Timo Erkkila
  33. Cancer Genomics Core Laboratory, MD Anderson Cancer Center, Houston, Texas 77030, USA.

    • Wei Zhang
  34. Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

    • Giovanni Ciriello,
    • Nils Weinhold,
    • Nikolaus Schultz,
    • Jianjiong Gao,
    • Ethan Cerami,
    • Benjamin Gross,
    • Anders Jacobsen,
    • Rileen Sinha,
    • B. Arman Aksoy,
    • Yevgeniy Antipin,
    • Boris Reva,
    • Barry S. Taylor &
    • Chris Sander
  35. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

    • Ronglai Shen
  36. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

    • Marc Ladanyi
  37. Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA.

    • Pavana Anur &
    • Paul T. Spellman
  38. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

    • Yiling Lu,
    • Gordon B. Mills &
    • Ana Maria Gonzalez-Angulo
  39. Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

    • Yiling Lu &
    • Gordon B. Mills
  40. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

    • Wenbin Liu,
    • Roel R. G. Verhaak,
    • Rehan Akbani,
    • Nianxiang Zhang,
    • Bradley M. Broom,
    • Tod D. Casasent,
    • Chris Wakefield,
    • Anna K. Unruh,
    • Keith Baggerly,
    • Kevin Coombes &
    • John N. Weinstein
  41. Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA.

    • David Haussler,
    • Joshua M. Stuart,
    • Stephen C. Benz,
    • Jingchun Zhu,
    • Christopher C. Szeto,
    • Evan O. Paull,
    • Daniel Carlin,
    • Christopher Wong,
    • Artem Sokolov,
    • Sam Ng,
    • Theodore C. Goldstein,
    • Kyle Ellrott,
    • Mia Grifford,
    • Christopher Wilks,
    • Singer Ma &
    • Brian Craft
  42. Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, California 95064, USA.

    • David Haussler
  43. Buck Institute for Research on Aging, Novato, California 94945, USA.

    • Christopher C. Benz,
    • Gary K. Scott,
    • Christina Yau,
    • Janita Thusberg &
    • Sean Mooney
  44. Center for Bioinformatics and Information Technology, National Cancer Institute, Rockville, Maryland 20852, USA.

    • Chunhua Yan,
    • Ying Hu,
    • Daoud Meerzaman &
    • Kenneth Buetow
  45. The Ohio State University College of Medicine, Department of Pathology, Columbus, Ohio 43205, USA.

    • Julie M. Gastier-Foster,
    • Nilsa C. Ramirez &
    • Robert E. Pyatt
  46. The Ohio State University College of Medicine, Department Pediatrics, Columbus, Ohio 43205, USA.

    • Julie M. Gastier-Foster &
    • Peter White
  47. The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio 43205, USA.

    • Julie M. Gastier-Foster,
    • Jay Bowen,
    • Nilsa C. Ramirez,
    • Aaron D. Black,
    • Robert E. Pyatt,
    • Peter White,
    • Erik J. Zmuda,
    • Jessica Frick,
    • Tara M. Lichtenberg,
    • Robin Brookens,
    • Myra M. George,
    • Mark A. Gerken,
    • Hollie A. Harper,
    • Kristen M. Leraas,
    • Lisa J. Wise,
    • Teresa R. Tabler,
    • Cynthia McAllister,
    • Thomas Barr &
    • Melissa Hart-Kothari
  48. ABS Inc. Indianapolis, Indiana 46204, USA.

    • Katie Tarvin
  49. ABS Inc. Wilmington, Delaware 19801, USA.

    • Charles Saller
  50. Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.

    • George Sandusky &
    • Colleen Mitchell
  51. Helen F. Graham Cancer Center, Christiana Care, Newark, Delaware 19713, USA.

    • Mary V. Iacocca,
    • Jennifer Brown,
    • Brenda Rabeno,
    • Christine Czerwinski &
    • Nicholas Petrelli
  52. Moscow City Clinical Oncology Dispensary 1 and the Central IHC Laboratory of the Moscow Health Department, Moscow 105005, Russia.

    • Oleg Dolzhansky
  53. Russian Cancer Research Center, Moscow 115478, Russia.

    • Mikhail Abramov
  54. Cureline, Inc., South San Francisco, California 94080, USA.

    • Olga Voronina &
    • Olga Potapova
  55. Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.

    • Jeffrey R. Marks
  56. The Greater Poland Cancer Centre, Poznań 61-866, Poland.

    • Wiktoria M. Suchorska,
    • Dawid Murawa,
    • Witold Kycler,
    • Matthew Ibbs,
    • Konstanty Korski,
    • Arkadiusz Spychała,
    • Paweł Murawa,
    • Jacek J. Brzeziński,
    • Hanna Perz,
    • Radosław Łaźniak,
    • Marek Teresiak,
    • Honorata Tatka,
    • Ewa Leporowska,
    • Marta Bogusz-Czerniewicz,
    • Julian Malicki,
    • Andrzej Mackiewicz &
    • Maciej Wiznerowicz
  57. Poznan University of Medical Sciences, Poznań 61-701, Poland.

    • Marta Bogusz-Czerniewicz,
    • Julian Malicki,
    • Andrzej Mackiewicz &
    • Maciej Wiznerowicz
  58. ILSBio, LLC, Chestertown, Maryland 21620, USA.

    • Xuan Van Le &
    • Bernard Kohl
  59. Ministry of Health, Hanoi, Vietnam.

    • Nguyen Viet Tien
  60. ILSBio LLC, Karachi, Pakistan.

    • Richard Thorp &
    • Khurram Zaki Khan
  61. Hue Central Hospital, Hue City, Vietnam.

    • Nguyen Van Bang &
    • Bui Duc Phu
  62. Stanford University Medical Center, Stanford, California 94305, USA.

    • Howard Sussman
  63. Center for Minority Health Research, University of Texas, MD Anderson Cancer Center, Houston, Texas 07703, USA.

    • Richard Hajek
  64. National Cancer Institute, Hanoi, Vietnam.

    • Nguyen Phi Hung
  65. Ho Chi Minh City Cancer Center, Vietnam.

    • Tran Viet The Phuong
  66. Can Tho Cancer Center, Can Tho, Vietnam.

    • Huynh Quyet Thang
  67. International Genomics Consortium, Phoenix, Arizona 85004, USA.

    • Robert Penny,
    • David Mallery,
    • Erin Curley,
    • Candace Shelton &
    • Peggy Yena
  68. Mayo Clinic, Rochester, Minnesota 55905, USA.

    • James N. Ingle,
    • Fergus J. Couch &
    • Wilma L. Lingle
  69. Department of Surgery, Breast Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

    • Tari A. King
  70. Department of Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.

    • Ana Maria Gonzalez-Angulo,
    • Gordon B. Mills,
    • Mary D. Dyer,
    • Shuying Liu,
    • Xiaolong Meng &
    • Modesto Patangan
  71. University of California at San Francisco; San Francisco, California 94143, USA.

    • Frederic Waldman
  72. Cancer Diagnostics; Nichols Institute, Quest Diagnostics; San Juan Capistrano, California 92675, USA.

    • Frederic Waldman
  73. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94115, USA.

    • Hubert Stöppler
  74. UNC Tissue Procurement Facility, Department of Pathology, UNC Lineberger Cancer Center, Chapel Hill, North Carolina 27599, USA.

    • Leigh Thorne,
    • Mei Huang &
    • Lori Boice
  75. Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

    • Carl Morrison,
    • Carmelo Gaudioso &
    • Wiam Bshara
  76. Department of Pathology, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.

    • Kelly Daily,
    • Sophie C. Egea,
    • Mark D. Pegram &
    • Carmen Gomez-Fernandez
  77. University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.

    • Rajiv Dhir
  78. Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.

    • Rohit Bhargava &
    • Adam Brufsky
  79. Walter Reed National Military Medical Center, Bethesda, Maryland 20899-5600, USA.

    • Craig D. Shriver,
    • Jeffrey A. Hooke &
    • Jamie Leigh Campbell
  80. Windber Research Institute, Windber, Pennsylvania 15963, USA.

    • Richard J. Mural,
    • Hai Hu,
    • Stella Somiari,
    • Caroline Larson,
    • Brenda Deyarmin,
    • Leonid Kvecher,
    • Chunqing Luo &
    • Yaqin Chen
  81. MDR Global, LLC, Windber, Pennsylvania 15963, USA.

    • Albert J. Kovatich
  82. Breast Cancer Program, Washington University, St Louis, Missouri 63110, USA.

    • Matthew J. Ellis &
    • Ron Bose
  83. Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.

    • Matthew J. Ellis &
    • Ron Bose
  84. Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois 60637, USA.

    • Thomas Stricker &
    • Kevin White
  85. Center for Clinical Cancer Genetics, The University of Chicago, Chicago, Illinois 60637, USA.

    • Olufunmilayo Olopade
  86. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.

    • Li-Wei Chang
  87. SRA International, 4300 Fair Lakes Court, Fairfax, Virginia 22033, USA.

    • Todd Pihl,
    • Mark Jensen,
    • Robert Sfeir,
    • Ari Kahn,
    • Anna Chu,
    • Prachi Kothiyal,
    • Zhining Wang,
    • Eric Snyder,
    • Joan Pontius,
    • Brenda Ayala,
    • Mark Backus,
    • Jessica Walton,
    • Julien Baboud,
    • Dominique Berton,
    • Matthew Nicholls,
    • Deepak Srinivasan,
    • Rohini Raman,
    • Stanley Girshik,
    • Peter Kigonya,
    • Shelley Alonso,
    • Rashmi Sanbhadti,
    • Sean Barletta &
    • David Pot
  88. The Cancer Genome Atlas Program Office, Center for Cancer Genomics, National Cancer Institute, Bethesda, Maryland 20852, USA.

    • Margi Sheth,
    • John A. Demchok,
    • Kenna R. Mills Shaw,
    • Liming Yang,
    • Roy W. Tarnuzzer,
    • Jiashan Zhang,
    • Laura A. L. Dillon &
    • Peter Fielding
  89. TCGA Consultant, Scimentis, LLC, Statham, Georgia 30666, USA.

    • Greg Eley
  90. MLF Consulting, Arlington, Massachusetts 02474, USA.

    • Martin L. Ferguson
  91. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Bradley A. Ozenberger,
    • Mark S. Guyer,
    • Heidi J. Sofia &
    • Jacqueline D. Palchik

Consortia

  1. The Cancer Genome Atlas Network

  2. Genome sequencing centres: Washington University in St Louis

    • Daniel C. Koboldt,
    • Robert S. Fulton,
    • Michael D. McLellan,
    • Heather Schmidt,
    • Joelle Kalicki-Veizer,
    • Joshua F. McMichael,
    • Lucinda L. Fulton,
    • David J. Dooling,
    • Li Ding,
    • Elaine R. Mardis &
    • Richard K. Wilson
  3. Genome characterization centres: BC Cancer Agency

    • Adrian Ally,
    • Miruna Balasundaram,
    • Yaron S. N. Butterfield,
    • Rebecca Carlsen,
    • Candace Carter,
    • Andy Chu,
    • Eric Chuah,
    • Hye-Jung E. Chun,
    • Robin J. N. Coope,
    • Noreen Dhalla,
    • Ranabir Guin,
    • Carrie Hirst,
    • Martin Hirst,
    • Robert A. Holt,
    • Darlene Lee,
    • Haiyan I. Li,
    • Michael Mayo,
    • Richard A. Moore,
    • Andrew J. Mungall,
    • Erin Pleasance,
    • A. Gordon Robertson,
    • Jacqueline E. Schein,
    • Arash Shafiei,
    • Payal Sipahimalani,
    • Jared R. Slobodan,
    • Dominik Stoll,
    • Angela Tam,
    • Nina Thiessen,
    • Richard J. Varhol,
    • Natasja Wye,
    • Thomas Zeng,
    • Yongjun Zhao,
    • Inanc Birol,
    • Steven J. M. Jones &
    • Marco A. Marra
  4. Broad Institute

    • Andrew D. Cherniack,
    • Gordon Saksena,
    • Robert C. Onofrio,
    • Nam H. Pho,
    • Scott L. Carter,
    • Steven E. Schumacher,
    • Barbara Tabak,
    • Bryan Hernandez,
    • Jeff Gentry,
    • Huy Nguyen,
    • Andrew Crenshaw,
    • Kristin Ardlie,
    • Rameen Beroukhim,
    • Wendy Winckler,
    • Gad Getz,
    • Stacey B. Gabriel &
    • Matthew Meyerson
  5. Brigham & Women’s Hospital & Harvard Medical School

    • Lynda Chin,
    • Peter J. Park &
    • Raju Kucherlapati
  6. University of North Carolina, Chapel Hill

    • Katherine A. Hoadley,
    • J. Todd Auman,
    • Cheng Fan,
    • Yidi J. Turman,
    • Yan Shi,
    • Ling Li,
    • Michael D. Topal,
    • Xiaping He,
    • Hann-Hsiang Chao,
    • Aleix Prat,
    • Grace O. Silva,
    • Michael D. Iglesia,
    • Wei Zhao,
    • Jerry Usary,
    • Jonathan S. Berg,
    • Michael Adams,
    • Jessica Booker,
    • Junyuan Wu,
    • Anisha Gulabani,
    • Tom Bodenheimer,
    • Alan P. Hoyle,
    • Janae V. Simons,
    • Matthew G. Soloway,
    • Lisle E. Mose,
    • Stuart R. Jefferys,
    • Saianand Balu,
    • Joel S. Parker,
    • D. Neil Hayes &
    • Charles M. Perou
  7. University of Southern California/Johns Hopkins

    • Simeen Malik,
    • Swapna Mahurkar,
    • Hui Shen,
    • Daniel J. Weisenberger,
    • Timothy Triche Jr,
    • Phillip H. Lai,
    • Moiz S. Bootwalla,
    • Dennis T. Maglinte,
    • Benjamin P. Berman,
    • David J. Van Den Berg,
    • Stephen B. Baylin &
    • Peter W. Laird
  8. Genome data analysis: Baylor College of Medicine

    • Chad J. Creighton &
    • Lawrence A. Donehower
  9. Broad Institute

    • Gad Getz,
    • Michael Noble,
    • Doug Voet,
    • Gordon Saksena,
    • Nils Gehlenborg,
    • Daniel DiCara,
    • Juinhua Zhang,
    • Hailei Zhang,
    • Chang-Jiun Wu,
    • Spring Yingchun Liu,
    • Michael S. Lawrence,
    • Lihua Zou,
    • Andrey Sivachenko,
    • Pei Lin,
    • Petar Stojanov,
    • Rui Jing,
    • Juok Cho,
    • Raktim Sinha,
    • Richard W. Park,
    • Marc-Danie Nazaire,
    • Jim Robinson,
    • Helga Thorvaldsdottir,
    • Jill Mesirov,
    • Peter J. Park &
    • Lynda Chin
  10. Institute for Systems Biology

    • Sheila Reynolds,
    • Richard B. Kreisberg,
    • Brady Bernard,
    • Ryan Bressler,
    • Timo Erkkila,
    • Jake Lin,
    • Vesteinn Thorsson,
    • Wei Zhang &
    • Ilya Shmulevich
  11. Memorial Sloan-Kettering Cancer Center

    • Giovanni Ciriello,
    • Nils Weinhold,
    • Nikolaus Schultz,
    • Jianjiong Gao,
    • Ethan Cerami,
    • Benjamin Gross,
    • Anders Jacobsen,
    • Rileen Sinha,
    • B. Arman Aksoy,
    • Yevgeniy Antipin,
    • Boris Reva,
    • Ronglai Shen,
    • Barry S. Taylor,
    • Marc Ladanyi &
    • Chris Sander
  12. Oregon Health & Science University

    • Pavana Anur &
    • Paul T. Spellman
  13. The University of Texas MD Anderson Cancer Center

    • Yiling Lu,
    • Wenbin Liu,
    • Roel R. G. Verhaak,
    • Gordon B. Mills,
    • Rehan Akbani,
    • Nianxiang Zhang,
    • Bradley M. Broom,
    • Tod D. Casasent,
    • Chris Wakefield,
    • Anna K. Unruh,
    • Keith Baggerly,
    • Kevin Coombes &
    • John N. Weinstein
  14. University of California, Santa Cruz/Buck Institute

    • David Haussler,
    • Christopher C. Benz,
    • Joshua M. Stuart,
    • Stephen C. Benz,
    • Jingchun Zhu,
    • Christopher C. Szeto,
    • Gary K. Scott,
    • Christina Yau,
    • Evan O. Paull,
    • Daniel Carlin,
    • Christopher Wong,
    • Artem Sokolov,
    • Janita Thusberg,
    • Sean Mooney,
    • Sam Ng,
    • Theodore C. Goldstein,
    • Kyle Ellrott,
    • Mia Grifford,
    • Christopher Wilks,
    • Singer Ma &
    • Brian Craft
  15. NCI

    • Chunhua Yan,
    • Ying Hu &
    • Daoud Meerzaman
  16. Biospecimen core resource: Nationwide Children’s Hospital Biospecimen Core Resource

    • Julie M. Gastier-Foster,
    • Jay Bowen,
    • Nilsa C. Ramirez,
    • Aaron D. Black,
    • Robert E. Pyatt,
    • Peter White,
    • Erik J. Zmuda,
    • Jessica Frick,
    • Tara M. Lichtenberg,
    • Robin Brookens,
    • Myra M. George,
    • Mark A. Gerken,
    • Hollie A. Harper,
    • Kristen M. Leraas,
    • Lisa J. Wise,
    • Teresa R. Tabler,
    • Cynthia McAllister,
    • Thomas Barr &
    • Melissa Hart-Kothari
  17. Tissue source sites: ABS-IUPUI

    • Katie Tarvin,
    • Charles Saller,
    • George Sandusky &
    • Colleen Mitchell
  18. Christiana

    • Mary V. Iacocca,
    • Jennifer Brown,
    • Brenda Rabeno,
    • Christine Czerwinski &
    • Nicholas Petrelli
  19. Cureline

    • Oleg Dolzhansky,
    • Mikhail Abramov,
    • Olga Voronina &
    • Olga Potapova
  20. Duke University Medical Center

    • Jeffrey R. Marks
  21. The Greater Poland Cancer Centre

    • Wiktoria M. Suchorska,
    • Dawid Murawa,
    • Witold Kycler,
    • Matthew Ibbs,
    • Konstanty Korski,
    • Arkadiusz Spychała,
    • Paweł Murawa,
    • Jacek J. Brzeziński,
    • Hanna Perz,
    • Radosław Łaźniak,
    • Marek Teresiak,
    • Honorata Tatka,
    • Ewa Leporowska,
    • Marta Bogusz-Czerniewicz,
    • Julian Malicki,
    • Andrzej Mackiewicz &
    • Maciej Wiznerowicz
  22. ILSBio

    • Xuan Van Le,
    • Bernard Kohl,
    • Nguyen Viet Tien,
    • Richard Thorp,
    • Nguyen Van Bang,
    • Howard Sussman,
    • Bui Duc Phu,
    • Richard Hajek,
    • Nguyen Phi Hung,
    • Tran Viet The Phuong,
    • Huynh Quyet Thang &
    • Khurram Zaki Khan
  23. International Genomics Consortium

    • Robert Penny,
    • David Mallery,
    • Erin Curley,
    • Candace Shelton &
    • Peggy Yena
  24. Mayo Clinic

    • James N. Ingle,
    • Fergus J. Couch &
    • Wilma L. Lingle
  25. MSKCC

    • Tari A. King
  26. MD Anderson Cancer Center

    • Ana Maria Gonzalez-Angulo,
    • Gordon B. Mills,
    • Mary D. Dyer,
    • Shuying Liu,
    • Xiaolong Meng &
    • Modesto Patangan
  27. University of California San Francisco

    • Frederic Waldman &
    • Hubert Stöppler
  28. University of North Carolina

    • W. Kimryn Rathmell,
    • Leigh Thorne,
    • Mei Huang,
    • Lori Boice &
    • Ashley Hill
  29. Roswell Park Cancer Institute

    • Carl Morrison,
    • Carmelo Gaudioso &
    • Wiam Bshara
  30. University of Miami

    • Kelly Daily,
    • Sophie C. Egea,
    • Mark D. Pegram &
    • Carmen Gomez-Fernandez
  31. University of Pittsburgh

    • Rajiv Dhir,
    • Rohit Bhargava &
    • Adam Brufsky
  32. Walter Reed National Military Medical Center

    • Craig D. Shriver,
    • Jeffrey A. Hooke,
    • Jamie Leigh Campbell,
    • Richard J. Mural,
    • Hai Hu,
    • Stella Somiari,
    • Caroline Larson,
    • Brenda Deyarmin,
    • Leonid Kvecher &
    • Albert J. Kovatich
  33. Disease working group

    • Matthew J. Ellis,
    • Tari A. King,
    • Hai Hu,
    • Fergus J. Couch,
    • Richard J. Mural,
    • Thomas Stricker,
    • Kevin White,
    • Olufunmilayo Olopade,
    • James N. Ingle,
    • Chunqing Luo,
    • Yaqin Chen,
    • Jeffrey R. Marks,
    • Frederic Waldman,
    • Maciej Wiznerowicz,
    • Ron Bose,
    • Li-Wei Chang,
    • Andrew H. Beck &
    • Ana Maria Gonzalez-Angulo
  34. Data coordination centre

    • Todd Pihl,
    • Mark Jensen,
    • Robert Sfeir,
    • Ari Kahn,
    • Anna Chu,
    • Prachi Kothiyal,
    • Zhining Wang,
    • Eric Snyder,
    • Joan Pontius,
    • Brenda Ayala,
    • Mark Backus,
    • Jessica Walton,
    • Julien Baboud,
    • Dominique Berton,
    • Matthew Nicholls,
    • Deepak Srinivasan,
    • Rohini Raman,
    • Stanley Girshik,
    • Peter Kigonya,
    • Shelley Alonso,
    • Rashmi Sanbhadti,
    • Sean Barletta &
    • David Pot
  35. Project team: National Cancer Institute

    • Margi Sheth,
    • John A. Demchok,
    • Kenna R. Mills Shaw,
    • Liming Yang,
    • Greg Eley,
    • Martin L. Ferguson,
    • Roy W. Tarnuzzer,
    • Jiashan Zhang,
    • Laura A. L. Dillon,
    • Kenneth Buetow &
    • Peter Fielding
  36. National Human Genome Research Institute

    • Bradley A. Ozenberger,
    • Mark S. Guyer,
    • Heidi J. Sofia &
    • Jacqueline D. Palchik

Contributions

TCGA research network contributed collectively to this study. Biospecimens were provided by tissue source sites and processed by a Biospecimens Core Resource. Data generation and analyses were performed by genome sequencing centres, cancer genome characterization centres, and genome data analysis centres. RPPA analysis was performed at the MD Anderson Cancer Center in association with the genome data analysis centre. All data were released through the Data Coordinating Center. Project activities were coordinated by NCI and NHGRI project teams. We also acknowledge the following TCGA investigators of the Breast Analysis Working Group who contributed substantially to the analysis and writing of this manuscript: Project leaders, C.M.P., M.J.E.; manuscript coordinator, C.M.P., K.A.H.; data coordinator, K.A.H.; analysis coordinator, C.M.P., K.A.H.; DNA sequence analysis, D.C.K., L.D.; mRNA microarray analysis; K.A.H., C.F.; miRNA sequence analysis, A.G.R., A.C.; DNA methylation analysis, S. Malik, S. Mahurkar, P.W.L.; copy number analysis; A.D.C., M.M.; protein analysis, W.L., R.G.W.V., G.B.M.; pathway/integrated analysis, C.J.C., C.Y., J.M.S., C.C.B., G.C., C.S., S.R., I.S.; biospecimen core resource, T.L., J.B., J.M.G.; pathology and clinical expertise, T.A.K., H.H., R.J.M., J.N.I., T.S., F.W.

Competing financial interests

Charles M. Perou and Matthew J. Ellis are inventors on patent filing for PAM50 and have equity interest in Bioclassifier LLC. Joel S. Parker is an inventor on patent filing for PAM50.

All of the primary sequence files are deposited in CGHub (https://cghub.ucsc.edu/); all other data including mutation annotation file are deposited at the Data Coordinating Center (http://cancergenome.nih.gov/). Sample lists, data matrices and supporting data can be found at http://tcga-data.nci.nih.gov/docs/publications/brca_2012/. The data can be explored via the ISB Regulome Explorer (http://explorer.cancerregulome.org/) and the cBio Cancer Genomics Portal (http://cbioportal.org). Data descriptions can be found at https://wiki.nci.nih.gov/display/TCGA/TCGA+Data+Primer and in Supplementary Methods.

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    Supplementary information

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    1. Supplementary Information (14.1M)

      This file contains Supplementary Figures 1-20, Supplementary Methods 1-15 (with additional figures and tables) and Supplementary References.

    Zip files

    1. Supplementary Tables (1M)

      This zipped file contains Supplementary Tables 1-8. This file was replaced on 15 November 2012 to correct an error in Supplementary Table 5.

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