Comprehensive molecular profiling of lung adenocarcinoma

Journal name:
Nature
Volume:
511,
Pages:
543–550
Date published:
DOI:
doi:10.1038/nature13385
Received
Accepted
Published online

Abstract

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

At a glance

Figures

  1. Somatic mutations in lung adenocarcinoma.
    Figure 1: Somatic mutations in lung adenocarcinoma.

    a, Co-mutation plot from whole exome sequencing of 230 lung adenocarcinomas. Data from TCGA samples were combined with previously published data12 for statistical analysis. Co-mutation plot for all samples used in the statistical analysis (n = 412) can be found in Supplementary Fig. 2. Significant genes with a corrected P value less than 0.025 were identified using the MutSig2CV algorithm and are ranked in order of decreasing prevalence. b, c, The differential patterns of mutation between samples classified as transversion high and transversion low samples (b) or male and female patients (c) are shown for all samples used in the statistical analysis (n = 412). Stars indicate statistical significance using the Fisher’s exact test (black stars: q < 0.05, grey stars: P < 0.05) and are adjacent to the sample set with the higher percentage of mutated samples.

  2. Aberrant RNA transcripts in lung adenocarcinoma associated with somatic DNA translocation or mutation.
    Figure 2: Aberrant RNA transcripts in lung adenocarcinoma associated with somatic DNA translocation or mutation.

    a, Normalized exon level RNA expression across fusion gene partners. Grey boxes around genes mark the regions that are removed as a consequence of the fusion. Junction points of the fusion events are also listed in Supplementary Table 9. Exon numbers refer to reference transcripts listed in Supplementary Table 9. b, MET exon 14 skipping observed in the presence of exon 14 splice site mutation (ss mut), splice site deletion (ss del) or a Y1003* mutation. A total of 22 samples had insufficient coverage around exon 14 for quantification. The percentage skipping is (total expression minus exon 14 expression)/total expression. c, Significant differences in the frequency of 129 alternative splicing events in mRNA from tumours with U2AF1 S34F tumours compared to U2AF1 WT tumours (q value <0.05). Consistent with the function of U2AF1 in 3′ splice site recognition, most splicing differences involved cassette exon and alternative 3′ splice site events (chi-squared test, P < 0.001).

  3. Identification of novel candidate driver genes.
    Figure 3: Identification of novel candidate driver genes.

    a, GISTIC analysis of focal amplifications in oncogene-negative (n = 87) and oncogene-positive (n = 143) TCGA samples identifies focal gains of MET and ERBB2 that are specific to the oncogene-negative set (purple). b, TP53, KEAP1, NF1 and RIT1 mutations are significantly enriched in samples otherwise lacking oncogene mutations (adjusted P < 0.05 by Fisher’s exact test). c, Co-mutation plot of variants of known significance within the RTK/RAS/RAF pathway in lung adenocarcinoma. Not shown are the 63 tumours lacking an identifiable driver lesion. Only canonical driver events, as defined in Supplementary Fig. 9, and proposed driver events, are shown; hence not every alteration found is displayed. d, New candidate driver oncogenes (blue: 13% of cases) and known somatically activated drivers events (red: 63%) that activate the RTK/RAS/RAF pathway can be found in the majority of the 230 lung adenocarcinomas.

  4. Pathway alterations in lung adenocarcinoma.
    Figure 4: Pathway alterations in lung adenocarcinoma.

    a, Somatic alterations involving key pathway components for RTK signalling, mTOR signalling, oxidative stress response, proliferation and cell cycle progression, nucleosome remodelling, histone methylation, and RNA splicing/processing. b, c, Proteomic analysis by RPPA (n = 181) P values by two-sided t-test. Box plots represent 5%, 25%, 75%, median, and 95%. PP, proximal proliferative; TRU, terminal respiratory unit; PI, proximal inflammatory. c, mTOR signalling may be activated, by either Akt (for example, via PI(3)K) or inactivation of AMPK (for example, via STK11 loss). Tumours were separated into three main groups: those with PI(3)K-AKT activation, through either PIK3CA activating mutation or unknown mechanism (high p-AKT); those with LKB1-AMPK inactivation, through either STK11 mutation or unknown mechanism with low levels of LKB1 and p-AMPK; and those showing none of the above features.

  5. Integrative analysis.
    Figure 5: Integrative analysis.

    ac, Integrating unsupervised analyses of 230 lung adenocarcinomas reveals significant interactions between molecular subtypes. Tumours are displayed as columns, grouped by mRNA expression subtypes (a), DNA methylation subtypes (b), and integrated subtypes by iCluster analysis (c). All displayed features are significantly associated with subtypes depicted. The CIMP phenotype is defined by the most variable CpG island and promoter probes.

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Author information

Affiliations

  1. University of California San Francisco, San Francisco, California 94158, USA.

    • Eric A. Collisson &
    • Barry S. Taylor
  2. The Eli and Edythe L. Broad Institute, Cambridge, Massachusetts 02142, USA.

    • Joshua D. Campbell,
    • Angela N. Brooks,
    • Alice H. Berger,
    • Juliann Chmielecki,
    • Gad Getz,
    • Peter S. Hammerman,
    • Bryan Hernandez,
    • Carrie Sougnez,
    • Andrew D. Cherniack,
    • Mara Rosenberg,
    • Matthew Meyerson,
    • Stacey B. Gabriel,
    • Kristian Cibulskis,
    • Jaegil Kim,
    • Chip Stewart,
    • Lee Lichtenstein,
    • Eric S. Lander,
    • Michael S. Lawrence,
    • Marcin Imielinski,
    • Robert C. Onofrio,
    • Travis Zack,
    • Elena Helman,
    • Chandra Sekhar Pedamallu,
    • Jill Mesirov,
    • Gordon Saksena,
    • Steven E. Schumacher,
    • Scott L. Carter,
    • Levi Garraway,
    • Rameen Beroukhim,
    • Juok Cho,
    • Daniel DiCara,
    • David Heiman,
    • Pei Lin,
    • William Mallard,
    • Douglas Voet,
    • Hailei Zhang,
    • Lihua Zou,
    • Michael S. Noble,
    • Nils Gehlenborg,
    • Helga Thorvaldsdottir,
    • Marc-Danie Nazaire &
    • Jim Robinson
  3. Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.

    • Angela N. Brooks,
    • Matthew Meyerson,
    • Levi Garraway &
    • Rameen Beroukhim
  4. Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

    • William Lee,
    • Marc Ladanyi,
    • Nikolaus Schultz,
    • Ronglai Shen,
    • William D. Travis,
    • B. Arman Aksoy,
    • Giovanni Ciriello,
    • Gideon Dresdner,
    • Jianjiong Gao,
    • Benjamin Gross,
    • Venkatraman E. Seshan,
    • Boris Reva,
    • Rileen Sinha,
    • S. Onur Sumer,
    • Nils Weinhold,
    • Chris Sander,
    • Natasha Rekhtman,
    • Maureen Zakowski &
    • Valerie W. Rusch
  5. University of Michigan, Ann Arbor, Michigan 48109, USA.

    • David G. Beer
  6. Johns Hopkins University, Baltimore, Maryland 21287, USA.

    • Leslie Cope,
    • Ludmila Danilova,
    • James G. Herman,
    • Stephen B. Baylin,
    • Peter Illei,
    • Edward Gabrielson,
    • James Shin,
    • Beverly Lee,
    • Kristen Rodgers,
    • Dante Trusty &
    • Malcolm V. Brock
  7. Baylor College of Medicine, Houston, Texas 77030, USA.

    • Chad J. Creighton &
    • David Wheeler
  8. Washington University, St. Louis, Missouri 63108, USA.

    • Li Ding,
    • Ramaswamy Govindan,
    • Cyriac Kandoth,
    • Robert Fulton,
    • Lucinda L. Fulton,
    • Michael D. McLellan,
    • Richard K. Wilson,
    • Kai Ye,
    • Catrina C. Fronick,
    • Christopher A. Maher,
    • Christopher A. Miller,
    • Michael C. Wendl,
    • Christopher Cabanski,
    • Elaine Mardis,
    • Mark A. Watson,
    • Sandra McDonald &
    • Bryan Meyers
  9. Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Gad Getz,
    • Raju Kucherlapati,
    • Angela Hadjipanayis,
    • Marcin Imielinski,
    • Eran Hodis,
    • Levi Garraway,
    • Rameen Beroukhim,
    • Matthew Meyerson,
    • Semin Lee,
    • Angeliki Pantazi,
    • Xiaojia Ren,
    • Lixing Yang,
    • Peng-Chieh Chen,
    • Michael Parfenov,
    • Andrew Wei Xu,
    • Netty Santoso &
    • Peter J. Park
  10. Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Gad Getz &
    • Marcin Imielinski
  11. University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    • D. Neil Hayes,
    • Matthew D. Wilkerson,
    • Katherine A. Hoadley,
    • J. Todd Auman,
    • Shaowu Meng,
    • Yan Shi,
    • Elizabeth Buda,
    • Scot Waring,
    • Umadevi Veluvolu,
    • Donghui Tan,
    • Piotr A. Mieczkowski,
    • Corbin D. Jones,
    • Janae V. Simons,
    • Matthew G. Soloway,
    • Tom Bodenheimer,
    • Stuart R. Jefferys,
    • Jeffrey Roach,
    • Alan P. Hoyle,
    • Junyuan Wu,
    • Saianand Balu,
    • Darshan Singh,
    • Jan F. Prins,
    • J.S. Marron,
    • Joel S. Parker,
    • Charles M. Perou,
    • Patrick K. Kimes,
    • Mei Huang,
    • Leigh B. Thorne,
    • Lori Boice,
    • Ashley Hill Salazar,
    • William K. Funkhouser &
    • W. Kimryn Rathmell
  12. University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.

    • John V. Heymach,
    • Rileen Sinha,
    • John N. Weinstein,
    • Lauren Averett Byers,
    • Robert A. Holt,
    • Harshad S. Mahadeshwar,
    • Alexei Protopopov,
    • Sahil Seth,
    • Xingzhi Song,
    • Jiabin Tang,
    • Jianhua Zhang,
    • Lynda Chin,
    • Bradley M. Broom,
    • Jing Wang,
    • Yiling Lu,
    • Patrick Kwok Shing Ng,
    • Lixia Diao,
    • Wenbin Liu,
    • Christopher I. Amos,
    • Rehan Akbani,
    • Gordon B. Mills &
    • Richard Hajek
  13. Princess Margaret Cancer Centre, Toronto, Ontario M5G 2M9, Canada.

    • Igor Jurisica &
    • Ming-Sound Tsao
  14. Brigham and Women’s Hospital Boston, Massachusetts 02115, USA.

    • David Kwiatkowski,
    • Angela Hadjipanayis,
    • Semin Lee,
    • Angeliki Pantazi,
    • Michael Parfenov,
    • Andrew Wei Xu,
    • Netty Santoso,
    • Peter J. Park,
    • Raju Kucherlapati &
    • William G. Richards
  15. BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.

    • Gordon Robertson,
    • Andy Chu,
    • Miruna Balasundaram,
    • Yaron S. N. Butterfield,
    • Rebecca Carlsen,
    • Eric Chuah,
    • Noreen Dhalla,
    • Ranabir Guin,
    • Carrie Hirst,
    • Darlene Lee,
    • Haiyan I. Li,
    • Michael Mayo,
    • Richard A. Moore,
    • Andrew J. Mungall,
    • Jacqueline E. Schein,
    • Payal Sipahimalani,
    • Angela Tam,
    • Richard Varhol,
    • A. Gordon Robertson,
    • Natasja Wye,
    • Nina Thiessen,
    • Steven J. M. Jones &
    • Marco A. Marra
  16. Mayo Clinic, Rochester, Minnesota 55905, USA.

    • Dennis A. Wigle,
    • Michael K. Asiedu &
    • Farhad Kosari
  17. University of Southern California, Los Angeles, California 90033, USA.

    • Daniel J. Weisenberger,
    • Peter W. Laird,
    • Dennis T. Maglinte,
    • Philip H. Lai,
    • Moiz S. Bootwalla,
    • David J. Van Den Berg &
    • Timothy Triche Jr
  18. University of California Santa Cruz, Santa Cruz, California 95064, USA.

    • Amie Radenbaugh,
    • Singer Ma,
    • Joshua M. Stuart,
    • Sam Ng,
    • Jingchun Zhu &
    • David Haussler
  19. Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.

    • Eric S. Lander
  20. University of Kentucky, Lexington, Kentucky 40515, USA.

    • Jinze Liu
  21. Buck Institute for Age Research, Novato, California 94945, USA.

    • Christopher C. Benz &
    • Christina Yau
  22. Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, California 95064, USA.

    • David Haussler
  23. Oregon Health and Science University, Portland, Oregon 97239, USA.

    • Paul T. Spellman
  24. International Genomics Consortium, Phoenix, Arizona 85004, USA.

    • Erin Curley,
    • Joseph Paulauskis,
    • Kevin Lau,
    • Scott Morris,
    • Troy Shelton,
    • David Mallery,
    • Johanna Gardner &
    • Robert Penny
  25. Analytical Biological Services, Inc., Wilmington, Delaware 19801, USA.

    • Charles Saller &
    • Katherine Tarvin
  26. University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

    • Robert Cerfolio &
    • Ayesha Bryant
  27. Cleveland Clinic, Cleveland, Ohio 44195, USA.

    • Daniel P. Raymond,
    • Nathan A. Pennell &
    • Carol Farver
  28. Christiana Care, Newark, Delaware 19713, USA.

    • Christine Czerwinski,
    • Lori Huelsenbeck-Dill,
    • Mary Iacocca,
    • Nicholas Petrelli,
    • Brenda Rabeno,
    • Jennifer Brown &
    • Thomas Bauer
  29. Cureline, Inc., South San Francisco, California 94080, USA.

    • Oleg Dolzhanskiy,
    • Olga Potapova,
    • Daniil Rotin,
    • Olga Voronina,
    • Elena Nemirovich-Danchenko &
    • Konstantin V. Fedosenko
  30. Emory University, Atlanta, Georgia 30322, USA.

    • Anthony Gal,
    • Madhusmita Behera,
    • Suresh S. Ramalingam &
    • Gabriel Sica
  31. Fox Chase Cancer Center, Philadelphia, Philadelphia 19111, USA.

    • Douglas Flieder,
    • Jeff Boyd &
    • JoEllen Weaver
  32. ILSbio, Chestertown, Maryland 21620, USA.

    • Bernard Kohl &
    • Dang Huy Quoc Thinh
  33. Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.

    • George Sandusky
  34. Individumed, Silver Spring, Maryland 20910, USA.

    • Hartmut Juhl
  35. The Prince Charles Hospital and the University of Queensland Thoracic Research Center, Brisbane, 4032, Australia.

    • Edwina Duhig,
    • Belinda Clarke,
    • Ian A. Yang,
    • Kwun M. Fong,
    • Lindy Hunter,
    • Morgan Windsor &
    • Rayleen V. Bowman
  36. Sullivan Nicolaides Pathology & John Flynn Hospital, Tugun 4680, Australia.

    • Edwina Duhig
  37. Lahey Hospital and Medical Center, Burlington, Massachusetts 01805, USA.

    • Christina Williamson,
    • Eric Burks,
    • Kimberly Rieger-Christ,
    • Antonia Holway &
    • Travis Sullivan
  38. NYU Langone Medical Center, New York, New York 10016, USA.

    • Paul Zippile,
    • James Suh,
    • Harvey Pass,
    • Chandra Goparaju &
    • Yvonne Owusu-Sarpong
  39. Ontario Tumour Bank, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.

    • John M. S. Bartlett,
    • Sugy Kodeeswaran,
    • Jeremy Parfitt,
    • Harmanjatinder Sekhon &
    • Monique Albert
  40. Penrose St. Francis Health Services, Colorado Springs, Colorado 80907, USA.

    • John Eckman &
    • Jerome B. Myers
  41. Roswell Park Cancer Center, Buffalo, New York 14263, USA.

    • Richard Cheney,
    • Carl Morrison &
    • Carmelo Gaudioso
  42. Rush University Medical Center, Chicago, Illinois 60612, USA.

    • Jeffrey A. Borgia,
    • Philip Bonomi,
    • Mark Pool &
    • Michael J. Liptay
  43. St. Petersburg Academic University, St Petersburg 199034, Russia.

    • Fedor Moiseenko &
    • Irina Zaytseva
  44. Thoraxklinik am Universitätsklinikum Heidelberg, 69126 Heidelberg, Germany.

    • Hendrik Dienemann,
    • Michael Meister &
    • Thomas R. Muley
  45. University Heidelberg, 69120 Heidelberg, Germany.

    • Philipp A. Schnabel
  46. University of Cologne, 50931 Cologne, Germany.

    • Martin Peifer
  47. University of Miami, Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.

    • Carmen Gomez-Fernandez,
    • Lynn Herbert &
    • Sophie Egea
  48. University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.

    • Rajiv Dhir,
    • Samuel A. Yousem,
    • Sanja Dacic,
    • Frank Schneider &
    • Jill M. Siegfried
  49. Center Hospitalier Universitaire Vaudois, Lausanne and European Thoracic Oncology Platform, CH-1011 Lausanne, Switzerland.

    • Solange Peters &
    • Igor Letovanec
  50. Ziauddin University Hospital, Karachi, 75300, Pakistan.

    • Khurram Z. Khan
  51. SRA International, Inc., Fairfax, Virginia 22033, USA.

    • Mark A. Jensen,
    • Eric E. Snyder,
    • Deepak Srinivasan,
    • Ari B. Kahn,
    • Julien Baboud &
    • David A. Pot
  52. National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Kenna R. Mills Shaw,
    • Margi Sheth,
    • Tanja Davidsen,
    • John A. Demchok,
    • Liming Yang,
    • Zhining Wang,
    • Roy Tarnuzzer &
    • Jean Claude Zenklusen
  53. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Bradley A. Ozenberger &
    • Heidi J. Sofia

Consortia

  1. The Cancer Genome Atlas Research Network

  2. Disease analysis working group

    • Eric A. Collisson,
    • Joshua D. Campbell,
    • Angela N. Brooks,
    • Alice H. Berger,
    • William Lee,
    • Juliann Chmielecki,
    • David G. Beer,
    • Leslie Cope,
    • Chad J. Creighton,
    • Ludmila Danilova,
    • Li Ding,
    • Gad Getz,
    • Peter S. Hammerman,
    • D. Neil Hayes,
    • Bryan Hernandez,
    • James G. Herman,
    • John V. Heymach,
    • Igor Jurisica,
    • Raju Kucherlapati,
    • David Kwiatkowski,
    • Marc Ladanyi,
    • Gordon Robertson,
    • Nikolaus Schultz,
    • Ronglai Shen,
    • Rileen Sinha,
    • Carrie Sougnez,
    • Ming-Sound Tsao,
    • William D. Travis,
    • John N. Weinstein,
    • Dennis A. Wigle,
    • Matthew D. Wilkerson,
    • Andy Chu,
    • Andrew D. Cherniack,
    • Angela Hadjipanayis,
    • Mara Rosenberg,
    • Daniel J. Weisenberger,
    • Peter W. Laird,
    • Amie Radenbaugh,
    • Singer Ma,
    • Joshua M. Stuart,
    • Lauren Averett Byers,
    • Stephen B. Baylin,
    • Ramaswamy Govindan &
    • Matthew Meyerson
  3. Genome sequencing centres: The Eli & Edythe L. Broad Institute

    • Mara Rosenberg,
    • Stacey B. Gabriel,
    • Kristian Cibulskis,
    • Carrie Sougnez,
    • Jaegil Kim,
    • Chip Stewart,
    • Lee Lichtenstein,
    • Eric S. Lander,
    • Michael S. Lawrence &
    • Gad Getz
  4. Washington University in St. Louis

    • Cyriac Kandoth,
    • Robert Fulton,
    • Lucinda L. Fulton,
    • Michael D. McLellan,
    • Richard K. Wilson,
    • Kai Ye,
    • Catrina C. Fronick,
    • Christopher A. Maher,
    • Christopher A. Miller,
    • Michael C. Wendl,
    • Christopher Cabanski,
    • Li Ding,
    • Elaine Mardis &
    • Ramaswamy Govindan
  5. Baylor College of Medicine

    • Chad J. Creighton &
    • David Wheeler
  6. Genome characterization centres: Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency

    • Miruna Balasundaram,
    • Yaron S. N. Butterfield,
    • Rebecca Carlsen,
    • Andy Chu,
    • Eric Chuah,
    • Noreen Dhalla,
    • Ranabir Guin,
    • Carrie Hirst,
    • Darlene Lee,
    • Haiyan I. Li,
    • Michael Mayo,
    • Richard A. Moore,
    • Andrew J. Mungall,
    • Jacqueline E. Schein,
    • Payal Sipahimalani,
    • Angela Tam,
    • Richard Varhol,
    • A. Gordon Robertson,
    • Natasja Wye,
    • Nina Thiessen,
    • Robert A. Holt,
    • Steven J. M. Jones &
    • Marco A. Marra
  7. The Eli & Edythe L. Broad Institute

    • Joshua D. Campbell,
    • Angela N. Brooks,
    • Juliann Chmielecki,
    • Marcin Imielinski,
    • Robert C. Onofrio,
    • Eran Hodis,
    • Travis Zack,
    • Carrie Sougnez,
    • Elena Helman,
    • Chandra Sekhar Pedamallu,
    • Jill Mesirov,
    • Andrew D. Cherniack,
    • Gordon Saksena,
    • Steven E. Schumacher,
    • Scott L. Carter,
    • Bryan Hernandez,
    • Levi Garraway,
    • Rameen Beroukhim,
    • Stacey B. Gabriel,
    • Gad Getz &
    • Matthew Meyerson
  8. Harvard Medical School/Brigham & Women’s Hospital/MD Anderson Cancer Center

    • Angela Hadjipanayis,
    • Semin Lee,
    • Harshad S. Mahadeshwar,
    • Angeliki Pantazi,
    • Alexei Protopopov,
    • Xiaojia Ren,
    • Sahil Seth,
    • Xingzhi Song,
    • Jiabin Tang,
    • Lixing Yang,
    • Jianhua Zhang,
    • Peng-Chieh Chen,
    • Michael Parfenov,
    • Andrew Wei Xu,
    • Netty Santoso,
    • Lynda Chin,
    • Peter J. Park &
    • Raju Kucherlapati
  9. University of North Carolina, Chapel Hill

    • Katherine A. Hoadley,
    • J. Todd Auman,
    • Shaowu Meng,
    • Yan Shi,
    • Elizabeth Buda,
    • Scot Waring,
    • Umadevi Veluvolu,
    • Donghui Tan,
    • Piotr A. Mieczkowski,
    • Corbin D. Jones,
    • Janae V. Simons,
    • Matthew G. Soloway,
    • Tom Bodenheimer,
    • Stuart R. Jefferys,
    • Jeffrey Roach,
    • Alan P. Hoyle,
    • Junyuan Wu,
    • Saianand Balu,
    • Darshan Singh,
    • Jan F. Prins,
    • J.S. Marron,
    • Joel S. Parker,
    • D. Neil Hayes &
    • Charles M. Perou
  10. University of Kentucky

    • Jinze Liu
  11. The USC/JHU Epigenome Characterization Center

    • Leslie Cope,
    • Ludmila Danilova,
    • Daniel J. Weisenberger,
    • Dennis T. Maglinte,
    • Philip H. Lai,
    • Moiz S. Bootwalla,
    • David J. Van Den Berg,
    • Timothy Triche Jr,
    • Stephen B. Baylin &
    • Peter W. Laird
  12. Genome data analysis centres: The Eli & Edythe L. Broad Institute

    • Mara Rosenberg,
    • Lynda Chin,
    • Jianhua Zhang,
    • Juok Cho,
    • Daniel DiCara,
    • David Heiman,
    • Pei Lin,
    • William Mallard,
    • Douglas Voet,
    • Hailei Zhang,
    • Lihua Zou,
    • Michael S. Noble,
    • Michael S. Lawrence,
    • Gordon Saksena,
    • Nils Gehlenborg,
    • Helga Thorvaldsdottir,
    • Jill Mesirov,
    • Marc-Danie Nazaire,
    • Jim Robinson &
    • Gad Getz
  13. Memorial Sloan-Kettering Cancer Center

    • William Lee,
    • B. Arman Aksoy,
    • Giovanni Ciriello,
    • Barry S. Taylor,
    • Gideon Dresdner,
    • Jianjiong Gao,
    • Benjamin Gross,
    • Venkatraman E. Seshan,
    • Marc Ladanyi,
    • Boris Reva,
    • Rileen Sinha,
    • S. Onur Sumer,
    • Nils Weinhold,
    • Nikolaus Schultz,
    • Ronglai Shen &
    • Chris Sander
  14. University of California, Santa Cruz/Buck Institute

    • Sam Ng,
    • Singer Ma,
    • Jingchun Zhu,
    • Amie Radenbaugh,
    • Joshua M. Stuart,
    • Christopher C. Benz,
    • Christina Yau &
    • David Haussler
  15. Oregon Health & Sciences University

    • Paul T. Spellman
  16. University of North Carolina, Chapel Hill

    • Matthew D. Wilkerson,
    • Joel S. Parker,
    • Katherine A. Hoadley,
    • Patrick K. Kimes,
    • D. Neil Hayes &
    • Charles M. Perou
  17. The University of Texas MD Anderson Cancer Center

    • Bradley M. Broom,
    • Jing Wang,
    • Yiling Lu,
    • Patrick Kwok Shing Ng,
    • Lixia Diao,
    • Lauren Averett Byers,
    • Wenbin Liu,
    • John V. Heymach,
    • Christopher I. Amos,
    • John N. Weinstein,
    • Rehan Akbani &
    • Gordon B. Mills
  18. Biospecimen core resource: International Genomics Consortium

    • Erin Curley,
    • Joseph Paulauskis,
    • Kevin Lau,
    • Scott Morris,
    • Troy Shelton,
    • David Mallery,
    • Johanna Gardner &
    • Robert Penny
  19. Tissue source sites: Analytical Biological Service, Inc.

    • Charles Saller &
    • Katherine Tarvin
  20. Brigham & Women’s Hospital

    • William G. Richards
  21. University of Alabama at Birmingham

    • Robert Cerfolio &
    • Ayesha Bryant
  22. Cleveland Clinic

    • Daniel P. Raymond,
    • Nathan A. Pennell &
    • Carol Farver
  23. Christiana Care

    • Christine Czerwinski,
    • Lori Huelsenbeck-Dill,
    • Mary Iacocca,
    • Nicholas Petrelli,
    • Brenda Rabeno,
    • Jennifer Brown &
    • Thomas Bauer
  24. Cureline

    • Oleg Dolzhanskiy,
    • Olga Potapova,
    • Daniil Rotin,
    • Olga Voronina,
    • Elena Nemirovich-Danchenko &
    • Konstantin V. Fedosenko
  25. Emory University

    • Anthony Gal,
    • Madhusmita Behera,
    • Suresh S. Ramalingam &
    • Gabriel Sica
  26. Fox Chase Cancer Center

    • Douglas Flieder,
    • Jeff Boyd &
    • JoEllen Weaver
  27. ILSbio

    • Bernard Kohl &
    • Dang Huy Quoc Thinh
  28. Indiana University

    • George Sandusky
  29. Indivumed

    • Hartmut Juhl
  30. John Flynn Hospital

    • Edwina Duhig
  31. Johns Hopkins University

    • Peter Illei,
    • Edward Gabrielson,
    • James Shin,
    • Beverly Lee,
    • Kristen Rodgers,
    • Dante Trusty &
    • Malcolm V. Brock
  32. Lahey Hospital & Medical Center

    • Christina Williamson,
    • Eric Burks,
    • Kimberly Rieger-Christ,
    • Antonia Holway &
    • Travis Sullivan
  33. Mayo Clinic

    • Dennis A. Wigle,
    • Michael K. Asiedu &
    • Farhad Kosari
  34. Memorial Sloan-Kettering Cancer Center

    • William D. Travis,
    • Natasha Rekhtman,
    • Maureen Zakowski &
    • Valerie W. Rusch
  35. NYU Langone Medical Center

    • Paul Zippile,
    • James Suh,
    • Harvey Pass,
    • Chandra Goparaju &
    • Yvonne Owusu-Sarpong
  36. Ontario Tumour Bank

    • John M. S. Bartlett,
    • Sugy Kodeeswaran,
    • Jeremy Parfitt,
    • Harmanjatinder Sekhon &
    • Monique Albert
  37. Penrose St. Francis Health Services

    • John Eckman &
    • Jerome B. Myers
  38. Roswell Park Cancer Institute

    • Richard Cheney,
    • Carl Morrison &
    • Carmelo Gaudioso
  39. Rush University Medical Center

    • Jeffrey A. Borgia,
    • Philip Bonomi,
    • Mark Pool &
    • Michael J. Liptay
  40. St. Petersburg Academic University

    • Fedor Moiseenko &
    • Irina Zaytseva
  41. Thoraxklinik am Universitätsklinikum Heidelberg, Member of Biomaterial Bank Heidelberg (BMBH) & Biobank Platform of the German Centre for Lung Research (DZL)

    • Hendrik Dienemann,
    • Michael Meister,
    • Philipp A. Schnabel &
    • Thomas R. Muley
  42. University of Cologne

    • Martin Peifer
  43. University of Miami

    • Carmen Gomez-Fernandez,
    • Lynn Herbert &
    • Sophie Egea
  44. University of North Carolina

    • Mei Huang,
    • Leigh B. Thorne,
    • Lori Boice,
    • Ashley Hill Salazar,
    • William K. Funkhouser &
    • W. Kimryn Rathmell
  45. University of Pittsburgh

    • Rajiv Dhir,
    • Samuel A. Yousem,
    • Sanja Dacic,
    • Frank Schneider &
    • Jill M. Siegfried
  46. The University of Texas MD Anderson Cancer Center

    • Richard Hajek
  47. Washington University School of Medicine

    • Mark A. Watson,
    • Sandra McDonald &
    • Bryan Meyers
  48. Queensland Thoracic Research Center

    • Belinda Clarke,
    • Ian A. Yang,
    • Kwun M. Fong,
    • Lindy Hunter,
    • Morgan Windsor &
    • Rayleen V. Bowman
  49. Center Hospitalier Universitaire Vaudois

    • Solange Peters &
    • Igor Letovanec
  50. Ziauddin University Hospital

    • Khurram Z. Khan
  51. Data Coordination Centre

    • Mark A. Jensen,
    • Eric E. Snyder,
    • Deepak Srinivasan,
    • Ari B. Kahn,
    • Julien Baboud &
    • David A. Pot
  52. Project team: National Cancer Institute

    • Kenna R. Mills Shaw,
    • Margi Sheth,
    • Tanja Davidsen,
    • John A. Demchok,
    • Liming Yang,
    • Zhining Wang,
    • Roy Tarnuzzer &
    • Jean Claude Zenklusen
  53. National Human Genome Research Institute

    • Bradley A. Ozenberger &
    • Heidi J. Sofia
  54. Expert pathology panel

    • William D. Travis,
    • Richard Cheney,
    • Belinda Clarke,
    • Sanja Dacic,
    • Edwina Duhig,
    • William K. Funkhouser,
    • Peter Illei,
    • Carol Farver,
    • Natasha Rekhtman,
    • Gabriel Sica,
    • James Suh &
    • Ming-Sound Tsao

Contributions

The Cancer Genome Atlas Research Network contributed collectively to this study. Biospecimens were provided by the tissue source sites and processed by the biospecimen core resource. Data generation and analyses were performed by the genome sequencing centres, cancer genome characterization centres and genome data analysis centres. All data were released through the data coordinating centre. The National Cancer Institute and National Human Genome Research Institute project teams coordinated project activities. We also acknowledge the following TCGA investigators who made substantial contributions to the project: E. A. Collisson (manuscript coordinator); J. D. Campbell, J. Chmielecki, (analysis coordinators); C. Sougnez (data coordinator); J. D. Campbell, M. Rosenberg, W. Lee, J. Chmielecki, M. Ladanyi, and G. Getz (DNA sequence analysis); M. D. Wilkerson, A. N. Brooks, and D. N. Hayes (mRNA sequence analysis); L. Danilova and L. Cope (DNA methylation analysis); A. D. Cherniack (copy number analysis); M. D. Wilkerson and A. Hadjipanayis (translocations); N. Schultz, W. Lee, E. A. Collisson, A. H. Berger, J. Chmielecki, C. J. Creighton, L. A. Byers and M. Ladanyi (pathway analysis); A. Chu and A. G. Robertson (miRNA sequence analysis); W. Travis and D. A. Wigle (pathology and clinical expertise); L. A. Byers and G. B. Mills (reverse phase protein arrays); S. B. Baylin, R. Govindan and M. Meyerson (project chairs).

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

The primary and processed data used to generate the analyses presented here can be downloaded by registered users from The Cancer Genome Atlas at (https://tcga-data.nci.nih.gov/tcga/tcgaDownload.jsp). All of the primary sequence files are deposited in cgHub and all other data are deposited at the Data Coordinating Center (DCC) for public access (http://cancergenome.nih.gov/), (https://cghub.ucsc.edu/) and (https://tcga-data.nci.nih.gov/docs/publications/luad_2014/).

Author details

    Supplementary information

    PDF files

    1. Supplementary Information (12.2 MB)

      This file contains Supplementary Methods and Results, Supplementary Figures 1-15 and additional references – see separate excel for Supplementary Tables 1-14).

    Excel files

    1. Supplementary Tables (3.2 MB)

      This file contains Supplementary Tables 1-14

    Additional data