Abstract
Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.
| Original language | English |
|---|---|
| Pages (from-to) | 519-525 |
| Number of pages | 7 |
| Journal | Nature |
| Volume | 489 |
| Issue number | 7417 |
| DOIs | |
| State | Published - Sep 27 2012 |
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In: Nature, Vol. 489, No. 7417, 27.09.2012, p. 519-525.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Comprehensive genomic characterization of squamous cell lung cancers
AU - Hammerman, Peter S.
AU - Voet, Doug
AU - Lawrence, Michael S.
AU - Voet, Douglas
AU - Jing, Rui
AU - Cibulskis, Kristian
AU - Sivachenko, Andrey
AU - Stojanov, Petar
AU - McKenna, Aaron
AU - Lander, Eric S.
AU - Gabriel, Stacey
AU - Getz, Gad
AU - Imielinski, Marcin
AU - Helman, Elena
AU - Hernandez, Bryan
AU - Pho, Nam H.
AU - Meyerson, Matthew
AU - Chu, Andy
AU - Hye-Chun, Jung E.
AU - Mungall, Andrew J.
AU - Pleasance, Erin
AU - Robertson, A. Gordon
AU - Sipahimalani, Payal
AU - Stoll, Dominik
AU - Balasundaram, Miruna
AU - Birol, Inanc
AU - Butterfield, Yaron S.N.
AU - Chuah, Eric
AU - Coope, Robin J.N.
AU - Corbett, Richard
AU - Dhalla, Noreen
AU - Guin, Ranabir
AU - He, An
AU - Hirst, Carrie
AU - Hirst, Martin
AU - Holt, Robert A.
AU - Lee, Darlene
AU - Li, Haiyan I.
AU - Mayo, Michael
AU - Moore, Richard A.
AU - Mungall, Karen
AU - Nip, Ka Ming
AU - Olshen, Adam
AU - Schein, Jacqueline E.
AU - Slobodan, Jared R.
AU - Tam, Angela
AU - Thiessen, Nina
AU - Varhol, Richard
AU - Zeng, Thomas
AU - Zhao, Yongjun
AU - Jones, Steven J.M.
AU - Marra, Marco A.
AU - Saksena, Gordon
AU - Cherniack, Andrew D.
AU - Schumacher, Stephen E.
AU - Tabak, Barbara
AU - Carter, Scott L.
AU - Nguyen, Huy
AU - Onofrio, Robert C.
AU - Crenshaw, Andrew
AU - Ardlie, Kristin
AU - Beroukhim, Rameen
AU - Winckler, Wendy
AU - Protopopov, Alexei
AU - Zhang, Jianhua
AU - Hadjipanayis, Angela
AU - Lee, Semin
AU - Xi, Ruibin
AU - Yang, Lixing
AU - Ren, Xiaojia
AU - Zhang, Hailei
AU - Shukla, Sachet
AU - Chen, Peng Chieh
AU - Haseley, Psalm
AU - Lee, Eunjung
AU - Chin, Lynda
AU - Park, Peter J.
AU - Kucherlapati, Raju
AU - Socci, Nicholas D.
AU - Liang, Yupu
AU - Schultz, Nikolaus
AU - Borsu, Laetitia
AU - Lash, Alex E.
AU - Viale, Agnes
AU - Sander, Chris
AU - Ladanyi, Marc
AU - Auman, J. Todd
AU - Hoadley, Katherine A.
AU - Wilkerson, Matthew D.
AU - Shi, Yan
AU - Liquori, Christina
AU - Meng, Shaowu
AU - Li, Ling
AU - Turman, Yidi J.
AU - Topal, Michael D.
AU - Tan, Donghui
AU - Waring, Scot
AU - Buda, Elizabeth
AU - Walsh, Jesse
AU - Jones, Corbin D.
AU - Mieczkowski, Piotr A.
AU - Singh, Darshan
AU - Wu, Junyuan
AU - Gulabani, Anisha
AU - Dolina, Peter
AU - Bodenheimer, Tom
AU - Hoyle, Alan P.
AU - Simons, Janae V.
AU - Soloway, Matthew G.
AU - Stuart, Joshua
AU - Mose, Lisle E.
AU - Jefferys, Stuart R.
AU - Balu, Saianand
AU - O'Connor, Brian D.
AU - Chiang, Derek
AU - Liu, Jinze
AU - Chiang, Derek Y.
AU - Hayes, D. Neil
AU - Perou, Charles M.
AU - Cope, Leslie
AU - Weisenberger, Daniel
AU - Danilova, Ludmila
AU - Weisenberger, Daniel J.
AU - Maglinte, Dennis T.
AU - Pan, Fei
AU - Van Den Berg, David J.
AU - Triche, Timothy
AU - Herman, James G.
AU - Baylin, Stephen B.
AU - Laird, Peter W.
AU - Noble, Michael
AU - Gehlenborg, Nils
AU - DiCara, Daniel
AU - Zhang, Jinhua
AU - Wu, Chang Jiun
AU - Liu, Spring Yingchun
AU - Zou, Lihua
AU - Lin, Pei
AU - Cho, Juok
AU - Nazaire, Marc Danie
AU - Robinson, Jim
AU - Thorvaldsdottir, Helga
AU - Mesirov, Jill
AU - Sinha, Rileen
AU - Ciriello, Giovanni
AU - Cerami, Ethan
AU - Gross, Benjamin
AU - Jacobsen, Anders
AU - Gao, Jianjiong
AU - Aksoy, B. Arman
AU - Weinhold, Nils
AU - Ramirez, Ricardo
AU - Taylor, Barry S.
AU - Antipin, Yevgeniy
AU - Reva, Boris
AU - Mo, Qianxing
AU - Seshan, Venkatraman
AU - Paik, Paul K.
AU - Akbani, Rehan
AU - Zhang, Nianxiang
AU - Broom, Bradley M.
AU - Casasent, Tod
AU - Unruh, Anna
AU - Wakefield, Chris
AU - Cason, R. Craig
AU - Baggerly, Keith A.
AU - Weinstein, John N.
AU - Haussler, David
AU - Benz, Christopher C.
AU - Stuart, Joshua M.
AU - Zhu, Jingchun
AU - Szeto, Christopher
AU - Scott, Gary K.
AU - Yau, Christina
AU - Ng, Sam
AU - Goldstein, Ted
AU - Waltman, Peter
AU - Sokolov, Artem
AU - Collisson, Eric
AU - Ellrott, Kyle
AU - Collisson, Eric A.
AU - Zerbino, Daniel
AU - Ma, Singer
AU - Craft, Brian
AU - Du, Ying
AU - Cabanski, Christopher
AU - Walter, Vonn
AU - Marron, J. S.
AU - Liu, Yufeng
AU - Wang, Kai
AU - Prins, Jan F.
AU - Creighton, Chad J.
AU - Zhang, Yiqun
AU - Travis, William D.
AU - Rekhtman, Natasha
AU - Yi, Joanne
AU - Aubry, Marie C.
AU - Cheney, Richard
AU - Dacic, Sanja
AU - Flieder, Douglas
AU - Funkhouser, William
AU - Illei, Peter
AU - Myers, Jerome
AU - Tsao, Ming Sound
AU - Penny, Robert
AU - Mallery, David
AU - Shelton, Troy
AU - Hatfield, Martha
AU - Morris, Scott
AU - Yena, Peggy
AU - Shelton, Candace
AU - Sherman, Mark
AU - Paulauskis, Joseph
AU - Govindan, Ramaswamy
AU - Azodo, Ijeoma
AU - Beer, David
AU - Bose, Ron
AU - Byers, Lauren A.
AU - Carbone, David
AU - Chang, Li Wei
AU - Chun, Elizabeth
AU - Ding, Li
AU - Heymach, John
AU - Ida, Cristiane
AU - Johnson, Bruce
AU - Jurisica, Igor
AU - Kaufman, Jacob
AU - Kosari, Farhad
AU - Kwiatkowski, David
AU - Maher, Christopher A.
AU - Pao, William
AU - Peifer, Martin
AU - Robertson, Gordon
AU - Rusch, Valerie
AU - Siegfried, Jill
AU - Sougnez, Carrie
AU - Thomas, Roman K.
AU - Tomaszek, Sandra
AU - Vaske, Charles
AU - Wheeler, David
AU - Wigle, Dennis A.
AU - Wilks, Christopher
AU - Zhang, Jianjua John
AU - Jensen, Mark A.
AU - Sfeir, Robert
AU - Kahn, Ari B.
AU - Chu, Anna L.
AU - Kothiyal, Prachi
AU - Wang, Zhining
AU - Snyder, Eric E.
AU - Pontius, Joan
AU - Pihl, Todd D.
AU - Backus, Mark
AU - Walton, Jessica
AU - Baboud, Julien
AU - Berton, Dominique L.
AU - Nicholls, Matthew C.
AU - Srinivasan, Deepak
AU - Raman, Rohini
AU - Girshik, Stanley
AU - Kigonya, Peter A.
AU - Alonso, Shelley
AU - Sanbhadti, Rashmi N.
AU - Barletta, Sean P.
AU - Greene, John M.
AU - Pot, David A.
AU - Bandarchi-Chamkhaleh, Bizhan
AU - Boyd, Jeff
AU - Weaver, Joellen
AU - Azodo, Ijeoma A.
AU - Tomaszek, Sandra C.
AU - Yang, Ping
AU - Brock, Malcolm V.
AU - Rogers, Kristen
AU - Rutledge, Marian
AU - Brown, Travis
AU - Lee, Beverly
AU - Shin, James
AU - Trusty, Dante
AU - Dhir, Rajiv
AU - Siegfried, Jill M.
AU - Potapova, Olga
AU - Fedosenko, Konstantin V.
AU - Zakowski, Maureen
AU - Nemirovich-Danchenko, Elena
AU - Iacocca, Mary V.
AU - Brown, Jennifer
AU - Rabeno, Brenda
AU - Czerwinski, Christine
AU - Petrelli, Nicholas
AU - Fan, Zhen
AU - Todaro, Nicole
AU - Eckman, John
AU - Rathmell, W. Kimryn
AU - Thorne, Leigh B.
AU - Huang, Mei
AU - Boice, Lori
AU - Hill, Ashley
AU - Curley, Erin
AU - Morrison, Carl
AU - Gaudioso, Carmelo
AU - Bartlett, John M.S.
AU - Kodeeswaran, Sugy
AU - Zanke, Brent
AU - Sekhon, Harman
AU - David, Kerstin
AU - Juhl, Hartmut
AU - Le, Xuan Van
AU - Kohl, Bernard
AU - Thorp, Richard
AU - Tien, Nguyen Viet
AU - Bang, Nguyen Van
AU - Sussman, Howard
AU - Phu, Bui Duc
AU - Hajek, Richard
AU - Hung, Nguyen Phi
AU - Khan, Khurram Z.
AU - Muley, Thomas
AU - Mills Shaw, Kenna R.
AU - Sheth, Margi
AU - Yang, Liming
AU - Demchok, John A.
AU - Davidsen, Tanja
AU - Buetow, Ken
AU - Eley, Greg
AU - Ferguson, Martin
AU - Dillon, Laura A.L.
AU - Schaefer, Carl
AU - Guyer, Mark S.
AU - Ozenberger, Bradley A.
AU - Palchik, Jacqueline D.
AU - Peterson, Jane
AU - Sofia, Heidi J.
AU - Thomson, Elizabeth
AU - Johnson, Bruce E.
AU - Shen, Ronglai
N1 - Funding Information: Acknowledgements This study was supported by NIH grants U24 CA126561, U24 CA126551, U24 CA126554, U24 CA126543, U24 CA126546, 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.
PY - 2012/9/27
Y1 - 2012/9/27
N2 - Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.
AB - Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.
UR - http://www.scopus.com/inward/record.url?scp=84866894408&partnerID=8YFLogxK
U2 - 10.1038/nature11404
DO - 10.1038/nature11404
M3 - Article
C2 - 22960745
AN - SCOPUS:84866894408
SN - 0028-0836
VL - 489
SP - 519
EP - 525
JO - Nature
JF - Nature
IS - 7417
ER -