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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.; M. Mastrogianakis, Gena; Olson, Jeffrey J.; Mikkelsen, Tom; Lehman, Norman; Aldape, Ken; Alfred Yung, W. K.; Bogler, Oliver; 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.; Oâ 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, Narayan; Ren, Georgia; Yao, Jun; Wiedemeyer, W. Ruprecht; Kim, Hyunsoo; Won Kong, Sek; 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; Mi Yi, Joo; 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; Gi Choi, Yoon; 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; Qing Wang, Wei; Qin, Li-Xuan; Seshan, Venkatraman E.; Villafania, Liliana; Cavatore, Magali; Borsu, Laetitia; Viale, Agnes; Gerald, William; Sander, Chris; Ladanyi, Marc; Perou, Charles M.; Neil Hayes, D.; 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; Zhang, Jinghui; Weinstein, John N.; Barker, Anna; Gerhard, Daniela S.; Vockley, Joseph; Compton, Carolyn; Vaught, Jim; Fielding, Peter; Ferguson, Martin L.; Schaefer, Carl; Madhavan, Subhashree; Buetow, Kenneth H.; Collins, Francis; Good, Peter; Guyer, Mark; Ozenberger, Brad; Peterson, Jane; Thomson, Elizabeth; The Cancer Genome Atlas Research Network; Tissue source sites: Duke University Medical School; Emory University; Henry Ford Hospital; MD Anderson Cancer Center; University of California San Francisco; Genome sequencing centres: Baylor College of Medicine; Broad Institute of MIT and Harvard; Washington University in St Louis; Cancer genome characterization centres: Broad Institute/Dana-Farber Cancer Institute; Harvard Medical School/Dana-Farber Cancer Institute; Johns Hopkins/University of Southern California; HudsonAlpha Institute/Stanford University; Lawrence Berkeley National Laboratory; Memorial Sloan-Kettering Cancer Center; University of North Carolina, Chapel Hill; Biospecimen Core Resource; Data Coordinating Center; Project teams: National Cancer Institute; National Human Genome Research Institute; Van Meir, Erwin G.; ;; Olson, Jeffrey J.; ;; Milosavljevic, Aleksandar; ;; Lander, Eric S.; ;; Winckler, Wendy; ;; Verhaak, Roel G. W.; ;; Beroukhim, Rameen; ;; Weir, Barbara A.; ;; Garraway, Levi; ;; Golub, Todd; ;; Meyerson, Matthew; ;; Chin, Lynda; ;; Kohane, Isaac S.; ;; Park, Peter J.; ;
Журнал: Nature
Дата: 2008

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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 glioblastomasâ the most common type of adult brain cancerâ 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.
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