1. Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
2. Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
3. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
4. Institute of Pathology, University of Ulm, Ulm 89081, Germany
5. Genome Sequencing Center,
6. Division of Statistical Genomics and,
7. Department of Pathology and Immunology, Washington University in Saint Louis, Saint Louis, Missouri 63130, USA
8. University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
9. 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
10. Center for Integrated Oncology and Department I for Internal Medicine, University of Cologne, Cologne 50931, Germany
11. Departments of Medicine, Surgery, Pathology, and Computational Biology,
12. Human Oncology and Pathogenesis Program,
13. Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
14. Section of Thoracic Surgery, Department of Surgery and,
15. Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
16. Department of Pathology and,
17. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
18. Department of Surgery, Nagoya City University Medical School, Nagoya 467-8602, Japan
19. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA
20. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
21. Department of Thoracic and Cardiovascular Surgery,
22. Department of Epidemiology,
23. Department of Pathology and,
24. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
25. University Health Network and Princess Margaret Hospital, Toronto M5G 2C4, Canada
26. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
27. These authors contributed equally to this work.

Correspondence to: Matthew Meyerson^1,2,16 Correspondence and requests for materials should be addressed to M.M. (Email: matthew_meyerson@dfci.harvard.edu).

Abstract

Somatic alterations in cellular DNA underlie almost all human cancers¹. The prospect of targeted therapies² and the development of high-resolution, genome-wide approaches^{3, 4, 5, 6, 7, 8} are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.

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