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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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B. Thota, S. K. Shukla, M. R. Srividya, S. D. Shwetha, A. Arivazhagan, K. Thennarasu, Y. T. Chickabasaviah, A. S. Hegde, B. A. Chandramouli, K. Somasundaram, et al. (2012)
Am J Clin Pathol 138, 177-184
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Discovery in Context: Leveraging Multidimensional Glioblastoma Datasets to Identify Targetable Regulatory Networks.
I. Babic and P. S. Mischel (2012)
Cancer Discovery 2, 676-678
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An analysis of substitution, deletion and insertion mutations in cancer genes.
P. Iengar (2012)
Nucleic Acids Res. 40, 6401-6413
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Relationship between Tumor Enhancement, Edema, IDH1 Mutational Status, MGMT Promoter Methylation, and Survival in Glioblastoma.
J. A. Carrillo, A. Lai, P. L. Nghiemphu, H. J. Kim, H. S. Phillips, S. Kharbanda, P. Moftakhar, S. Lalaezari, W. Yong, B. M. Ellingson, et al. (2012)
AJNR Am. J. Neuroradiol. 33, 1349-1355
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In vivo models of primary brain tumors: pitfalls and perspectives.
P. C. Huszthy, I. Daphu, S. P. Niclou, D. Stieber, J. M. Nigro, P. O. Sakariassen, H. Miletic, F. Thorsen, and R. Bjerkvig (2012)
Neuro Oncology 14, 979-993
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microRNA Regulatory Network Inference Identifies miR-34a as a Novel Regulator of TGF-{beta} Signaling in Glioblastoma.
G. Genovese, A. Ergun, S. A. Shukla, B. Campos, J. Hanna, P. Ghosh, S. N. Quayle, K. Rai, S. Colla, H. Ying, et al. (2012)
Cancer Discovery 2, 736-749
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SPRED proteins provide a NF-ty link to Ras suppression.
A. I. McClatchey and K. Cichowski (2012)
Genes & Dev. 26, 1515-1519
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