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Characterizing the Cancer in Lung Adenocarcinoma

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Characterizing the Cancer in Lung Adenocarcinoma doi:10.1038/nature06358 LETTERS Characterizing the cancer genome in lung adenocarcinoma 1,2 1 2 3,4 5 1,2 1,2 Barbara A. Weir *, Michele S. Woo *, Gad Getz *, Sven Perner , Li Ding , Rameen Beroukhim , William M. Lin , 6 6 3 1,2 8 1,2,9,10 Michael A. Province , Aldi Kraja , Laura A. Johnson , Kinjal Shah , Mitsuo Sato , Roman K. Thomas , 3 6 11,12 14 1,2 Justine A. Barletta , Ingrid B. Borecki , Stephen Broderick , Andrew C. Chang , Derek Y. Chiang , 3,16 1 18 8 15 1,2 Lucian R. Chirieac , Jeonghee Cho , Yoshitaka Fujii , Adi F. Gazdar , Thomas Giordano , Heidi Greulich , 1,2 1 11 11 5 3,16 5 Megan Hanna , Bruce E. Johnson , Mark G. Kris , Alex Lash , Ling Lin , Neal Lindeman , Elaine R. Mardis , 19 8 19 1,2 14 5 John D. McPherson , John D. Minna , Margaret B. Morgan , Mark Nadel , Mark B. Orringer , John R. Osborne , 20 1,2 2 21 11 18 Brad Ozenberger , Alex H. Ramos , James Robinson , Jack A. Roth , Valerie Rusch , Hidefumi Sasaki , 25 2 22 25 2 Frances Shepherd , Carrie Sougnez , Margaret R. Spitz , Ming-Sound Tsao , David Twomey , 2 19 19 1,2 11 Roel G. W. Verhaak , George M. Weinstock , David A. Wheeler , Wendy Winckler , Akihiko Yoshizawa , 1 11 6 14 23,24 7 Soyoung Yu , Maureen F. Zakowski , Qunyuan Zhang , David G. Beer , Ignacio I. Wistuba , Mark A. Watson , 1,2 11,12 11 11,12 2,3 2 Levi A. Garraway , Marc Ladanyi , William D. Travis , William Pao , Mark A. Rubin , Stacey B. Gabriel , Richard A. Gibbs19, Harold E. Varmus13, Richard K. Wilson5, Eric S. Lander2,17,26 & Matthew Meyerson1,2,16 Somatic alterations in cellular DNA underlie almost all human DNAs were hybridized to Affymetrix 250K Sty single nucleotide cancers1. The prospect of targeted therapies2 and the development polymorphism (SNP) arrays. Genomic copy number for each of over of high-resolution, genome-wide approaches3–8 are now spurring 238,000 probe sets was determined by calculating the intensity ratio systematic efforts to characterize cancer genomes. Here we report between the tumour DNA and the average of a set of normal a large-scale project to characterize copy-number alterations in DNAs9,10. Segmented copy numbers for each tumour were inferred primary lung adenocarcinomas. By analysis of a large collection with the GLAD (gain and loss analysis of DNA) algorithm11 and of tumours (n 5 371) using dense single nucleotide polymorphism normalized to a median of two copies. Each copy number profile arrays, we identify a total of 57 significantly recurrent events. We was then subjected to quality control, resulting in 371 high-quality find that 26 of 39 autosomal chromosome arms show consistent samples used for further analysis, of which 242 had matched normal large-scale copy-number gain or loss, of which only a handful have samples (Methods). been linked to a specific gene. We also identify 31 recurrent focal To identify regions of copy-number alteration, we applied GISTIC events, including 24 amplifications and 7 homozygous deletions. (genomic identification of significant targets in cancer)12, a statistical Only six of these focal events are currently associated with known method that calculates a score that is based on both the amplitude and mutations in lung carcinomas. The most common event, amp­ frequency of copy-number changes at each position in the genome, lification of chromosome 14q13.3, is found in 12% of samples. using permutation testing to determine significance (Methods). On the basis of genomic and functional analyses, we identify GISTIC identified 26 large-scale events and 31 focal events, NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the reported below. Although the overall pattern is broadly consistent minimal 14q13.3 amplification interval and encodes a lineage- with the literature on lung cancer8,13–15, our sample size and resolu­ specific transcription factor, as a novel candidate proto-oncogene tion provide more power to accurately identify and localize both involved in a significant fraction of lung adenocarcinomas. More large-scale and focal chromosomal alterations. With respect to generally, our results indicate that many of the genes that are large-scale events, no single previous study has identified more than involved in lung adenocarcinoma remain to be discovered. 5 of the gains or 11 of the losses13,14 (Supplementary Table 2). With A collection of 528 snap-frozen lung adenocarcinoma resection respect to focal events, three recent studies8,14,15 report a total of ,200 specimens, with at least 70% estimated tumour content, was selected events, including 23 of the 31 recurrent focal events observed in our by a panel of thoracic pathologists (Supplementary Table 1); samples study. The overlap among these three studies is limited to only four were anonymized to protect patient privacy. Tumour and normal events (amplification of EGFR, CCNE1, MDM2 and 8p11, all seen 1Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. 2Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. 3Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA. 4Institute of Pathology, University of Ulm, Ulm 89081, Germany. 5Genome Sequencing Center, 6Division of Statistical Genomics and 7Department of Pathology and Immunology, Washington University in Saint Louis, Saint Louis, Missouri 63130, USA. 8University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. 9Max Planck Institute for Neurological Research with Klaus-Joachim-Zu¨lch Laboratories of the Max-Planck Society and the Medical Faculty of the University of Cologne, Cologne 50931, Germany. 10Center for Integrated Oncology and Department I for Internal Medicine, University of Cologne, Cologne 50931, Germany. 11Departments of Medicine, Surgery, Pathology, and Computational Biology, 12Human Oncology and Pathogenesis Program, 13Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. 14Section of Thoracic Surgery, Department of Surgery and 15Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA. 16Department of Pathology and 17Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. 18Department of Surgery, Nagoya City University Medical School, Nagoya 467-8602, Japan. 19Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. 20National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. 21Department of Thoracic and Cardiovascular Surgery, 22Department of Epidemiology, 23Department of Pathology and 24Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. 25University Health Network and Princess Margaret Hospital, Toronto M5G 2C4, Canada. 26Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. *These authors contributed equally to this work. 1 ©2007 Nature Publishing Group LETTERS NATURE here; Supplementary Table 3 and Supplementary Results). A gen­ partitioned into tertiles on the basis of overall variation in copy- ome-wide view of segmented copy number reveals that most number amplitude, each shows similar regions of amplification chromosomal arms undergo either amplification or deletion across and loss across the genome. The attenuation seen in many samples a large proportion of the samples (Fig. 1a). The distinctive pattern of is consistent with admixture with euploid non-tumour DNA, which amplification and loss is also apparent when the median copy num­ we estimate at 50%, 65% and 78% respectively in the three tertiles ber for each chromosome arm is plotted (Supplementary Fig. 1 and (Supplementary Results and Supplementary Fig. 2). The significant Supplementary Table 4). In total, GISTIC identifies 26 large segments non-tumour admixture in these tumour samples also makes it (at least half of a chromosome arm), 10 with significant gains and 16 difficult to assess genome-wide loss of heterozygosity (LOH). with significant losses (Fig. 1b and Supplementary Table 5). Because normal DNA admixture limits sensitivity, we report LOH Visual inspection reveals that similar chromosomal patterns of only in the top tertile; we see both LOH associated with copy-number copy number loss and gain across the genome are found in almost loss and copy-neutral LOH (chromosomes 17p and 19p) (Supple­ all samples, but that the samples show substantial differences in the mentary Results, Supplementary Figs 3 and 4, and Supplementary amplitude of copy-number variation (Fig. 1a). When the samples are Table 6). a b Large-scale q value Large-scale deletions amplifications Top tertile Middle tertile Bottom tertile –40 –20 –20 –40 –60 (>50% of arm) 10 10 0.25 0.25 10 10 10 (>50% of arm) Chr 1q 1 3p 5p 2 5q 6p 6q 7p 3 7q 8p 9p 8q 4 9q 10q 5 12p 13q 15q 6 16p 17p 17q 7 18q 19p 19q 20p 8 20q 21q 0.13 0.09 0.05 0.05 0.11 0.15 0.19 22q Score 9 c Focal q value Focal 10 deletions Chr 10–10 10–6 10–2 0.25 0.25 10–5 10–10 10–15 amplifications 1 1q21.2 11 2p15 2 12 3 3q26.2 4 5p15.33 13 5p15.31 5q11.2 5 5p14.3 14 6p21.33 6 6p21.1 15 7p11.2 7q11.22 7 7q21.2 16 8 8p11.23 9p23 8q21.13 17 8q24.21 9p21.3 9 18 10q23.31 10 11q13.3 19 11 20 12p12.1 12 21 12q14.1 22 13q14.2 13 12q15 14 14q13.3 15 16 17q12 Deletion Neutral Amplification 17 18q11.2 18q23 18 19q12 19 19q13.12 20 20q13.32 21 0.03 0.02 0.006 0.009 0.02 0.03 0.04 0.05 22q11.21 22 Score Figure 1 | Large-scale genomic events in lung adenocarcinoma.
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