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Somatic mutations affect key pathways in lung adenocarcinoma

Author

Listed:
  • Li Ding

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Gad Getz

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA)

  • David A. Wheeler

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Elaine R. Mardis

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Michael D. McLellan

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Kristian Cibulskis

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA)

  • Carrie Sougnez

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA)

  • Heidi Greulich

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
    Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Donna M. Muzny

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Margaret B. Morgan

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Lucinda Fulton

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Robert S. Fulton

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Qunyuan Zhang

    (Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Michael C. Wendl

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Michael S. Lawrence

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA)

  • David E. Larson

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Ken Chen

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • David J. Dooling

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Aniko Sabo

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Alicia C. Hawes

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Hua Shen

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Shalini N. Jhangiani

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Lora R. Lewis

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Otis Hall

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Yiming Zhu

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Tittu Mathew

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Yanru Ren

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Jiqiang Yao

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Steven E. Scherer

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Kerstin Clerc

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Ginger A. Metcalf

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Brian Ng

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Aleksandar Milosavljevic

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Manuel L. Gonzalez-Garay

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • John R. Osborne

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Rick Meyer

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Xiaoqi Shi

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Yuzhu Tang

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Daniel C. Koboldt

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Ling Lin

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Rachel Abbott

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Tracie L. Miner

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Craig Pohl

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Ginger Fewell

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Carrie Haipek

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Heather Schmidt

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Brian H. Dunford-Shore

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Aldi Kraja

    (Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Seth D. Crosby

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Christopher S. Sawyer

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Tammi Vickery

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Sacha Sander

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Jody Robinson

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Wendy Winckler

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
    Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Jennifer Baldwin

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA)

  • Lucian R. Chirieac

    (Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA
    Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Amit Dutt

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
    Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Tim Fennell

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA)

  • Megan Hanna

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
    Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Bruce E. Johnson

    (Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Robert C. Onofrio

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA)

  • Roman K. Thomas

    (Max-Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max-Planck Society and the Medical Faculty of the University of Cologne
    University of Cologne)

  • Giovanni Tonon

    (Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Barbara A. Weir

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
    Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Xiaojun Zhao

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
    Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Liuda Ziaugra

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA)

  • Michael C. Zody

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA)

  • Thomas Giordano

    (Department of Pathology,)

  • Mark B. Orringer

    (Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA)

  • Jack A. Roth

    (Department of Thoracic and Cardiovascular Surgery,)

  • Margaret R. Spitz

    (and)

  • Ignacio I. Wistuba

    (Department of Thoracic and Cardiovascular Surgery,
    The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA)

  • Bradley Ozenberger

    (National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA)

  • Peter J. Good

    (National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA)

  • Andrew C. Chang

    (Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA)

  • David G. Beer

    (Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA)

  • Mark A. Watson

    (Washington University in St Louis, St Louis, Missouri 63108, USA)

  • Marc Ladanyi

    (Surgery, Pathology, and Computational Biology
    Human Oncology and Pathogenesis Program, and)

  • Stephen Broderick

    (Surgery, Pathology, and Computational Biology)

  • Akihiko Yoshizawa

    (Surgery, Pathology, and Computational Biology)

  • William D. Travis

    (Surgery, Pathology, and Computational Biology)

  • William Pao

    (Surgery, Pathology, and Computational Biology
    Human Oncology and Pathogenesis Program, and)

  • Michael A. Province

    (Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • George M. Weinstock

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

  • Harold E. Varmus

    (Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA)

  • Stacey B. Gabriel

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA)

  • Eric S. Lander

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA)

  • Richard A. Gibbs

    (Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA)

  • Matthew Meyerson

    (Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
    Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Richard K. Wilson

    (The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA)

Abstract

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers—including NF1, APC, RB1 and ATM—and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.

Suggested Citation

  • Li Ding & Gad Getz & David A. Wheeler & Elaine R. Mardis & Michael D. McLellan & Kristian Cibulskis & Carrie Sougnez & Heidi Greulich & Donna M. Muzny & Margaret B. Morgan & Lucinda Fulton & Robert S., 2008. "Somatic mutations affect key pathways in lung adenocarcinoma," Nature, Nature, vol. 455(7216), pages 1069-1075, October.
    • Handle: RePEc:nat:nature:v:455:y:2008:i:7216:d:10.1038_nature07423
    DOI: 10.1038/nature07423
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    Cited by:

    1. Irati Macaya & Marta Roman & Connor Welch & Rodrigo Entrialgo-Cadierno & Marina Salmon & Alba Santos & Iker Feliu & Joanna Kovalski & Ines Lopez & Maria Rodriguez-Remirez & Sara Palomino-Echeverria & , 2023. "Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Yasuhiko Haga & Yoshitaka Sakamoto & Keiko Kajiya & Hitomi Kawai & Miho Oka & Noriko Motoi & Masayuki Shirasawa & Masaya Yotsukura & Shun-Ichi Watanabe & Miyuki Arai & Junko Zenkoh & Kouya Shiraishi &, 2023. "Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Dzana Dervovic & Ahmad A. Malik & Edward L. Y. Chen & Masahiro Narimatsu & Nina Adler & Somaieh Afiuni-Zadeh & Dagmar Krenbek & Sebastien Martinez & Ricky Tsai & Jonathan Boucher & Jacob M. Berman & K, 2023. "In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    4. Solip Park & Fran Supek & Ben Lehner, 2021. "Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    5. Xue Bai & Ze-Qin Guo & Yan-Pei Zhang & Zhen-zhen Fan & Li-Juan Liu & Li Liu & Li-Li Long & Si-Cong Ma & Jian Wang & Yuan Fang & Xin-Ran Tang & Yu-Jie Zeng & Xinghua Pan & De-Hua Wu & Zhong-Yi Dong, 2023. "CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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