Comprehensive genomic characterization defines human glioblastoma genes and core pathways
2008; Nature Portfolio; Volume: 455; Issue: 7216 Linguagem: Inglês
10.1038/nature07385
ISSN1476-4687
AutoresRoger E. McLendon, Allan H. Friedman, D D Bigner, Erwin G. Van Meir, Daniel J. Brat, Gena M. Mastrogianakis, Jeffrey J. Olson, Tom Mikkelsen, Norman L. Lehman, Ken Aldape, W.K. Alfred Yung, Oliver Bögler, John N. Weinstein, Scott Vandenberg, Mitchel S. Berger, Michael D. Prados, Donna M. Muzny, Margaret Morgan, Stephen W. Scherer, Aniko Sabo, Lynn Nazareth, Lora Lewis, Otis Hall, Yiming Zhu, Yanru Ren, Omar Alvi, Jiqiang Yao, Alicia Hawes, Shalini N. 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, L A Donehower, David A. Wheeler, Richard A. Gibbs, Kristian Cibulskis, Carrie Sougnez, Tim Fennell, Scott Mahan, Jane Wilkinson, Liuda Ziaugra, Robert C. Onofrio, Toby Bloom, Robert Nicol, Kristin Ardlie, Jennifer N. Baldwin, Stacey Gabriel, Eric S. Lander, Jun Li, Robert S. Fulton, Michael D. McLellan, John Wallis, David E. Larson, Xiaoqi Shi, Rachel M. 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 D. Delehaunty, Chris Markovic, G.M. Swift, William Courtney, Craig Pohl, Scott Abbott, Amy Hawkins, Shin Leong, Carrie A. Haipek, Heather K. Schmidt, Maddy Wiechert, Tammi L. Vickery, S. P. 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 L. Carter, Derek Y. Chiang, Josh Gould, Supriya Gupta, Josh Korn, Craig H. Mermel, Jill P. Mesirov, Stefano Monti, Huy Nguyen, Melissa Parkin, Michael Reich, Nicolas Stransky, Barbara A. Weir, Levi A. Garraway, Todd R. Golub, Matthew Meyerson, Lynda Chin, Alexei Protopopov, Jianhua Zhang, Ilana Perna, Sandy Aronson, Narayanan Sathiamoorthy, Georgia Ren, Jun Yao, W. Ruprecht Wiedemeyer, Hyun Soo Kim, Won Kong Sek, Yonghong Xiao, Isaac S. Kohane, J.G. 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 Absher, Jun Z. Li, Audrey Southwick, Shannon D. Brady, Amita Aggarwal, Tisha Chung, Gavin Sherlock, James D. Brooks, Richard M. Myers, Paul T. Spellman, Elizabeth Purdom, Lakshmi R. Jakkula, Anna Lapuk, Henry Marr, Shannon Dorton, Gi Choi Yoon, Ju Han, Amrita Ray, Victoria Wang, Steffen Durinck, Mark D. Robinson, Nicholas J. Wang, Karen Vranizan, Vivian Peng, Eric Van Name, Gerald Fontenay, John Ngai, John G. Conboy, Bahram Parvin, Heidi S. Feiler, Terence P. Speed, Joe W. Gray, Cameron Brennan, Nicholas D. Socci, Adam B. Olshen, Barry S. Taylor, Alex E. Lash, Nikolaus Schultz, Boris Reva, Yevgeniy Antipin, Alexey Stukalov, Benjamin Groß, Ethan Cerami, Qing Wang Wei, Li Qin, Venkatraman Seshan, Liliana Villafania, Magali Cavatore, Laetitia Borsu, Agnès Viale, William L. Gerald, Chris Sander, Marc Ladanyi, Charles M. Perou, D. Neil Hayes, Michael D. Topal, Katherine A. Hoadley, Yuan Qi, S. Balu, Yan Shi, Junyuan Wu, Robert Penny, Michael Bittner, Troy Shelton, Elizabeth Lenkiewicz, Scott Morris, Debbie Beasley, Sheri Sanders, A Kahn, Robert Sfeir, Jessica Chen, David Nassau, Larry Feng, Erin Hickey, Anna D. Barker, Daniela S. Gerhard, Joseph G. Vockley, Carolyn C. Compton, Jim Vaught, Peter L. Fielding, Martin L. Ferguson, Carl G. Schaefer, Jinghui Zhang, Subhashree Madhavan, Kenneth H. Buetow, Francis S. Collins, Peter J. Good, Mark Guyer, Brad Ozenberger, Jane L. Peterson, Elizabeth J. Thomson,
Tópico(s)Epigenetics and DNA Methylation
ResumoHuman 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. The Cancer Genome Atlas, a large-scale genomics project to catalogue cancer-linked mutations, is starting to produce results. Glioblastoma, the most common brain cancer, was the first target for the project and the initial results, published AOP on 4 September, are now in print. Genes newly implicated in glioblastoma include tumour suppressors (NF1, RB1, ATM and APC) and several tyrosine kinase genes. Glioblastoma is extremely resistant to therapy, hence the potential importance of the development of a possible model system. Zheng et al. report that mice lacking the tumour suppressors p53 and Pten develop tumours resembling human glioblastomas, associated with increased Myc protein levels. As well as offering a potential system for testing therapeutics, this points to c-Myc as a possible drug target. With a comprehensive analysis of sequencing data, DNA copy number, gene expression and DNA methylation in a large number of human glioblastomas, The Cancer Genome Atlas project initiative provides a broad overview of the genes and pathways that are altered in this cancer type.
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