Comprehensive molecular profiling of lung adenocarcinoma

作者：Eric A. Collisson, Barry S. Taylor, Joshua C. Campbell, Angela N. Brooks, Alice H. Berger, Juliann Chmielecki, Getz Gs, Peter S. Hammerman, BRYAN HERNANDEZ, Carrie L. Sougnez, Andrew D. Cherniack, Mara Rosenberg, Matthew Meyerson, Stacey B. Gabriel, Kristian Cibulskis, Jaegil Kim, Chip Stewart, Lichtenstein Lm, Eric S. Lander (7797983), Michael S. Lawrence, Marcin Imielinski, Robert C. Onofrio, Travis Zack, Elena Helman, Chandra Sekhar Pedamallu, Jill P. Mesirov, Gordon Saksena, Steven E. Schumacher, Scott L. Carter, Levi Garraway, Rameen Beroukhim, Juok Cho, Daniel DiCara, David I. Heiman, Pei Lin, William Mallard, Douglas Voet, Hailei Zhang, Lihua Zou, Michael S. Noble, Nils Gehlenborg, Helga Thorvaldsdóttir, Marc-Danie Nazaire, Jim Robinson, W M Lee, Marc Ladanyi, Nikolaus Schultz, Ronglai Shen, William David Travis, B. Arman Aksoy, Giovanni Ciriello, Gideon Dresdner, Jianjiong Gao, Benjamin Gross, Venkatraman 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, D M Trusty, Malcolm V. Brock, Chad J. Creighton, David Wheeler, Li Ding, Ramaswamy Govindan, Cyriac Kandoth, R J Fulton, Lucinda Fulton, Michael D. McLellan, Richard K. Wilson, Kai Ye, Catrina C. Fronick, Christopher A. Maher, Christopher A. Miller, Michael C. Wendl, Christopher R. Cabanski, Elaine Mardis, Watson Ms, Sandra McDonald, Bryan Meyers, Raju Kucherlapati, Angela Hadjipanayis, Eran Hodis, So Lee, Angeliki Pantazi, Xiaojia Ren, Lixing Yang, Peng‐Chieh Chen, Michael Parfenov, Andrew Wei Xu, Netty Santoso, P H Park, D Neil Hayes, Matthew D. Wilkerson, Katherine A. Hoadley, Auman Jt, 孟绍武, 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 H. Salazar, William K. Funkhouser, W. Kimryn Rathmell, John Victor Heymach, John N. Weinstein, Byers Lw, Robert A. Holt, Harshad S. Mahadeshwar, Alexei Protopopov, Sahil Seth, Xingzhi Song, Jiabin Tang, Jianhua Zhang, Lynda Chin, Bradley M. Broom, Yi-Xiang Wang, Yiling Lu, Patrick Kwok Shing Ng, Lixia Diao, Wenbin Liu, Christopher I. Amos, Rehan Akbani, Gordon B. Mills, Richard Hajek, Igor Jurišica, Tsao Ml, David Kwiatkowski, Wg Richards, Gordon Robertson, Andy Chu, Miruna Balasundaram, Yaron S.N. Butterfield, Rebecca Birch Carlsen, Eric Chuah, Noreen Dhalla, Ranabir Guin, C F Hirst, Darlene Lee, Haiyan I. Li, Michael Mayo, Richard A. Moore, Andrew J. 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, Wigle Dt, Michael K. Asiedu, Farhad Kosari, Daniel J. Weisenberger, P O Laird, Dennis T. Maglinte, Philip H. Lai, Moiz Bootwalla, David J. Van Den Berg, Timothy Triche, Amie Radenbaugh, Singer Ma, Joshua M. Stuart, Sam Ng, Jingchun Zhu, David Haussler, J S Liu, Christopher C. Benz, Christina S. F. Yau, Paul T. Spellman, Erin Curley, Joseph Paulauskis, Kevin Lau, Scott Morris, Troy Shelton, David Mallery, Johanna Gardner, Robert Penny, Saller Cf, Katherine Tarvin, Robert Cerfolio, Ayesha Bryant, Daniel P. Raymond, Nathan A. Pennell, C. E. Farver, Christine Czerwinski, Lori Huelsenbeck-Dill, Mary Iacocca, Nicholas Petrelli, Brenda Rabeno, Jennifer Brown, Thomas Bauer, Oleg Dolzhanskiy, Olga Potapova, Д. Л. Ротин, Olga Voronina, Elena Nemirovich-Danchenko, Konstantin Fedosenko, A A 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 A. Williamson, E C Burks, Kimberly Rieger-Christ, Antonia H. Holway, Travis Sullivan, Paul Zippile, James Suh, Harvey Pass, Chandra Goparaju, Yvonne Owusu-Sarpong, John M.S. Bartlett, Sugy Kodeeswaran, Jeremy R. Parfitt, Harmanjatinder Sekhon, Monique Albert, John Eckman, Jerome Myers, Richard Cheney, Carl Morrison, Carmelo Gaudioso, Jeffrey A. Borgia, Philip Bonomi, Mark Pool, Michael J. Liptay, Fedor Moiseenko, Irina Zaytseva, H. Dienemann, Michael Meister, Thomas R Muley, Philipp A. Schnabel, Martin Peifer, Carmen R 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, Srinivasan Dp, A Kahn, Julien Baboud, David Pot, Kenna R. Mills Shaw, Margi Sheth, Tanja Davidsen, John A. Demchok, Liming Yang, Zhining Wang, Roy W. Tarnuzzer, Jean Claude Zenklusen, Bradley A. Ozenberger, Heidi J. Sofia · 发表于：Nature · 年份：2014 · DOI：10.1038/nature13385 · 被引用次数：5976 · 研究领域：Lung Cancer Treatments and Mutations、Cancer Genomics and Diagnostics、RNA modifications and cancer

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 s...