1. The Genome Center at Washington University, Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA
2. Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
3. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA
4. Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
5. Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA
6. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
7. Department of Pathology and Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
8. 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, Cologne 50931, Germany
9. Center for Integrated Oncology and Department I for Internal Medicine, University of Cologne, Cologne 50931, Germany
10. Department of Pathology,
11. Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA
12. Department of Thoracic and Cardiovascular Surgery,
13. Department of Epidemiology, and,
14. Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
15. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
16. Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri 63108, USA
17. Departments of Medicine, Surgery, Pathology, and Computational Biology
18. Human Oncology and Pathogenesis Program, and
19. Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
20. These authors contributed equally to this work.

Correspondence to: Matthew Meyerson^2,4Richard K. Wilson¹ Correspondence and requests for materials should be addressed to R.K.W. (Email: rwilson@wustl.edu) or M.M. (Email: matthew_meyerson@dfci.harvard.edu).

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.

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