Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Roger McLendon, Allan Friedman, Darrell Bigner, Erwin G. Van Meir, Daniel J. Brat, Gena M. Mastrogianakis, Jeffrey J. Olson, Tom Mikkelsen, Norman Lehman, Ken Aldape, W. K.Alfred Yung, Oliver Bogler, John N. Weinstein, Scott VandenBerg, Mitchel Berger, Michael Prados, Donna Muzny, Margaret Morgan, Steve Scherer, Aniko SaboLynn Nazareth, Lora Lewis, Otis Hall, Yiming Zhu, Yanru Ren, Omar Alvi, Jiqiang Yao, Alicia Hawes, Shalini Jhangiani, Gerald Fowler, Anthony San Lucas, Christie Kovar, Andrew Cree, Huyen Dinh, Jireh Santibanez, Vandita Joshi, Manuel L. Gonzalez-Garay, Christopher A. Miller, Aleksandar Milosavljevic, Larry Donehower, David A. Wheeler, Richard A. Gibbs, Kristian Cibulskis, Carrie Sougnez, Tim Fennell, Scott Mahan, Jane Wilkinson, Liuda Ziaugra, Robert Onofrio, Toby Bloom, Rob Nicol, Kristin Ardlie, Jennifer Baldwin, Stacey Gabriel, Eric S. Lander, Li Ding, Robert S. Fulton, Michael D. McLellan, John Wallis, David E. Larson, Xiaoqi Shi, Rachel Abbott, Lucinda Fulton, Ken Chen, Daniel C. Koboldt, Michael C. Wendl, Rick Meyer, Yuzhu Tang, Ling Lin, John R. Osborne, Brian H. Dunford-Shore, Tracie L. Miner, Kim Delehaunty, Chris Markovic, Gary Swift, William Courtney, Craig Pohl, Scott Abbott, Amy Hawkins, Shin Leong, Carrie Haipek, Heather Schmidt, Maddy Wiechert, Tammi Vickery, Sacha Scott, David J. Dooling, Asif Chinwalla, George M. Weinstock, Elaine R. Mardis, Richard K. Wilson, Gad Getz, Wendy Winckler, Roel G.W. Verhaak, Michael S. Lawrence, Michael O'Kelly, Jim Robinson, Gabriele Alexe, Rameen Beroukhim, Scott Carter, Derek Chiang, Josh Gould, Supriya Gupta, Josh Korn, Craig Mermel, Jill Mesirov, Stefano Monti, Huy Nguyen, Melissa Parkin, Michael Reich, Nicolas Stransky, Barbara A. Weir, Levi Garraway, Todd Golub, Matthew Meyerson, Lynda Chin, Alexei Protopopov, Jianhua Zhang, Ilana Perna, Sandy Aronson, Narayanan Sathiamoorthy, Georgia Ren, Jun Yao, W. Ruprecht Wiedemeyer, Hyunsoo Kim, Won Kong Sek, Yonghong Xiao, Isaac S. Kohane, Jon Seidman, Peter J. Park, Raju Kucherlapati, Peter W. Laird, Leslie Cope, James G. Herman, Daniel J. Weisenberger, Fei Pan, David Van Den Berg, Leander Van Neste, Mi Yi Joo, Kornel E. Schuebel, Stephen B. Baylin, Devin M. Absher, Jun Z. Li, Audrey Southwick, Shannon Brady, Amita Aggarwal, Tisha Chung, Gavin Sherlock, James D. Brooks, Richard M. Myers, Paul T. Spellman, Elizabeth Purdom, Lakshmi R. Jakkula, Anna V. Lapuk, Henry Marr, Shannon Dorton, Gi Choi Yoon, Ju Han, Amrita Ray, Victoria Wang, Steffen Durinck, Mark Robinson, Nicholas J. Wang, Karen Vranizan, Vivian Peng, Eric Van Name, Gerald V. Fontenay, John Ngai, John G. Conboy, Bahram Parvin, Heidi S. Feiler, Terence P. Speed, Joe W. Gray, Cameron Brennan, Nicholas D. Socci, Adam Olshen, Barry S. Taylor, Alex Lash, Nikolaus Schultz, Boris Reva, Yevgeniy Antipin, Alexey Stukalov, Benjamin Gross, Ethan Cerami, Qing Wang Wei, Li Xuan Qin, Venkatraman E. Seshan, Liliana Villafania, Magali Cavatore, Laetitia Borsu, Agnes Viale, William Gerald, Chris Sander, Marc Ladanyi, Charles M. Perou, D. Neil Hayes, Michael D. Topal, Katherine A. Hoadley, Yuan Qi, Sai Balu, Yan Shi, Junyuan Wu, Robert Penny, Michael Bittner, Troy Shelton, Elizabeth Lenkiewicz, Scott Morris, Debbie Beasley, Sheri Sanders, Ari Kahn, Robert Sfeir, Jessica Chen, David Nassau, Larry Feng, Erin Hickey, Anna Barker, Daniela S. Gerhard, Joseph Vockley, Carolyn Compton, Jim Vaught, Peter Fielding, Martin L. Ferguson, Carl Schaefer, Jinghui Zhang, Subhashree Madhavan, Kenneth H. Buetow, Francis Collins, Peter Good, Mark Guyer, Brad Ozenberger, Jane Peterson, Elizabeth Thomson

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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 languageEnglish (US)
Pages (from-to)1061-1068
Number of pages8
JournalNature
Volume455
Issue number7216
DOIs
StatePublished - Oct 23 2008

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McLendon, R., Friedman, A., Bigner, D., Van Meir, E. G., Brat, D. J., Mastrogianakis, G. M., Olson, J. J., Mikkelsen, T., Lehman, N., Aldape, K., Yung, W. K. A., Bogler, O., Weinstein, J. N., VandenBerg, S., Berger, M., Prados, M., Muzny, D., Morgan, M., Scherer, S., ... Thomson, E. (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 455(7216), 1061-1068. https://doi.org/10.1038/nature07385