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Science 321 (5897): 1807-1812

Copyright © 2008 by the American Association for the Advancement of Science

An Integrated Genomic Analysis of Human Glioblastoma Multiforme

D. Williams Parsons,1,2* Siân Jones,1* Xiaosong Zhang,1* Jimmy Cheng-Ho Lin,1* Rebecca J. Leary,1* Philipp Angenendt,1* 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.,1 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,1 Giovanni Parmigiani,1 Bert Vogelstein,1{dagger} Victor E. Velculescu,1{dagger} Kenneth W. Kinzler1{dagger}

Abstract: 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.

1 Ludwig Center for Cancer Genetics and Therapeutics, and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
2 Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston TX 77030, 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.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: bertvog{at}gmail.com (B.V.); velculescu{at}jhmi.edu (V.E.V.); kinzlke{at}jhmi.edu (K.W.K.)


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R. Popovic, M. Y. Shah, and J. D. Licht (2013)
Therapeutic Advances in Hematology 4, 81-91
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IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival.
S. Leu, S. von Felten, S. Frank, E. Vassella, I. Vajtai, E. Taylor, M. Schulz, G. Hutter, J. Hench, P. Schucht, et al. (2013)
Neuro Oncology 15, 469-479
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PTEN suppresses SPARC-induced pMAPKAPK2 and inhibits SPARC-induced Ser78 HSP27 phosphorylation in glioma.
R. Alam, C. R. Schultz, W. A. Golembieski, L. M. Poisson, and S. A. Rempel (2013)
Neuro Oncology 15, 451-461
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Somatic Mutations in GRM1 in Cancer Alter Metabotropic Glutamate Receptor 1 Intracellular Localization and Signaling.
J. L. Esseltine, M. D. Willard, I. H. Wulur, M. E. Lajiness, T. D. Barber, and S. S. G. Ferguson (2013)
Mol. Pharmacol. 83, 770-780
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Cancer Genome Landscapes.
B. Vogelstein, N. Papadopoulos, V. E. Velculescu, S. Zhou, L. A. Diaz Jr., and K. W. Kinzler (2013)
Science 339, 1546-1558
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Mixed Lineage Kinase MLK4 Is Activated in Colorectal Cancers Where It Synergistically Cooperates with Activated RAS Signaling in Driving Tumorigenesis.
M. Martini, M. Russo, S. Lamba, E. Vitiello, E. H. Crowley, F. Sassi, D. Romanelli, M. Frattini, A. Marchetti, and A. Bardelli (2013)
Cancer Res. 73, 1912-1921
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PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies.
A. Iwanami, B. Gini, C. Zanca, T. Matsutani, A. Assuncao, A. Nael, J. Dang, H. Yang, S. Zhu, J. Kohyama, et al. (2013)
PNAS 110, 4339-4344
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How Molecular Testing Can Help (and Hurt) in the Workup of Gliomas.
K. Clark, Z. Voronovich, and C. Horbinski (2013)
Am J Clin Pathol 139, 275-288
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