Year: 2014
Type: article
Study design: Observational Study
Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis. An integrated transcriptome, genome, methylome and proteome analysis of over 200 lung adenocarcinomas reveals high rates of somatic mutations, 18 statistically significantly mutated genes including RIT1 and MGA, splicing changes, and alterations in MAPK and PI(3)K pathway activity. This report from The Cancer Genome Atlas Research Network presents molecular profiling of 230 resected untreated lung adenocarcinomas. Integrated analyses of transcriptome, genome, methylome and proteome collectively identify high rates of somatic mutation, significantly mutated genes including RIT1 and MGA, splicing alterations driven by somatic genomic changes, and point to as yet unidentified lesions that alter MAPK and PI(3)K pathway activity. These data establish a foundation for classification and further investigations of the leading cause of cancer death worldwide.
Source: Nature
DOI: 10.1038/nature13385
Authors: Eric A. Collisson, Barry S. Taylor, Joshua D. Campbell, Angela N. Brooks, Alice H. Berger, Juliann Chmielecki, Gad Getz, Peter S. Hammerman, Bryan Hernandez, Carrie Sougnez, Andrew D. Cherniack, Mara Rosenberg, Matthew Meyerson, Stacey B. Gabriel, Kristian Cibulskis, Jaegil Kim, Chip Stewart, Lee Lichtenstein, Eric S. Lander, Michael S. Lawrence, Marcin Imielinski, Robert C. Onofrio, Travis Zack, Elena Helman, Chandra Sekhar Pedamallu, Jill Mesirov, Gordon Saksena, Steven E. Schumacher, Scott L. Carter, Levi Garraway, Rameen Beroukhim, Juok Cho, Daniel DiCara, David Heiman, Pei Lin, William Mallard, Douglas Voet, Hailei Zhang, Lihua Zou, Michael S. Noble, Nils Gehlenborg, Helga Thorvaldsdottir, Marc-Danie Nazaire, Jim Robinson, William Lee, Marc Ladanyi, Nikolaus Schultz, Ronglai Shen, William D. Travis, B. Arman Aksoy, Giovanni Ciriello, Gideon Dresdner, Jianjiong Gao, Benjamin Gross, Venkatraman E. Seshan, Boris Reva, Rileen Sinha, S. Onur Sumer, Nils Weinhold, Chris Sander, Natasha Rekhtman, Maureen Zakowski, Valerie W. Rusch, David G. Beer, Leslie Cope, Ludmila Danilova, James G. Herman, Stephen B. Baylin, Peter Illei, Edward Gabrielson, James Shin, Beverly Lee, Kristen Rodgers, Dante Trusty, Malcolm V. Brock, Chad J. Creighton, David Wheeler, Li Ding, Ramaswamy Govindan, Cyriac Kandoth, Robert Fulton, Lucinda L. Fulton, Michael D. McLellan, Richard K. Wilson, Kai Ye, Catrina C. Fronick, Christopher A. Maher, Christopher A. Miller, Michael C. Wendl, Christopher Cabanski, Elaine Mardis, Mark A. Watson, Sandra McDonald, Bryan Meyers, Raju Kucherlapati, Angela Hadjipanayis, Eran Hodis, Semin Lee, Angeliki Pantazi, Xiaojia Ren, Lixing Yang, Peng-Chieh Chen, Michael Parfenov, Andrew Wei Xu, Netty Santoso, Peter J. Park, D. Neil Hayes, Matthew D. Wilkerson, Katherine A. Hoadley, J. Todd Auman, Shaowu Meng, Yan Shi, Elizabeth Buda, Scot Waring, Umadevi Veluvolu, Donghui Tan, Piotr A. Mieczkowski, Corbin D. Jones, Janae V. Simons, Matthew G. Soloway, Tom Bodenheimer, Stuart R. Jefferys, Jeffrey Roach, Alan P. Hoyle, Junyuan Wu, Saianand Balu, Darshan Singh, Jan F. Prins, J.S. Marron, Joel S. Parker, Charles M. Perou, Patrick K. Kimes, Mei Huang, Leigh B. Thorne, Lori Boice, Ashley Hill Salazar, William K. Funkhouser, W. Kimryn Rathmell, John V. Heymach, John N. Weinstein, Lauren Averett Byers, Robert A. Holt, Harshad S. Mahadeshwar, Alexei Protopopov, Sahil Seth, Xingzhi Song, Jiabin Tang, Jianhua Zhang, Lynda Chin, Bradley M. Broom, Jing Wang, Yiling Lu, Patrick Kwok Shing Ng, Lixia Diao, Wenbin Liu, Christopher I. Amos, Rehan Akbani, Gordon B. Mills, Richard Hajek, Igor Jurisica, Ming-Sound Tsao, David Kwiatkowski, William G. Richards, Gordon Robertson, Andy Chu, Miruna Balasundaram, Yaron S. N. Butterfield, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Ranabir Guin, Carrie Hirst, Darlene Lee, Haiyan I. Li, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Richard Varhol, A. Gordon Robertson, Natasja Wye, Nina Thiessen, Steven J. M. Jones, Marco A. Marra, Dennis A. Wigle, Michael K. Asiedu, Farhad Kosari, Daniel J. Weisenberger, Peter W. Laird, Dennis T. Maglinte, Philip H. Lai, Moiz S. Bootwalla, David J. Van Den Berg, Timothy Triche Jr, Amie Radenbaugh, Singer Ma, Joshua M. Stuart, Sam Ng, Jingchun Zhu, David Haussler, Jinze Liu, Christopher C. Benz, Christina Yau, Paul T. Spellman, Erin Curley, Joseph Paulauskis, Kevin Lau, Scott Morris, Troy Shelton, David Mallery, Johanna Gardner, Robert Penny, Charles Saller, Katherine Tarvin, Robert Cerfolio, Ayesha Bryant, Daniel P. Raymond, Nathan A. Pennell, Carol Farver, Christine Czerwinski, Lori Huelsenbeck-Dill, Mary Iacocca, Nicholas Petrelli, Brenda Rabeno, Jennifer Brown, Thomas Bauer, Oleg Dolzhanskiy, Olga Potapova, Daniil Rotin, Olga Voronina, Elena Nemirovich-Danchenko, Konstantin V. Fedosenko, Anthony Gal, Madhusmita Behera, Suresh S. Ramalingam, Gabriel Sica, Douglas Flieder, Jeff Boyd, JoEllen Weaver, Bernard Kohl, Dang Huy Quoc Thinh, George Sandusky, Hartmut Juhl, Edwina Duhig, Belinda Clarke, Ian A. Yang, Kwun M. Fong, Lindy Hunter, Morgan Windsor, Rayleen V. Bowman, Christina Williamson, Eric Burks, Kimberly Rieger-Christ, Antonia Holway, Travis Sullivan, Paul Zippile, James Suh, Harvey Pass, Chandra Goparaju, Yvonne Owusu-Sarpong, John M. S. Bartlett, Sugy Kodeeswaran, Jeremy Parfitt, Harmanjatinder Sekhon, Monique Albert, John Eckman, Jerome B. Myers, Richard Cheney, Carl Morrison, Carmelo Gaudioso, Jeffrey A. Borgia, Philip Bonomi, Mark Pool, Michael J. Liptay, Fedor Moiseenko, Irina Zaytseva, Hendrik Dienemann, Michael Meister, Thomas R. Muley, Philipp A. Schnabel, Martin Peifer, Carmen Gomez-Fernandez, Lynn Herbert, Sophie Egea, Rajiv Dhir, Samuel A. Yousem, Sanja Dacic, Frank Schneider, Jill M. Siegfried, Solange Peters, Igor Letovanec, Khurram Z. Khan, Mark A. Jensen, Eric E. Snyder, Deepak Srinivasan, Ari B. Kahn, Julien Baboud, David A. Pot, Kenna R. Mills Shaw, Margi Sheth, Tanja Davidsen, John A. Demchok, Liming Yang, Zhining Wang, Roy Tarnuzzer, Jean Claude Zenklusen, Bradley A. Ozenberger, Heidi J. Sofia
Institutions: University of California, San Francisco, Broad Institute, Dana-Farber Cancer Institute, Harvard University, Massachusetts General Hospital, Massachusetts Institute of Technology, Memorial Sloan Kettering Cancer Center, The University of Texas MD Anderson Cancer Center, University of Michigan, Johns Hopkins University, Baylor College of Medicine, Washington University in St. Louis, Brigham and Women's Hospital, National Institutes of Health, National Cancer Institute, University of North Carolina at Chapel Hill, Princess Margaret Cancer Centre, BC Cancer Agency, Mayo Clinic, University of Southern California, University of California, Santa Cruz, Howard Hughes Medical Institute, University of Kentucky, Buck Institute for Research on Aging, Oregon Health & Science University, International Genomics Consortium, Analytical Biological Services (United States), University of Alabama at Birmingham, Cleveland Clinic, Emory University, Fox Chase Cancer Center, Indiana University School of Medicine, The University of Queensland, Prince Charles Hospital, Sullivan Nicolaides Pathology, Lahey Hospital and Medical Center, NYU Langone Health, Ontario Institute for Cancer Research, Penrose-St. Francis Health Services, Roswell Park Comprehensive Cancer Center, Rush University Medical Center, Saint Petersburg Academic University, University Hospital Heidelberg, Heidelberg University, University of Cologne, University of Miami, Sylvester Comprehensive Cancer Center, University of Pittsburgh, Centre Hospitalier Universitaire Vaudois, Ziauddin Hospital, Ziauddin University, SRA International (United States), National Human Genome Research Institute
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Awards: Large Scale Sequencing and Analysis of Genomes, Cancer Genomics Center, The USC-JHU Cancer Epigenome Characterization Center, A Platform for Large-Scale Genomic Discovery, The BCM Tumor Genome Characterization Center, MSKCC Center for Translational Cancer Genomic Analysis, Medical Scientist Training Program, Center for Cancer Genome Characterization, UCSC-Buck Inst. Genome Data Analysis Center for TCGA Research Network (GDAC), A Model for Preclinical Biomarker Discovery in Pancreatic Ductal Adenocarcinoma, The TCGA Cancer Genome Characterization Center at MSKCC, The Human Genome Sequencing Center, Harvard Genome Characterization Center, HudsonAlpha Cancer Genome Characterization Center, Cancer transcriptome characterization using massively parallel DNA sequencing, University of Pittsburgh Clinical and Translational Science Institute, Integrative Pipeline for Analysis & Translational Application of TCGA Data (GDAC), G5763114161, The Cancer Genome Atlas Data Analysis Center, Cancer Genome Characterization using Gene Expression and DNA Copy Number Analysis, Unlocking transcript diversity via differential analyses of splice graphs, Cloud Based Resource for Data Hosting, Visualization and Analysis Using UCSC Canc, Genome Characterization Center (GCC), Gene Expression Patterns in Human Tumors Identified Using Transcript Sequencing, TCGA Data Analysis Center at Berkeley, The Berkeley Cancer Genome Center, Center for Systems Analysis of the Cancer Regulome, Cancer Genome Characterization Center at Johns Hopkins, University of Kentucky Markey Cancer Center – Cancer Center Support Grant, Cancer Center Support Grant, Cancer Center Support Grant, Regional Oncology Research Center
OpenAlex ID: W2180481128