Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Published Online September 4, 2008
Science DOI: 10.1126/science.1164382

Research Articles

Submitted on August 7, 2008
Accepted on August 27, 2008

An Integrated Genomic Analysis of Human Glioblastoma Multiforme

D. Williams Parsons 1{dagger}, Siân Jones 2{dagger}, Xiaosong Zhang 2{dagger}, Jimmy Cheng-Ho Lin 2{dagger}, Rebecca J. Leary 2{dagger}, Philipp Angenendt 2{dagger}, Parminder Mankoo 3, Hannah Carter 3, I-Mei Siu 4, Gary L. Gallia 4, Alessandro Olivi 4, Roger McLendon 5, B. Ahmed Rasheed 5, Stephen Keir 5, Tatiana Nikolskaya 6, Yuri Nikolsky 7, Dana A. Busam 8, Hanna Tekleab 8, Luis A. Diaz Jr.2, James Hartigan 9, Doug R. Smith 9, Robert L. Strausberg 8, Suely Kazue Nagahashi Marie 10, Sueli Mieko Oba Shinjo 10, Hai Yan 5, Gregory J. Riggins 4, Darell D. Bigner 5, Rachel Karchin 3, Nick Papadopoulos 2, Giovanni Parmigiani 2, Bert Vogelstein 2*, Victor E. Velculescu 2*, Kenneth W. Kinzler 2*

1 Ludwig Center for Cancer Genetics and Therapeutics, and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston TX 77030, USA.
2 Ludwig Center for Cancer Genetics and Therapeutics, and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
3 Department of Biomedical Engineering, Institute of Computational Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21218, USA.
4 Department of Neurosurgery, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
5 Department of Pathology, Pediatric Brain Tumor Foundation, and Preston Robert Tisch Brain Tumor Center at Duke University Medical Center, Durham, NC 27710, USA.
6 Vavilov Institute for General Genetics, Moscow B333, 117809, Russia.
7 GeneGo, Inc., St. Joseph, MI 49085, USA.
8 J. Craig Venter Institute, Rockville, MD 20850, USA.
9 Agencourt Bioscience Corporation, Beverly, MA 01915, USA.
10 Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil.

* To whom correspondence should be addressed.
Bert Vogelstein , E-mail: bertvog{at}gmail.com
Victor E. Velculescu , E-mail: velculescu{at}jhmi.edu
Kenneth W. Kinzler , E-mail: kinzlke{at}welch.jhu.edu

{dagger}These authors contributed equally to this work.

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs, and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Paxillin-Kinase-Linker Tyrosine Phosphorylation Regulates Directional Cell Migration.
J. A. Yu, N. O. Deakin, and C. E. Turner (2009)
Mol. Biol. Cell 20, 4706-4719
   Abstract »    Full Text »    PDF »
Network of Cancer Genes: a web resource to analyze duplicability, orthology and network properties of cancer genes.
A. S. Syed, M. D'Antonio, and F. D. Ciccarelli (2009)
Nucleic Acids Res.
   Abstract »    Full Text »    PDF »
Genetic diagnosis by whole exome capture and massively parallel DNA sequencing.
M. Choi, U. I. Scholl, W. Ji, T. Liu, I. R. Tikhonova, P. Zumbo, A. Nayir, A. Bakkaloglu, S. Ozen, S. Sanjad, et al. (2009)
PNAS 106, 19096-19101
   Abstract »    Full Text »    PDF »
A novel algorithm for detecting differentially regulated paths based on gene set enrichment analysis.
A. Keller, C. Backes, A. Gerasch, M. Kaufmann, O. Kohlbacher, E. Meese, and H.-P. Lenhof (2009)
Bioinformatics 25, 2787-2794
   Abstract »    Full Text »    PDF »
Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer.
M. L. Sos, S. Fischer, R. Ullrich, M. Peifer, J. M. Heuckmann, M. Koker, S. Heynck, I. Stuckrath, J. Weiss, F. Fischer, et al. (2009)
PNAS 106, 18351-18356
   Abstract »    Full Text »    PDF »
Knowledge-based data analysis comes of age.
M. F. Ochs (2009)
Brief Bioinform
   Abstract »    Full Text »    PDF »
Cancer genome sequencing: a review.
E. R. Mardis and R. K. Wilson (2009)
Hum. Mol. Genet. 18, R163-R168
   Abstract »    Full Text »    PDF »
A Modified Sleeping Beauty Transposon System That Can Be Used to Model a Wide Variety of Human Cancers in Mice.
A. J. Dupuy, L. M. Rogers, J. Kim, K. Nannapaneni, T. K. Starr, P. Liu, D. A. Largaespada, T. E. Scheetz, N. A. Jenkins, and N. G. Copeland (2009)
Cancer Res. 69, 8150-8156
   Abstract »    Full Text »    PDF »
Sox11 Prevents Tumorigenesis of Glioma-Initiating Cells by Inducing Neuronal Differentiation.
T. Hide, T. Takezaki, Y. Nakatani, H. Nakamura, J.-i. Kuratsu, and T. Kondo (2009)
Cancer Res. 69, 7953-7959
   Abstract »    Full Text »    PDF »
A frequent kinase domain mutation that changes the interaction between PI3K{alpha} and the membrane.
D. Mandelker, S. B. Gabelli, O. Schmidt-Kittler, J. Zhu, I. Cheong, C.-H. Huang, K. W. Kinzler, B. Vogelstein, and L. M. Amzel (2009)
PNAS 106, 16996-17001
   Abstract »    Full Text »    PDF »
IDH1 Mutations as Molecular Signature and Predictive Factor of Secondary Glioblastomas.
S. Nobusawa, T. Watanabe, P. Kleihues, and H. Ohgaki (2009)
Clin. Cancer Res. 15, 6002-6007
   Abstract »    Full Text »    PDF »
Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells.
J. Yun, C. Rago, I. Cheong, R. Pagliarini, P. Angenendt, H. Rajagopalan, K. Schmidt, J. K. V. Willson, S. Markowitz, S. Zhou, et al. (2009)
Science 325, 1555-1559
   Abstract »    Full Text »    PDF »
EGFRvIII Deletion Mutations in Pediatric High-Grade Glioma and Response to Targeted Therapy in Pediatric Glioma Cell Lines.
D. A. Bax, N. Gaspar, S. E. Little, L. Marshall, L. Perryman, M. Regairaz, M. Viana-Pereira, R. Vuononvirta, S. Y. Sharp, J. S. Reis-Filho, et al. (2009)
Clin. Cancer Res. 15, 5753-5761
   Abstract »    Full Text »    PDF »
Cancer Genomes -- Continuing Progress.
J. R. Downing (2009)
N. Engl. J. Med. 361, 1111-1112
   Full Text »    PDF »
Oncogenic EGFR Signaling Networks in Glioma.
P. H. Huang, A. M. Xu, and F. M. White (2009)
Science Signaling 2, re6
   Abstract »    Full Text »    PDF »
Translating the cancer genome into clinically useful tools and strategies.
F. Innocenti and R. L. Schilsky (2009)
Dis. Model. Mech. 2, 426-429
   Full Text »    PDF »
Isocitrate Dehydrogenase 1 Codon 132 Mutation Is an Important Prognostic Biomarker in Gliomas.
M. Sanson, Y. Marie, S. Paris, A. Idbaih, J. Laffaire, F. Ducray, S. El Hallani, B. Boisselier, K. Mokhtari, K. Hoang-Xuan, et al. (2009)
J. Clin. Oncol. 27, 4150-4154
   Abstract »    Full Text »    PDF »
Saturation Density of Skin Fibroblasts as a Quantitative Screen for Human Cancer Susceptibility.
H. Rubin (2009)
Cancer Epidemiol. Biomarkers Prev. 18, 2366-2372
   Abstract »    Full Text »    PDF »
Multiplex padlock targeted sequencing reveals human hypermutable CpG variations.
J. B. Li, Y. Gao, J. Aach, K. Zhang, G. V. Kryukov, B. Xie, A. Ahlford, J.-K. Yoon, A. M. Rosenbaum, A. W. Zaranek, et al. (2009)
Genome Res. 19, 1606-1615
   Abstract »    Full Text »    PDF »
Identification of rare cancer driver mutations by network reconstruction.
A. Torkamani and N. J. Schork (2009)
Genome Res. 19, 1570-1578
   Abstract »    Full Text »    PDF »
Fyn and Src Are Effectors of Oncogenic Epidermal Growth Factor Receptor Signaling in Glioblastoma Patients.
K. V. Lu, S. Zhu, A. Cvrljevic, T. T. Huang, S. Sarkaria, D. Ahkavan, J. Dang, E. B. Dinca, S. B. Plaisier, I. Oderberg, et al. (2009)
Cancer Res. 69, 6889-6898
   Abstract »    Full Text »    PDF »
Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins.
T.-Y. Lee, S. Muschal, E. A. Pravda, J. Folkman, A. Abdollahi, and K. Javaherian (2009)
Blood 114, 1987-1998
   Abstract »    Full Text »    PDF »
Hypoxia-induced mediators and neurologic disease.
E. E. Benarroch (2009)
Neurology 73, 560-565
   Full Text »    PDF »
Cancer-Specific High-Throughput Annotation of Somatic Mutations: Computational Prediction of Driver Missense Mutations.
H. Carter, S. Chen, L. Isik, S. Tyekucheva, V. E. Velculescu, K. W. Kinzler, B. Vogelstein, and R. Karchin (2009)
Cancer Res. 69, 6660-6667
   Abstract »    Full Text »    PDF »
Copy number variation has little impact on bead-array-based measures of DNA methylation.
E. A. Houseman, B. C. Christensen, M. R. Karagas, M. R. Wrensch, H. H. Nelson, J. L. Wiemels, S. Zheng, J. K. Wiencke, K. T. Kelsey, and C. J. Marsit (2009)
Bioinformatics 25, 1999-2005
   Abstract »    Full Text »    PDF »
Adenomatous Polyposis Coli and Asef Function Downstream of Hepatocyte Growth Factor and Phosphatidylinositol 3-Kinase.
Y. Kawasaki, S. Tsuji, M. Sagara, K. Echizen, Y. Shibata, and T. Akiyama (2009)
J. Biol. Chem. 284, 22436-22443
   Abstract »    Full Text »    PDF »
Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia.
I. Radtke, C. G. Mullighan, M. Ishii, X. Su, J. Cheng, J. Ma, R. Ganti, Z. Cai, S. Goorha, S. B. Pounds, et al. (2009)
PNAS 106, 12944-12949
   Abstract »    Full Text »    PDF »
High-throughput molecular analysis in lung cancer: insights into biology and potential clinical applications.
S. Ocak, M. L. Sos, R. K. Thomas, and P. P. Massion (2009)
Eur. Respir. J. 34, 489-506
   Abstract »    Full Text »    PDF »
A Network Model of a Cooperative Genetic Landscape in Brain Tumors.
M. Bredel, D. M. Scholtens, G. R. Harsh, C. Bredel, J. P. Chandler, J. J. Renfrow, A. K. Yadav, H. Vogel, A. C. Scheck, R. Tibshirani, et al. (2009)
JAMA 302, 261-275
   Abstract »    Full Text »    PDF »
Monosomy of Chromosome 10 Associated With Dysregulation of Epidermal Growth Factor Signaling in Glioblastomas.
A. K. Yadav, J. J. Renfrow, D. M. Scholtens, H. Xie, G. E. Duran, C. Bredel, H. Vogel, J. P. Chandler, A. Chakravarti, P. A. Robe, et al. (2009)
JAMA 302, 276-289
   Abstract »    Full Text »    PDF »
One Step Forward Toward Identification of the Genetic Signature of Glioblastomas.
B. Pasche and R. M. Myers (2009)
JAMA 302, 325-326
   Full Text »    PDF »
Secretion of Tumor-Specific Antigen by Myeloma Cells Is Required for Cancer Immunosurveillance by CD4+ T Cells.
A. Corthay, K. U. Lundin, K. B. Lorvik, P. O. Hofgaard, and B. Bogen (2009)
Cancer Res. 69, 5901-5907
   Abstract »    Full Text »    PDF »
Sample Type Bias in the Analysis of Cancer Genomes.
D. A. Solomon, J.-S. Kim, H. W. Ressom, Z. Sibenaller, T. Ryken, W. Jean, D. Bigner, H. Yan, and T. Waldman (2009)
Cancer Res. 69, 5630-5633
   Abstract »    Full Text »    PDF »
MSH6 Mutations Arise in Glioblastomas during Temozolomide Therapy and Mediate Temozolomide Resistance.
S. Yip, J. Miao, D. P. Cahill, A. J. Iafrate, K. Aldape, C. L. Nutt, and D. N. Louis (2009)
Clin. Cancer Res. 15, 4622-4629
   Abstract »    Full Text »    PDF »
Mutation of FOXL2 in Granulosa-Cell Tumors of the Ovary.
S. P. Shah, M. Kobel, J. Senz, R. D. Morin, B. A. Clarke, K. C. Wiegand, G. Leung, A. Zayed, E. Mehl, S. E. Kalloger, et al. (2009)
N. Engl. J. Med. 360, 2719-2729
   Abstract »    Full Text »    PDF »
Cancer Genome Sequencing--An Interim Analysis.
E. J. Fox, J. J. Salk, and L. A. Loeb (2009)
Cancer Res. 69, 4948-4950
   Abstract »    Full Text »    PDF »
Identification of interactive networks of gene expression associated with osteosarcoma oncogenesis by integrated molecular profiling.
B. Sadikovic, M. Yoshimoto, S. Chilton-MacNeill, P. Thorner, J. A. Squire, and M. Zielenska (2009)
Hum. Mol. Genet. 18, 1962-1975
   Abstract »    Full Text »    PDF »
The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo.
J. T. Huse, C. Brennan, D. Hambardzumyan, B. Wee, J. Pena, S. H. Rouhanifard, C. Sohn-Lee, C. le Sage, R. Agami, T. Tuschl, et al. (2009)
Genes & Dev. 23, 1327-1337
   Abstract »    Full Text »    PDF »
Mitochondria and Reactive Oxygen Species.
F. Addabbo, M. Montagnani, and M. S. Goligorsky (2009)
Hypertension 53, 885-892
   Full Text »    PDF »
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation.
M. G. Vander Heiden, L. C. Cantley, and C. B. Thompson (2009)
Science 324, 1029-1033
   Abstract »    Full Text »    PDF »
IDH1 and IDH2 mutations in gliomas..
E. De Carli, X. Wang, S. Puget, F. Ducray, Y. Marie, M. Sanson, Z. Reitman, and H. Yan (2009)
N. Engl. J. Med. 360, 2248
   Full Text »    PDF »
EGFRvIII and DNA Double-Strand Break Repair: A Molecular Mechanism for Radioresistance in Glioblastoma.
B. Mukherjee, B. McEllin, C. V. Camacho, N. Tomimatsu, S. Sirasanagandala, S. Nannepaga, K. J. Hatanpaa, B. Mickey, C. Madden, E. Maher, et al. (2009)
Cancer Res. 69, 4252-4259
   Abstract »    Full Text »    PDF »
The role of autophagy in sensitizing malignant glioma cells to radiation therapy.
W. Zhuang, Z. Qin, and Z. Liang (2009)
Acta Biochim Biophys Sin 41, 341-351
   Abstract »    Full Text »    PDF »
Challenges in the Search for Drugs to Treat Central Nervous System Disorders.
S. J. Enna and M. Williams (2009)
J. Pharmacol. Exp. Ther. 329, 404-411
   Abstract »    Full Text »    PDF »
Genetic Mutations Associated with Cigarette Smoking in Pancreatic Cancer.
A. Blackford, G. Parmigiani, T. W. Kensler, C. Wolfgang, S. Jones, X. Zhang, D. W. Parsons, J. C.-H. Lin, R. J. Leary, J. R. Eshleman, et al. (2009)
Cancer Res. 69, 3681-3688
   Abstract »    Full Text »    PDF »
Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1{alpha}.
S. Zhao, Y. Lin, W. Xu, W. Jiang, Z. Zha, P. Wang, W. Yu, Z. Li, L. Gong, Y. Peng, et al. (2009)
Science 324, 261-265
   Abstract »    Full Text »    PDF »
Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene.
S. Jones, R. H. Hruban, M. Kamiyama, M. Borges, X. Zhang, D. W. Parsons, J. C.-H. Lin, E. Palmisano, K. Brune, E. M. Jaffee, et al. (2009)
Science 324, 217
   Abstract »    Full Text »    PDF »
Multiple Genes Exhibit Phenobarbital-Induced Constitutive Active/Androstane Receptor-Mediated DNA Methylation Changes during Liver Tumorigenesis and in Liver Tumors.
J. M. Phillips and J. I. Goodman (2009)
Toxicol. Sci. 108, 273-289
   Abstract »    Full Text »    PDF »
IDH1 Mutations Are Early Events in the Development of Astrocytomas and Oligodendrogliomas.
T. Watanabe, S. Nobusawa, P. Kleihues, and H. Ohgaki (2009)
Am. J. Pathol. 174, 1149-1153
   Abstract »    Full Text »    PDF »
A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53.
S. Sur, R. Pagliarini, F. Bunz, C. Rago, L. A. Diaz Jr., K. W. Kinzler, B. Vogelstein, and N. Papadopoulos (2009)
PNAS 106, 3964-3969
   Abstract »    Full Text »    PDF »
Tumor suppressors and cell metabolism: a recipe for cancer growth.
R. G. Jones and C. B. Thompson (2009)
Genes & Dev. 23, 537-548
   Abstract »    Full Text »    PDF »
Tumor-Induced Suppression of CTL Expansion and Subjugation by gp96-Ig Vaccination.
T. H. Schreiber, V. V. Deyev, J. D. Rosenblatt, and E. R. Podack (2009)
Cancer Res. 69, 2026-2033
   Abstract »    Full Text »    PDF »
IDH1 and IDH2 Mutations in Gliomas.
H. Yan, D. W. Parsons, G. Jin, R. McLendon, B. A. Rasheed, W. Yuan, I. Kos, I. Batinic-Haberle, S. Jones, G. J. Riggins, et al. (2009)
N. Engl. J. Med. 360, 765-773
   Abstract »    Full Text »    PDF »
Metabolic Enzymes as Oncogenes or Tumor Suppressors.
C. B. Thompson (2009)
N. Engl. J. Med. 360, 813-815
   Full Text »    PDF »
Is Anticancer Drug Development Heading in the Right Direction?.
T. W. Hambley and W. N. Hait (2009)
Cancer Res. 69, 1259-1262
   Abstract »    Full Text »    PDF »
Comparative analyses of gene copy number and mRNA expression in glioblastoma multiforme tumors and xenografts.
J. G. Hodgson, R.-F. Yeh, A. Ray, N. J. Wang, I. Smirnov, M. Yu, S. Hariono, J. Silber, H. S. Feiler, J. W. Gray, et al. (2009)
Neuro-oncol 11, 477-487
   Abstract »    Full Text »    PDF »
IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas.
K. Ichimura, D. M. Pearson, S. Kocialkowski, L. M. Backlund, R. Chan, D. T.W. Jones, and V. P. Collins (2009)
Neuro-oncol 11, 341-347
   Abstract »    Full Text »    PDF »
MODBASE, a database of annotated comparative protein structure models and associated resources.
U. Pieper, N. Eswar, B. M. Webb, D. Eramian, L. Kelly, D. T. Barkan, H. Carter, P. Mankoo, R. Karchin, M. A. Marti-Renom, et al. (2009)
Nucleic Acids Res. 37, D347-D354
   Abstract »    Full Text »    PDF »
Defining a Candidate Lung Cancer Gene.
F. J. Kaye (2008)
J Natl Cancer Inst 100, 1564-1565
   Full Text »    PDF »
Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses.
S. Jones, X. Zhang, D. W. Parsons, J. C.-H. Lin, R. J. Leary, P. Angenendt, P. Mankoo, H. Carter, H. Kamiyama, A. Jimeno, et al. (2008)
Science 321, 1801-1806
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)