Somatic mutations affect key pathways in lung adenocarcinoma

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. Fulton, Qunyuan Zhang, Michael C. Wendl, Michael S. Lawrence, David E. Larson, Ken Chen, David J. Dooling, Aniko Sabo, Alicia C. Hawes, Hua Shen, Shalini N. Jhangiani, Lora R. Lewis, Otis Hall, Yiming Zhu, Tittu Mathew, Yanru Ren, Jiqiang Yao, Steven E. Scherer, Kerstin Clerc, Ginger A. Metcalf, Brian Ng, Aleksandar Milosavljevic, Manuel L. Gonzalez-Garay, John R. Osborne, Rick Meyer, Xiaoqi Shi, Yuzhu Tang, Daniel C. Koboldt, Ling Lin, Rachel Abbott, Tracie L. Miner, Craig Pohl, Ginger Fewell, Carrie Haipek, Heather Schmidt, Brian H. Dunford-Shore, Aldi Kraja, Seth D. Crosby, Christopher S. Sawyer, Tammi Vickery, Sacha Sander, Jody Robinson, Wendy Winckler, Jennifer Baldwin, Lucian R. Chirieac, Amit Dutt, Tim Fennell, Megan Hanna, Bruce E. Johnson, Robert C. Onofrio, Roman K. Thomas, Giovanni Tonon, Barbara A. Weir, Xiaojun Zhao, Liuda Ziaugra, Michael C. Zody, Thomas Giordano, Mark B. Orringer, Jack A. Roth, Margaret R. Spitz, Ignacio I. Wistuba, Bradley Ozenberger, Peter J. Good, Andrew C. Chang, David G. Beer, Mark A. Watson, Marc Ladanyi, Stephen Broderick, Akihiko Yoshizawa, William D. Travis, William Pao, Michael A. Province, George M. Weinstock, Harold E. Varmus, Stacey B. Gabriel, Eric S. Lander, Richard A. Gibbs, Matthew Meyerson () and Richard K. Wilson ()
Additional contact information
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
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
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
Amit Dutt: Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, 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
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
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
Xiaojun Zhao: Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, 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,
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
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
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
Richard K. Wilson: The Genome Center at Washington University, Washington University School of Medicine, St Louis, Missouri 63108, USA

Nature, 2008, vol. 455, issue 7216, 1069-1075

Abstract: 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.

Date: 2008
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DOI: 10.1038/nature07423

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