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.
| Original language | English |
|---|---|
| Pages (from-to) | 543-550 |
| Number of pages | 8 |
| Journal | Nature |
| Volume | 511 |
| Issue number | 7511 |
| DOIs | |
| State | Published - 2014 |
| Externally published | Yes |
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In: Nature, Vol. 511, No. 7511, 2014, p. 543-550.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Comprehensive molecular profiling of lung adenocarcinoma
T2 - The cancer genome atlas research network
AU - Collisson, Eric A.
AU - Campbell, Joshua D.
AU - Brooks, Angela N.
AU - Berger, Alice H.
AU - Lee, William
AU - Chmielecki, Juliann
AU - Beer, David G.
AU - Cope, Leslie
AU - Creighton, Chad J.
AU - Danilova, Ludmila
AU - Ding, Li
AU - Getz, Gad
AU - Hammerman, Peter S.
AU - Hayes, D. Neil
AU - Hernandez, Bryan
AU - Herman, James G.
AU - Heymach, John V.
AU - Jurisica, Igor
AU - Kucherlapati, Raju
AU - Kwiatkowski, David
AU - Ladanyi, Marc
AU - Robertson, Gordon
AU - Schultz, Nikolaus
AU - Shen, Ronglai
AU - Sinha, Rileen
AU - Sougnez, Carrie
AU - Tsao, Ming Sound
AU - Travis, William D.
AU - Weinstein, John N.
AU - Wigle, Dennis A.
AU - Wilkerson, Matthew D.
AU - Chu, Andy
AU - Cherniack, Andrew D.
AU - Hadjipanayis, Angela
AU - Rosenberg, Mara
AU - Weisenberger, Daniel J.
AU - Laird, Peter W.
AU - Radenbaugh, Amie
AU - Ma, Singer
AU - Stuart, Joshua M.
AU - Byers, Lauren Averett
AU - Baylin, Stephen B.
AU - Govindan, Ramaswamy
AU - Meyerson, Matthew
AU - Gabriel, Stacey B.
AU - Cibulskis, Kristian
AU - Kim, Jaegil
AU - Stewart, Chip
AU - Lichtenstein, Lee
AU - Lander, Eric S.
AU - Lawrence, Michael S.
AU - Getz, E.
AU - Fulton, Robert
AU - Fulton, Lucinda L.
AU - McLellan, Michael D.
AU - Wilson, Richard K.
AU - Ye, Kai
AU - Fronick, Catrina C.
AU - Maher, Christopher A.
AU - Miller, Christopher A.
AU - Wendl, Michael C.
AU - Cabanski, Christopher
AU - Mardis, Elaine
AU - Wheeler, David
AU - Balasundaram, Miruna
AU - Butterfield, Yaron S.N.
AU - Carlsen, Rebecca
AU - Chuah, Eric
AU - Dhalla, Noreen
AU - Guin, Ranabir
AU - Hirst, Carrie
AU - Lee, Darlene
AU - Li, Haiyan I.
AU - Mayo, Michael
AU - Moore, Richard A.
AU - Mungall, Andrew J.
AU - Schein, Jacqueline E.
AU - Sipahimalani, Payal
AU - Tam, Angela
AU - Varhol, Richard
AU - Robertson, A. Gordon
AU - Wye, Natasja
AU - Thiessen, Nina
AU - Holt, Robert A.
AU - Jones, Steven J.M.
AU - Marra, Marco A.
AU - Imielinski, Marcin
AU - Onofrio, Robert C.
AU - Hodis, Eran
AU - Zack, Travis
AU - Helman, Elena
AU - Pedamallu, Chandra Sekhar
AU - Mesirov, Jill
AU - Saksena, Gordon
AU - Schumacher, Steven E.
AU - Carter, Scott L.
AU - Garraway, Levi
AU - Beroukhim, Rameen
AU - Lee, Semin
AU - Mahadeshwar, Harshad S.
AU - Pantazi, Angeliki
AU - Protopopov, Alexei
AU - Ren, Xiaojia
AU - Seth, Sahil
AU - Song, Xingzhi
AU - Tang, Jiabin
AU - Yang, Lixing
AU - Zhang, Jianhua
AU - Chen, Peng Chieh
AU - Parfenov, Michael
AU - Xu, Andrew Wei
AU - Santoso, Netty
AU - Chin, Lynda
AU - Park, Peter J.
AU - Hoadley, Katherine A.
AU - Auman, J. Todd
AU - Meng, Shaowu
AU - Shi, Yan
AU - Buda, Elizabeth
AU - Waring, Scot
AU - Veluvolu, Umadevi
AU - Tan, Donghui
AU - Mieczkowski, Piotr A.
AU - Jones, Corbin D.
AU - Simons, Janae V.
AU - Soloway, Matthew G.
AU - Bodenheimer, Tom
AU - Jefferys, Stuart R.
AU - Roach, Jeffrey
AU - Hoyle, Alan P.
AU - Wu, Junyuan
AU - Balu, Saianand
AU - Singh, Darshan
AU - Prins, Jan F.
AU - Marron, J. S.
AU - Parker, Joel S.
AU - Perou, Charles M.
AU - Liu, Jinze
AU - Maglinte, Dennis T.
AU - Lai, Philip H.
AU - Bootwalla, Moiz S.
AU - Van Den Berg, David J.
AU - Triche, Timothy
AU - Cho, Juok
AU - DiCara, Daniel
AU - Heiman, David
AU - Lin, Pei
AU - Mallard, William
AU - Voet, Douglas
AU - Zhang, Hailei
AU - Zou, Lihua
AU - Noble, Michael S.
AU - Gehlenborg, Nils
AU - Thorvaldsdottir, Helga
AU - Nazaire, Marc Danie
AU - Robinson, Jim
AU - Aksoy, B. Arman
AU - Ciriello, Giovanni
AU - Taylor, Barry S.
AU - Dresdner, Gideon
AU - Gao, Jianjiong
AU - Gross, Benjamin
AU - Seshan, Venkatraman E.
AU - Reva, Boris
AU - Sumer, S. Onur
AU - Weinhold, Nils
AU - Sander, Chris
AU - Ng, Sam
AU - Zhu, Jingchun
AU - Benz, Christopher C.
AU - Yau, Christina
AU - Haussler, David
AU - Spellman, Paul T.
AU - Kimes, Patrick K.
AU - Broom, Bradley M.
AU - Wang, Jing
AU - Lu, Yiling
AU - Ng, Patrick Kwok Shing
AU - Diao, Lixia
AU - Liu, Wenbin
AU - Amos, Christopher I.
AU - Akbani, Rehan
AU - Mills, Gordon B.
AU - Curley, Erin
AU - Paulauskis, Joseph
AU - Lau, Kevin
AU - Morris, Scott
AU - Shelton, Troy
AU - Mallery, David
AU - Gardner, Johanna
AU - Penny, Robert
AU - Saller, Charles
AU - Tarvin, Katherine
AU - Richards, William G.
AU - Cerfolio, Robert
AU - Bryant, Ayesha
AU - Raymond, Daniel P.
AU - Pennell, Nathan A.
AU - Farver, Carol
AU - Czerwinski, Christine
AU - Huelsenbeck-Dill, Lori
AU - Iacocca, Mary
AU - Petrelli, Nicholas
AU - Rabeno, Brenda
AU - Brown, Jennifer
AU - Bauer, Thomas
AU - Dolzhanskiy, Cureline Oleg
AU - Potapova, Olga
AU - Rotin, Daniil
AU - Voronina, Olga
AU - Nemirovich-Danchenko, Elena
AU - Fedosenko, Konstantin V.
AU - Gal, Anthony
AU - Behera, Madhusmita
AU - Ramalingam, Suresh S.
AU - Sica, Gabriel
AU - Flieder, Douglas
AU - Boyd, Jeff
AU - Weaver, Jo Ellen
AU - Kohl, Bernard
AU - Thinh, Dang Huy Quoc
AU - Sandusky, George
AU - Juhl, Hartmut
AU - Duhig, Edwina
AU - Illei, Peter
AU - Gabrielson, Edward
AU - Shin, James
AU - Lee, Beverly
AU - Rogers, Kristen
AU - Trusty, Dante
AU - Brock, Malcolm V.
AU - Williamson, Christina
AU - Burks, Eric
AU - Rieger-Christ, Kimberly
AU - Holway, Antonia
AU - Sullivan, Travis
AU - Asiedu, Michael K.
AU - Kosari, Farhad
AU - Rekhtman, Natasha
AU - Zakowski, Maureen
AU - Rusch, Valerie W.
AU - Zippile, Paul
AU - Suh, James
AU - Pass, Harvey
AU - Goparaju, Chandra
AU - Owusu-Sarpong, Yvonne
AU - Bartlett, John M.S.
AU - Kodeeswaran, Sugy
AU - Parfitt, Jeremy
AU - Sekhon, Harmanjatinder
AU - Albert, Monique
AU - Eckman, John
AU - Myers, Jerome B.
AU - Morrison, Carl
AU - Gaudioso, Carmelo
AU - Borgia, Jeffrey A.
AU - Bonomi, Philip
AU - Pool, Mark
AU - Liptay, Michael J.
AU - Moiseenko, Fedor
AU - Zaytseva, Irina
AU - Dienemann, Hendrik
AU - Meister, Michael
AU - Schnabel, Philipp A.
AU - Muley, Thomas R.
AU - Peifer, Martin
AU - Gomez-Fernandez, Carmen
AU - Herbert, Lynn
AU - Egea, Sophie
AU - Huang, Mei
AU - Thorne, Leigh B.
AU - Boice, Lori
AU - Salazar, Ashley Hill
AU - Funkhouser, William K.
AU - Rathmell, W. Kimryn
AU - Dhir, Rajiv
AU - Yousem, Samuel A.
AU - Dacic, Sanja
AU - Schneider, Frank
AU - Siegfried, Jill M.
AU - Hajek, Richard
AU - Watson, Mark A.
AU - McDonald, Sandra
AU - Meyers, Bryan
AU - Clarke, Belinda
AU - Yang, Ian A.
AU - Fong, Kwun M.
AU - Hunter, Lindy
AU - Windsor, Morgan
AU - Bowman, Rayleen V.
AU - Peters, Solange
AU - Letovanec, Igor
AU - Khan, Khurram Z.
AU - Jensen, Mark A.
AU - Snyder, Eric E.
AU - Srinivasan, Deepak
AU - Kahn, Ari B.
AU - Baboud, Julien
AU - Pot, David A.
AU - Shaw, Kenna R.Mills
AU - Sheth, Margi
AU - Davidsen, Tanja
AU - Demchok, John A.
AU - Yang, Liming
AU - Wang, Zhining
AU - Tarnuzzer, Roy
AU - Zenklusen, Jean Claude
AU - Ozenberger, Bradley A.
AU - Sofia, Heidi J.
AU - Cheney, Richard
N1 - Funding Information: Acknowledgements This study was supported by NIH grants: U24 CA126561, U24 CA126551, U24 CA126554, U24 CA126543, U24 CA126546, U24 CA137153, U24 CA126563, U24 CA126544, U24 CA143845, U24 CA143858, U24 CA144025, U24 CA143882, U24 CA143866, U24 CA143867, U24 CA143848, U24 CA143840, U24 CA143835, U24 CA143799, U24 CA143883, U24 CA143843, U54 HG003067, U54 HG003079 and U54 HG003273. We thank K. Guebert and L. Gaffney for assistance and C. Gunter for review.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84905029258&partnerID=8YFLogxK
U2 - 10.1038/nature13385
DO - 10.1038/nature13385
M3 - Article
C2 - 25079552
AN - SCOPUS:84905029258
SN - 0028-0836
VL - 511
SP - 543
EP - 550
JO - Nature
JF - Nature
IS - 7511
ER -