An Integrated Genomic Analysis of Human Glioblastoma Multiforme
D. Williams Parsons1,2*,
Jimmy Cheng-Ho Lin1*,
Rebecca J. Leary1*,
Gary L. Gallia4,
B. Ahmed Rasheed5,
Dana A. Busam8,
Luis A. Diaz, Jr.1,
Doug R. Smith9,
Robert L. Strausberg8,
Suely Kazue Nagahashi Marie10,
Sueli Mieko Oba Shinjo10,
Gregory J. Riggins4,
Darell D. Bigner5,
Victor E. Velculescu1, and
Kenneth W. Kinzler1
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.
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).
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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.
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