Abstract
Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 1061-1068 |
| Number of pages | 8 |
| Journal | Nature |
| Volume | 455 |
| Issue number | 7216 |
| DOIs | |
| State | Published - Oct 23 2008 |
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Comprehensive genomic characterization defines human glioblastoma genes and core pathways. / McLendon, Roger; Friedman, Allan; Bigner, Darrell; Van Meir, Erwin G.; Brat, Daniel J.; Mastrogianakis, Gena M.; Olson, Jeffrey J.; Mikkelsen, Tom; Lehman, Norman; Aldape, Ken; Yung, W. K.Alfred; Bogler, Oliver; Weinstein, John N.; VandenBerg, Scott; Berger, Mitchel; Prados, Michael; Muzny, Donna; Morgan, Margaret; Scherer, Steve; Sabo, Aniko; Nazareth, Lynn; Lewis, Lora; Hall, Otis; Zhu, Yiming; Ren, Yanru; Alvi, Omar; Yao, Jiqiang; Hawes, Alicia; Jhangiani, Shalini; Fowler, Gerald; San Lucas, Anthony; Kovar, Christie; Cree, Andrew; Dinh, Huyen; Santibanez, Jireh; Joshi, Vandita; Gonzalez-Garay, Manuel L.; Miller, Christopher A.; Milosavljevic, Aleksandar; Donehower, Larry; Wheeler, David A.; Gibbs, Richard A.; Cibulskis, Kristian; Sougnez, Carrie; Fennell, Tim; Mahan, Scott; Wilkinson, Jane; Ziaugra, Liuda; Onofrio, Robert; Bloom, Toby; Nicol, Rob; Ardlie, Kristin; Baldwin, Jennifer; Gabriel, Stacey; Lander, Eric S.; Ding, Li; Fulton, Robert S.; McLellan, Michael D.; Wallis, John; Larson, David E.; Shi, Xiaoqi; Abbott, Rachel; Fulton, Lucinda; Chen, Ken; Koboldt, Daniel C.; Wendl, Michael C.; Meyer, Rick; Tang, Yuzhu; Lin, Ling; Osborne, John R.; Dunford-Shore, Brian H.; Miner, Tracie L.; Delehaunty, Kim; Markovic, Chris; Swift, Gary; Courtney, William; Pohl, Craig; Abbott, Scott; Hawkins, Amy; Leong, Shin; Haipek, Carrie; Schmidt, Heather; Wiechert, Maddy; Vickery, Tammi; Scott, Sacha; Dooling, David J.; Chinwalla, Asif; Weinstock, George M.; Mardis, Elaine R.; Wilson, Richard K.; Getz, Gad; Winckler, Wendy; Verhaak, Roel G.W.; Lawrence, Michael S.; O'Kelly, Michael; Robinson, Jim; Alexe, Gabriele; Beroukhim, Rameen; Carter, Scott; Chiang, Derek; Gould, Josh; Gupta, Supriya; Korn, Josh; Mermel, Craig; Mesirov, Jill; Monti, Stefano; Nguyen, Huy; Parkin, Melissa; Reich, Michael; Stransky, Nicolas; Weir, Barbara A.; Garraway, Levi; Golub, Todd; Meyerson, Matthew; Chin, Lynda; Protopopov, Alexei; Zhang, Jianhua; Perna, Ilana; Aronson, Sandy; Sathiamoorthy, Narayanan; Ren, Georgia; Yao, Jun; Wiedemeyer, W. Ruprecht; Kim, Hyunsoo; Sek, Won Kong; Xiao, Yonghong; Kohane, Isaac S.; Seidman, Jon; Park, Peter J.; Kucherlapati, Raju; Laird, Peter W.; Cope, Leslie; Herman, James G.; Weisenberger, Daniel J.; Pan, Fei; Van Den Berg, David; Van Neste, Leander; Joo, Mi Yi; Schuebel, Kornel E.; Baylin, Stephen B.; Absher, Devin M.; Li, Jun Z.; Southwick, Audrey; Brady, Shannon; Aggarwal, Amita; Chung, Tisha; Sherlock, Gavin; Brooks, James D.; Myers, Richard M.; Spellman, Paul T.; Purdom, Elizabeth; Jakkula, Lakshmi R.; Lapuk, Anna V.; Marr, Henry; Dorton, Shannon; Yoon, Gi Choi; Han, Ju; Ray, Amrita; Wang, Victoria; Durinck, Steffen; Robinson, Mark; Wang, Nicholas J.; Vranizan, Karen; Peng, Vivian; Van Name, Eric; Fontenay, Gerald V.; Ngai, John; Conboy, John G.; Parvin, Bahram; Feiler, Heidi S.; Speed, Terence P.; Gray, Joe W.; Brennan, Cameron; Socci, Nicholas D.; Olshen, Adam; Taylor, Barry S.; Lash, Alex; Schultz, Nikolaus; Reva, Boris; Antipin, Yevgeniy; Stukalov, Alexey; Gross, Benjamin; Cerami, Ethan; Wei, Qing Wang; Qin, Li Xuan; Seshan, Venkatraman E.; Villafania, Liliana; Cavatore, Magali; Borsu, Laetitia; Viale, Agnes; Gerald, William; Sander, Chris; Ladanyi, Marc; Perou, Charles M.; Hayes, D. Neil; Topal, Michael D.; Hoadley, Katherine A.; Qi, Yuan; Balu, Sai; Shi, Yan; Wu, Junyuan; Penny, Robert; Bittner, Michael; Shelton, Troy; Lenkiewicz, Elizabeth; Morris, Scott; Beasley, Debbie; Sanders, Sheri; Kahn, Ari; Sfeir, Robert; Chen, Jessica; Nassau, David; Feng, Larry; Hickey, Erin; Barker, Anna; Gerhard, Daniela S.; Vockley, Joseph; Compton, Carolyn; Vaught, Jim; Fielding, Peter; Ferguson, Martin L.; Schaefer, Carl; Zhang, Jinghui; Madhavan, Subhashree; Buetow, Kenneth H.; Collins, Francis; Good, Peter; Guyer, Mark; Ozenberger, Brad; Peterson, Jane; Thomson, Elizabeth.
In: Nature, Vol. 455, No. 7216, 23.10.2008, p. 1061-1068.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Comprehensive genomic characterization defines human glioblastoma genes and core pathways
AU - McLendon, Roger
AU - Friedman, Allan
AU - Bigner, Darrell
AU - Van Meir, Erwin G.
AU - Brat, Daniel J.
AU - Mastrogianakis, Gena M.
AU - Olson, Jeffrey J.
AU - Mikkelsen, Tom
AU - Lehman, Norman
AU - Aldape, Ken
AU - Yung, W. K.Alfred
AU - Bogler, Oliver
AU - Weinstein, John N.
AU - VandenBerg, Scott
AU - Berger, Mitchel
AU - Prados, Michael
AU - Muzny, Donna
AU - Morgan, Margaret
AU - Scherer, Steve
AU - Sabo, Aniko
AU - Nazareth, Lynn
AU - Lewis, Lora
AU - Hall, Otis
AU - Zhu, Yiming
AU - Ren, Yanru
AU - Alvi, Omar
AU - Yao, Jiqiang
AU - Hawes, Alicia
AU - Jhangiani, Shalini
AU - Fowler, Gerald
AU - San Lucas, Anthony
AU - Kovar, Christie
AU - Cree, Andrew
AU - Dinh, Huyen
AU - Santibanez, Jireh
AU - Joshi, Vandita
AU - Gonzalez-Garay, Manuel L.
AU - Miller, Christopher A.
AU - Milosavljevic, Aleksandar
AU - Donehower, Larry
AU - Wheeler, David A.
AU - Gibbs, Richard A.
AU - Cibulskis, Kristian
AU - Sougnez, Carrie
AU - Fennell, Tim
AU - Mahan, Scott
AU - Wilkinson, Jane
AU - Ziaugra, Liuda
AU - Onofrio, Robert
AU - Bloom, Toby
AU - Nicol, Rob
AU - Ardlie, Kristin
AU - Baldwin, Jennifer
AU - Gabriel, Stacey
AU - Lander, Eric S.
AU - Ding, Li
AU - Fulton, Robert S.
AU - McLellan, Michael D.
AU - Wallis, John
AU - Larson, David E.
AU - Shi, Xiaoqi
AU - Abbott, Rachel
AU - Fulton, Lucinda
AU - Chen, Ken
AU - Koboldt, Daniel C.
AU - Wendl, Michael C.
AU - Meyer, Rick
AU - Tang, Yuzhu
AU - Lin, Ling
AU - Osborne, John R.
AU - Dunford-Shore, Brian H.
AU - Miner, Tracie L.
AU - Delehaunty, Kim
AU - Markovic, Chris
AU - Swift, Gary
AU - Courtney, William
AU - Pohl, Craig
AU - Abbott, Scott
AU - Hawkins, Amy
AU - Leong, Shin
AU - Haipek, Carrie
AU - Schmidt, Heather
AU - Wiechert, Maddy
AU - Vickery, Tammi
AU - Scott, Sacha
AU - Dooling, David J.
AU - Chinwalla, Asif
AU - Weinstock, George M.
AU - Mardis, Elaine R.
AU - Wilson, Richard K.
AU - Getz, Gad
AU - Winckler, Wendy
AU - Verhaak, Roel G.W.
AU - Lawrence, Michael S.
AU - O'Kelly, Michael
AU - Robinson, Jim
AU - Alexe, Gabriele
AU - Beroukhim, Rameen
AU - Carter, Scott
AU - Chiang, Derek
AU - Gould, Josh
AU - Gupta, Supriya
AU - Korn, Josh
AU - Mermel, Craig
AU - Mesirov, Jill
AU - Monti, Stefano
AU - Nguyen, Huy
AU - Parkin, Melissa
AU - Reich, Michael
AU - Stransky, Nicolas
AU - Weir, Barbara A.
AU - Garraway, Levi
AU - Golub, Todd
AU - Meyerson, Matthew
AU - Chin, Lynda
AU - Protopopov, Alexei
AU - Zhang, Jianhua
AU - Perna, Ilana
AU - Aronson, Sandy
AU - Sathiamoorthy, Narayanan
AU - Ren, Georgia
AU - Yao, Jun
AU - Wiedemeyer, W. Ruprecht
AU - Kim, Hyunsoo
AU - Sek, Won Kong
AU - Xiao, Yonghong
AU - Kohane, Isaac S.
AU - Seidman, Jon
AU - Park, Peter J.
AU - Kucherlapati, Raju
AU - Laird, Peter W.
AU - Cope, Leslie
AU - Herman, James G.
AU - Weisenberger, Daniel J.
AU - Pan, Fei
AU - Van Den Berg, David
AU - Van Neste, Leander
AU - Joo, Mi Yi
AU - Schuebel, Kornel E.
AU - Baylin, Stephen B.
AU - Absher, Devin M.
AU - Li, Jun Z.
AU - Southwick, Audrey
AU - Brady, Shannon
AU - Aggarwal, Amita
AU - Chung, Tisha
AU - Sherlock, Gavin
AU - Brooks, James D.
AU - Myers, Richard M.
AU - Spellman, Paul T.
AU - Purdom, Elizabeth
AU - Jakkula, Lakshmi R.
AU - Lapuk, Anna V.
AU - Marr, Henry
AU - Dorton, Shannon
AU - Yoon, Gi Choi
AU - Han, Ju
AU - Ray, Amrita
AU - Wang, Victoria
AU - Durinck, Steffen
AU - Robinson, Mark
AU - Wang, Nicholas J.
AU - Vranizan, Karen
AU - Peng, Vivian
AU - Van Name, Eric
AU - Fontenay, Gerald V.
AU - Ngai, John
AU - Conboy, John G.
AU - Parvin, Bahram
AU - Feiler, Heidi S.
AU - Speed, Terence P.
AU - Gray, Joe W.
AU - Brennan, Cameron
AU - Socci, Nicholas D.
AU - Olshen, Adam
AU - Taylor, Barry S.
AU - Lash, Alex
AU - Schultz, Nikolaus
AU - Reva, Boris
AU - Antipin, Yevgeniy
AU - Stukalov, Alexey
AU - Gross, Benjamin
AU - Cerami, Ethan
AU - Wei, Qing Wang
AU - Qin, Li Xuan
AU - Seshan, Venkatraman E.
AU - Villafania, Liliana
AU - Cavatore, Magali
AU - Borsu, Laetitia
AU - Viale, Agnes
AU - Gerald, William
AU - Sander, Chris
AU - Ladanyi, Marc
AU - Perou, Charles M.
AU - Hayes, D. Neil
AU - Topal, Michael D.
AU - Hoadley, Katherine A.
AU - Qi, Yuan
AU - Balu, Sai
AU - Shi, Yan
AU - Wu, Junyuan
AU - Penny, Robert
AU - Bittner, Michael
AU - Shelton, Troy
AU - Lenkiewicz, Elizabeth
AU - Morris, Scott
AU - Beasley, Debbie
AU - Sanders, Sheri
AU - Kahn, Ari
AU - Sfeir, Robert
AU - Chen, Jessica
AU - Nassau, David
AU - Feng, Larry
AU - Hickey, Erin
AU - Barker, Anna
AU - Gerhard, Daniela S.
AU - Vockley, Joseph
AU - Compton, Carolyn
AU - Vaught, Jim
AU - Fielding, Peter
AU - Ferguson, Martin L.
AU - Schaefer, Carl
AU - Zhang, Jinghui
AU - Madhavan, Subhashree
AU - Buetow, Kenneth H.
AU - Collins, Francis
AU - Good, Peter
AU - Guyer, Mark
AU - Ozenberger, Brad
AU - Peterson, Jane
AU - Thomson, Elizabeth
N1 - Funding Information: Acknowledgements We thank the members of TCGA’s External Scientific Committee, the Glioblastoma Disease Working Group (http:// cancergenome.nih.gov/components) and D. N. Louis for discussions; A. Mirick, J. Melone and C. Collins for administrative coordination of TCGA activities; and L. Gaffney for graphic art. This work was supported by the following grants from the United States National Institutes of Health: U54HG003067, U54HG003079, U54HG003273, U24CA126543, U24CA126544, U24CA126546, U24CA126551, U24CA126554, U24CA126561 and U24CA126563.
PY - 2008/10/23
Y1 - 2008/10/23
N2 - Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
AB - Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
UR - http://www.scopus.com/inward/record.url?scp=54549108740&partnerID=8YFLogxK
U2 - 10.1038/nature07385
DO - 10.1038/nature07385
M3 - Article
C2 - 18772890
AN - SCOPUS:54549108740
VL - 455
SP - 1061
EP - 1068
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7216
ER -