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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 Parsons1,2*, Siân Jones1*, Xiaosong Zhang1*, Jimmy Cheng-Ho Lin1*, Rebecca J. Leary1*, Philipp Angenendt1*, Parminder Mankoo3, Hannah Carter3, I-Mei Siu4, Gary L. Gallia4, Alessandro Olivi4, Roger McLendon5, B. Ahmed Rasheed5, Stephen Keir5, Tatiana Nikolskaya6, Yuri Nikolsky7, Dana A. Busam8, Hanna Tekleab8, Luis A. Diaz, Jr.1, James Hartigan9, Doug R. Smith9, Robert L. Strausberg8, Suely Kazue Nagahashi Marie10, Sueli Mieko Oba Shinjo10, Hai Yan5, Gregory J. Riggins4, Darell D. Bigner5, Rachel Karchin3, Nick Papadopoulos1, Giovanni Parmigiani1, Bert Vogelstein1{dagger}, Victor E. Velculescu1{dagger}, and Kenneth W. Kinzler1{dagger}

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.


Figure 1 Fig. 1.. Structure of the active site of IDH1. The crystal structure of the human cytosolic NADP(+)–dependent IDH is shown in ribbon format (PDBID: 1T0L) (44). The active cleft of IDH1 consists of a NADP-binding site and the isocitrate-metal ion-binding site. The alpha-carboxylate oxygen and the hydroxyl group of isocitrate chelate the Ca2+ ion. NADP is colored in orange, isocitrate in purple and Ca2+ in blue. The Arg132 residue, displayed in yellow, forms hydrophilic interactions, shown in red, with the alpha-carboxylate of isocitrate. Displayed image was created with UCSF Chimera software version 1.2422 (50). [View Larger Version of this Image (64K GIF file)]
 

Figure 2 Fig. 2.. Overall survival according to IDH1 mutation status. The hazard ratio for death among patients with wild-type IDH1 (n = 79), as compared to those with mutant IDH1 (n = 11), was 3.7 (95 percent confidence interval, 2.1 to 6.5; P < 0.001). The median survival was 3.8 years for patients with mutated IDH1, as compared to 1.1 years for patients with wild-type IDH1. [View Larger Version of this Image (13K GIF file)]
 


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