Abstract

To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined the exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor–normal pairs. Recurrent alterations in lung SqCCs were more similar to those of other squamous carcinomas than to alterations in lung ADCs. New significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types. New amplification peaks encompassed MIR21 in lung ADC, MIR205 in lung SqCC, and MAPK1 in both. Lung ADCs lacking receptor tyrosine kinase–Ras–Raf pathway alterations had mutations in SOS1, VAV1, RASA1, and ARHGAP35. Regarding neoantigens, 47% of the lung ADC and 53% of the lung SqCC tumors had at least five predicted neoepitopes. Although targeted therapies for lung ADC and SqCC are largely distinct, immunotherapies may aid in treatment for both subtypes.

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Acknowledgements

This work was supported by grants from the National Cancer Institute as part of The Cancer Genome Atlas project: U24CA126546, U24CA143867, U24CA143845, U24CA126544, and U24CA143883. Additionally, this work was funded by National Cancer Institute grant K08CA163677 (P.S.H.), grant 074-U01 from the government of the Russian Federation (A.A.), US Department of Defense contract W81XWH-12-1-0269 (M.M.), the American Cancer Society Research Professor Award (M.M.), and National Cancer Institute grant R35CA197568 (M.M.).

Author information

Affiliations

  1. Cancer Program, Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Joshua D Campbell
    • , Jaegil Kim
    • , Jeremiah Wala
    • , Alice H Berger
    • , Chandra Sekhar Pedamallu
    • , Sachet A Shukla
    • , Guangwu Guo
    • , Angela N Brooks
    • , Bradley A Murray
    • , Marcin Imielinski
    • , Mara Rosenberg
    • , Carrie Cibulskis
    • , Aruna Ramachandran
    • , David J Kwiatkowski
    • , Michael S Lawrence
    • , Catherine J Wu
    • , Peter S Hammerman
    • , Andrew D Cherniack
    • , Gad Getz
    • , Michael S Noble
    • , Hailei Zhang
    • , David I Heiman
    • , Juok Cho
    • , Nils Gehlenborg
    • , Gordon Saksena
    • , Doug Voet
    • , Pei Lin
    • , Scott Frazer
    • , Lynda Chin
    • , David Kwiatkowski
    • , Carrie Sougnez
    • , Steven E Schumacher
    • , Juliann Shih
    • , Rameen Beroukhim
    • , Travis I Zack
    • , Stacey B Gabriel
    •  & Matthew Meyerson
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Joshua D Campbell
    • , Jeremiah Wala
    • , Alice H Berger
    • , Chandra Sekhar Pedamallu
    • , Sachet A Shukla
    • , Guangwu Guo
    • , Angela N Brooks
    • , Bradley A Murray
    • , Marcin Imielinski
    • , Aruna Ramachandran
    • , Catherine J Wu
    • , Peter S Hammerman
    • , Andrew D Cherniack
    • , Juliann Shih
    • , Rameen Beroukhim
    •  & Matthew Meyerson
  3. Department of Pathology and Immunology, Washington University, St. Louis, Missouri, USA.

    • Anton Alexandrov
    • , Maxim N Artyomov
    •  & Robert Schreiber
  4. Computer Technologies Laboratory, ITMO University, St. Petersburg, Russia.

    • Anton Alexandrov
  5. Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA.

    • Marcin Imielinski
  6. Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Xin Hu
    • , Shiyun Ling
    • , Rehan Akbani
    • , John N Weinstein
    •  & Roel G W Verhaak
  7. Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Eric A Collisson
    •  & Eric Collisson
  8. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • David J Kwiatkowski
    •  & David Kwiatkowski
  9. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Gad Getz
  10. Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Ramaswamy Govindan
  11. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.

    • Matthew Meyerson
  12. National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Jean C Zenklusen
    • , Jiashan Zhang
    • , Ina Felau
    • , John A Demchok
    • , Liming Yang
    • , Zhining Wang
    • , Martin L Ferguson
    • , Roy Tarnuzzer
    • , Carolyn M Hutter
    • , Heidi J Sofia
    •  & Tanja Davidsen
  13. SRA International, Fairfax, Virginia, USA.

    • Todd Pihl
    • , Yunhu Wan
    • , Charlie Sun
    •  & Rashi Naresh
  14. Leidos Biomedical, Rockville, Maryland, USA.

    • Sudha Chudamani
    • , Jia Liu
    • , Laxmi Lolla
    •  & Ye Wu
  15. Baylor College of Medicine, Houston, Texas, USA.

    • Chad J Creighton
  16. University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • W Kimryn Rathmell
    • , J Todd Auman
    • , Lori Boice
    •  & Mei Huang
  17. Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • J Todd Auman
    • , Charles M Perou
    •  & Leigh B Thorne
  18. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Saianand Balu
    • , Tom Bodenheimer
    • , D Neil Hayes
    • , Katherine A Hoadley
    • , Alan P Hoyle
    • , Stuart R Jefferys
    • , Shaowu Meng
    • , Lisle E Mose
    • , Charles M Perou
    • , Yan Shi
    • , Janae V Simons
    • , Matthew G Soloway
    • , Junyuan Wu
    • , Joel S Parker
    •  & Leigh B Thorne
  19. Department of Internal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • D Neil Hayes
  20. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Katherine A Hoadley
    • , Piotr A Mieczkowski
    • , Charles M Perou
    • , Tara Skelly
    • , Donghui Tan
    • , Umadevi Veluvolu
    • , Joel S Parker
    •  & Matthew D Wilkerson
  21. Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Corbin D Jones
  22. Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Corbin D Jones
  23. Research Computing Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Jeffrey Roach
  24. University of North Carolina Tissue Procurement Facility, Chapel Hill, North Carolina, USA.

    • Lori Boice
    • , Mei Huang
    •  & Leigh B Thorne
  25. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.

    • Nils Gehlenborg
  26. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Lynda Chin
  27. University Health Network and Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

    • Ming-Sound Tsao
    • , Frances Allison
    •  & Dianne Chadwick
  28. Thoraxklinik am Universitätsklinikum Heidelberg, Heidelberg, Germany.

    • Thomas Muley
    • , Michael Meister
    •  & Hendrik Dienemann
  29. Translational Lung Research Centre Heidelberg, German Centre for Lung Research, Heidelberg, Germany.

    • Thomas Muley
    • , Michael Meister
    •  & Hendrik Dienemann
  30. Harvard Medical School, Boston, Massachusetts, USA.

    • Raju Kucherlapati
    •  & Peter Park
  31. Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Raju Kucherlapati
    •  & Peter Park
  32. Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

    • Jay Bowen
    • , Julie M Gastier-Foster
    • , Mark Gerken
    • , Kristen M Leraas
    • , Tara M Lichtenberg
    • , Nilsa C Ramirez
    • , Lisa Wise
    •  & Erik Zmuda
  33. The Ohio State University, Columbus, Ohio, USA.

    • Julie M Gastier-Foster
    •  & Nilsa C Ramirez
  34. Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, California, USA.

    • Josh Stuart
  35. Department of Translational Genomics, Cologne, Germany.

    • Martin Peifer
  36. Center for Molecular Medicine Cologne, Cologne, Germany.

    • Martin Peifer
  37. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Steven E Schumacher
    •  & Travis I Zack
  38. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Rameen Beroukhim
  39. Department of Thoracic Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, Texas, USA.

    • Lauren A Byers
  40. Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan, USA.

    • Peter W Laird
  41. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.

    • Daniel J Weisenberger
    • , David J Van Den Berg
    • , Moiz S Bootwalla
    • , Phillip H Lai
    •  & Dennis T Maglinte
  42. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.

    • Stephen B Baylin
    • , Ludmila Danilova
    •  & Leslie Cope
  43. Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.

    • James G Herman
  44. International Genomics Consortium, Phoenix, Arizona, USA.

    • Daniel J Crain
    • , Erin Curley
    • , Johanna Gardner
    • , Kevin Lau
    • , David Mallery
    • , Scott Morris
    • , Joeseph Paulauskis
    • , Robert Penny
    • , Candace Shelton
    • , Troy Shelton
    • , Mark Sherman
    •  & Peggy Yena
  45. Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Gordon B Mills

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Contributions

J.D.C. performed sample quality control, mutation calling and review, ABSOLUTE analysis of tumors from the cohort of Imielinski et al., identification and comparison of recurrently altered genes, mutational signature identification and characterization, identification of EGFR complex indels, and manuscript writing. A.A., M.N.A., and R.S. generated neoantigen calls. J.K. contributed to mutational signature analyses. J.W. contributed to EGFR complex indel characterization. A.H.B. contributed to oncogene-negative analysis and manuscript preparation. C.S.P. generated the pan-lung portal. A.N.B. identified MET exon 14 skipping events using RNA-seq. X.H. and R.G.W.V. generated fusion calls. S.L. and R.A. performed batch effect analyses. G. Guo contributed to MET exon 14 complex indel identification. M.R., M.I., M.S.L., and G. Getz contributed algorithms for mutation calling and analyses. B.A.M. and A.D.C. contributed to copy number and ABSOLUTE analyses. S.A.S. and C.J.W. performed HLA genotyping. C.C. contributed to sample coordination and quality control. A.R., A.D.C., E.A.C., J.N.W., P.S.H., and D.J.K. contributed to manuscript preparation. R.G. and M.M. conceived and designed the study and wrote the manuscript.

Competing interests

Some authors received research support from Bayer Pharmaceuticals (C.S.P., B.A.M., A.D.C., and M.M.).

Corresponding authors

Correspondence to Ramaswamy Govindan or Matthew Meyerson.

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https://doi.org/10.1038/ng.3564

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